Evidence Report/Technology Assessment 

Number 139 

Multivitamin/Mineral Supplements and Prevention of 

Chronic Disease 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0018 

Prepared by: 

The Johns Hopkins University Evidence-based Practice Center, Baltimore, MD 

Investigators 

Han-Yao Huang, Ph.D., M.P.H. 

Benjamin Caballero, M.D., Ph.D. 

Stephanie Chang, M.D., M.P.H. 

Anthony Alberg, Ph.D., M.P.H. 

Richard Semba, M.D., M.P.H. 

Christine Schneyer, M.D. 

Renee F. Wilson, M.Sc. 

Ting-Yuan Cheng, M.Sc. 

Gregory Prokopowicz, M.D., M.P.H. 

George J. Barnes II, B.A. 

Jason Vassy 

Eric B. Bass, M.D., M.P.H. 

AHRQ Publication No. 06-E012 

May 2006
This report is based on research conducted by The Johns Hopkins University Evidence-based 

Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), 

Rockville, MD (Contract No. 290-02-0018). The findings and conclusions in this document are 

those of the author(s), who are responsible for its content, and do not necessarily represent the 

views of AHRQ. No statement in this report should be construed as an official position of AHRQ 

or of the U.S. Department of Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and others 

make informed decisions about the provision of health care services. This report is intended as a 

reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for the development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 
ii

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Huang HY, Caballero B, Chang S, Alberg A, Semba R, Schneyer C, Wilson RF, Cheng TY, 

Prokopowicz G, Barnes II GJ, Vassy J, Bass EB. Multivitamin/Mineral Supplements and 

Prevention of Chronic Disease. Evidence Report/Technology Assessment No. 139. (Prepared by 

The Johns Hopkins University Evidence-based Practice Center under Contract No. 290-02-

0018). AHRQ Publication No. 06-E012. Rockville, MD: Agency for Healthcare Research and 

Quality. May 2006.

 

The investigators have no relevant financial interests in the report. The investigators 

have no employment, consultancies, honoraria, or stock ownership or options, or 

royalties from any organization or entity with a financial interest or financial conflict 

with the subject matter discussed in the report. 
iii

Preface 

 The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. This report was funded by the National Institutes of 

Health Office of Medical Applications of Research (NIH OMAR). The reports and assessments 

provide organizations with comprehensive, science-based information on common, costly 

medical conditions and new health care technologies. The EPCs systematically review the 

relevant scientific literature on topics assigned to them by AHRQ and conduct additional 

analyses when appropriate prior to developing their reports and assessments. 

 To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

 AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

 We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. 

Director 

Agency for Healthcare Research and Quality 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Beth A. Collins Sharp, Ph.D., R.N. 

Acting Director, EPC Program 

Agency for Healthcare Research and Quality 

Ernestine W. Murray, B.S.N., R.N., M.A.S. 

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 

Barnett Kramer, M.D., M.P.H. 

Director 

Office of Medical Applications of Research 

National Institutes of Health 
iv

Acknowledgments 

The Evidence-based Practice Center thanks Karen Robinson for her assistance in developing the 

search strategies; Steven Bressler and Archana Ramaswami, for their assistance with literature 

searching and database management; Gabriel Lai, Karran Phillips, Konstantinos K. Tsilidisand, 

and Amina Chaudhry for their assistance with article reviewing and data entry; Christine 

Napolitano for her assistance with budget matters, and Brenda Zacharko for her assistance with 

final preparations of the report. 
v 

Structured Abstract 

Objective. To review and synthesize published literature on the efficacy of multivitamin/mineral 

supplements and certain single nutrient supplements in the primary prevention of chronic disease 

in the general adult population, and on the safety of multivitamin/mineral supplements and 

certain single nutrient supplements, likely to be included in multivitamin/mineral supplements, in 

the general population of adults and children. 

Data Sources. All articles published through February 28, 2006, on MEDLINE,® EMBASE,®

and the Cochrane databases. 

Review Methods. Each article underwent double reviews on title, abstract, and inclusion 

eligibility. Two reviewers performed data abstraction and quality assessment. Differences in 

opinion were resolved through consensus adjudication. 

Results. Few trials have addressed the efficacy of multivitamin/mineral supplement use in 

chronic disease prevention in the general population of the United States. One trial on poorly 

nourished Chinese showed supplementation with combined β-carotene, vitamin E and selenium 

reduced gastric cancer incidence and mortality, and overall cancer mortality. In a French trial, 

combined vitamin C, vitamin E, β-carotene, selenium, and zinc reduced cancer risk in men but 

not in women. No cardiovascular benefit was evident in both trials. Multivitamin/mineral 

supplement use had no benefit for preventing cataract. Zinc/antioxidants had benefits for 

preventing advanced age-related macular degeneration in persons at high risk for the disease. 

With few exceptions, neither β-carotene nor vitamin E had benefits for preventing cancer, 

cardiovascular disease, cataract, and age-related macular degeneration. β-carotene 

supplementation increased lung cancer risk in smokers and persons exposed to asbestos. Folic 

acid alone or combined with vitamin B12 and/or vitamin B6 had no significant effects on 

cognitive function. Selenium may confer benefit for cancer prevention but not cardiovascular 

disease prevention. Calcium may prevent bone mineral density loss in postmenopausal women, 

and may reduce vertebral fractures, but not non-vertebral fractures. The evidence suggests dosedependent benefits of vitamin D with/without calcium for retaining bone mineral density and 

preventing hip fracture, non-vertebral fracture and falls. 

We found no consistent pattern of increased adverse effects of multivitamin/mineral 

supplements except for skin yellowing by β-carotene. 

Conclusion. Multivitamin/mineral supplement use may prevent cancer in individuals with poor 

or suboptimal nutritional status. The heterogeneity in the study populations limits generalization 

to United States population. Multivitamin/mineral supplements conferred no benefit in 

preventing cardiovascular disease or cataract, and may prevent advanced age-related macular 

degeneration only in high-risk individuals. The overall quality and quantity of the literature on 

the safety of multivitamin/mineral supplements is limited.
vii

Contents 

 

Executive Summary.........................................................................................................................1 

Evidence Report...........................................................................................................................11

Chapter 1. Introduction .................................................................................................................11 

Purpose.....................................................................................................................................11 

Specific Aims...........................................................................................................................11 

Use of Multivitamins/mineral Supplements in the United States............................................12 

Chronic Disease .......................................................................................................................13 

Common Pathologic Mechanisms of Chronic Diseases ..........................................................13 

Possible Mechanisms of Action of Vitamins and Minerals in 

 Chronic Disease Prevention................................................................................................14 

Factors that Affect the Efficacy and Safety of Vitamin/mineral Supplement 

Use in Chronic Disease Prevention....................................................................................15 

Tolerable Upper Levels of Daily Nutrient Intake....................................................................16 

Federal Regulation of Vitamin/mineral Supplements..............................................................16 

Conceptual Framework............................................................................................................17 

Chapter 2. Methods........................................................................................................................19 

Recruitment of Technical Experts and Peer Reviewers...........................................................19 

Key Questions..........................................................................................................................19 

Literature Search Methods.......................................................................................................19 

Sources...............................................................................................................................20 

Search terms and strategies................................................................................................20 

Organization and tracking of literature search...................................................................20 

Title Review.............................................................................................................................21 

Abstract Review.......................................................................................................................21 

Inclusion and exclusion criteria .........................................................................................21 

Article Inclusion/Exclusion .....................................................................................................22 

Article Review/ Data Abstraction............................................................................................22 

 Data abstracted to assess the efficacy of multivitamin/mineral supplements and 

 single nutrients (and related pairs of nutrients) in the primary prevention of 

 chronic diseases/conditions (Key Questions 1 and 3)..................................................23 

 Data abstracted to assess the safety of multivitamins/minerals and single nutrients 

 (selenium, iron, β-carotene, vitamin A, vitamin E, folic acid, and calcium 

 (with or without vitamin D)) (Key Questions 2 and 4)................................................23 

 Data abstracted from previous systematic reviews on vitamin D and calcium .................24 

 Data abstracted from previous systematic reviews on nutrients other than 

 vitamin D and calcium.................................................................................................24 

Quality Assessment..................................................................................................................25 

Data Synthesis..........................................................................................................................25 

Data Entry and Quality Control ...............................................................................................25

Grading of the Evidence ..........................................................................................................26 

Peer Review .............................................................................................................................26 
viii

Chapter 3. Results ..........................................................................................................................27 

Overall Results of Literature Search........................................................................................27 

Key Question 1: What is the efficacy determined in randomized controlled trials of 

multivitamin/mineral supplement use (defined as 3 or more vitamins and/or minerals 

without herbs, hormones, or drugs), each at a dose less than the upper limit determined by 

the food and nutrition board, in the general adult population for prevention against the 

development of one or more chronic diseases or conditions? ...........................................27 

Introduction........................................................................................................................27 

Results of literature search for Key Question 1.................................................................27 

Design of randomized controlled trials..............................................................................28 

Similarity and heterogeneity in study design among trials................................................29 

Study quality ......................................................................................................................29 

Cancer ................................................................................................................................29 

Cardiovascular disease.......................................................................................................30

Total Mortality...................................................................................................................30 

Cataract and age-related macular degeneration .................................................................31 

Summary............................................................................................................................32 

Key Question 2: What is Known About the Safety of use of Multivitamin/Mineral 

Supplements (As Defined In Question 1), in the General Population of Adults and 

Children, Based Primarily on Data From Randomized Controlled Trials and 

Observational Studies?.......................................................................................................32

Issues to Consider ..............................................................................................................32 

Review of data on the safety/risk of multivitamin/mineral supplements ..........................33 

Key Question 3: What is the Efficacy Determined in Randomized Controlled 

 Trials of Supplementation with Single Nutrients Or Functionally Related 

 Nutrient Pairs, Each at a Dose Less than the UL Determined by the Food and 

 Nutrition Board, in the General Adult Population for Prevention Against 

 the Development of One or More Chronic Diseases Or Conditions?................................34 

β-Carotene .........................................................................................................................34 

Vitamin A...........................................................................................................................37 

Vitamin E...........................................................................................................................38 

Folic Acid and B vitamins .................................................................................................41 

Vitamin B2 and niacin .......................................................................................................43 

Selenium ............................................................................................................................44 

Calcium and vitamin D ......................................................................................................46 

Key Question 4: What is Known about the Safety of use of the Following Single 

 Nutrients in the General Population of Adults and Children, Based Primarily 

 on Data From Randomized Controlled Trials and Observational Studies?.......................53 

Calcium and vitamin D ......................................................................................................53 

Vitamin A...........................................................................................................................53 

Vitamin E...........................................................................................................................54 

β-carotene ..........................................................................................................................54 

Selenium ............................................................................................................................55 

Iron.....................................................................................................................................55 
ix

Chapter 4. Discussion ....................................................................................................................57 

Summary of the Key Findings .................................................................................................57 

Efficacy of Multivitamins/mineral Supplements.....................................................................59 

Efficacy of β-carotene .............................................................................................................60 

Efficacy of Vitamin E ..............................................................................................................61 

Vitamin/mineral Supplement Use and Total Mortality ...........................................................62 

Timing and Duration of Supplement Use ................................................................................63 

Doses of Vitamin/mineral Supplements ..................................................................................64 

Safety Consideration................................................................................................................64 

Limitations ...............................................................................................................................65 

Conclusions..............................................................................................................................66 

Future Research .......................................................................................................................67 

Implications..............................................................................................................................68 

References and Included Studies ...................................................................................................69 

Figures

Figure 1. Conceptual framework for the prevention of chronic diseases and 

 conditions with vitamin/mineral supplements (circled numbers represent 

 the key questions addressed in this systematic review)...........................................................81 

Figure 2. Summary of literature search and review process (number of articles ). .......................82 

Figure 3. Relative risk (RR)of total cancer, gastric cancer and esophageal cancer 

 incidence in relation to multivitamin/mineral supplement use................................................83 

Figure 4. Relative risk (RR) of total cancer, gastric cancer and esophageal cancer 

 mortality in relation to multivitamin/mineral supplement use.................................................84 

Figure 5. Relative risk (RR)of cardiovascular disease incidence in relation to 

 multivitamin/mineral supplement use......................................................................................85 

Figure 6. Relative risk (RR) of all cause mortality in relation to multivitamin/ 

mineral supplement use............................................................................................................86 

Summary Tables

Table 1. Number of articles by key questions and disease categories...........................................89 

Table 2. Summary of randomized controlled trials on multivitamin/mineral 

 supplements and chronic disease prevention ...........................................................................90 

Table 3. Assessment of the quality of randomized controlled trials on the efficacy of 

 multivitamin/mineral supplements and single nutrients in the prevention of 

 chronic diseases and conditions...............................................................................................98 

Table 4. Grading of the quality of evidence of the efficacy of multivitamins/minerals 

 in the prevention of chronic disease.......................................................................................102

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease..........103 

Table 6. Grading of the quality of evidence of the efficacy of single nutrients in the 

 prevention of chronic disease.................................................................................................111 

Table 7. Summary of randomized controlled trials on vitamin E and chronic disease. ..............113 

 
x

Appendixes 

Appendix A: Technical Experts and Peer Reviewers 

Appendix B: Hand Searched Journals 

Appendix C: Detailed Electronic Database Search Strategies 

Appendix D: Excluded Articles 

Appendix E: Example Review Forms 

Appendix F: Evidence Tables 

Appendix G: List of Acronyms 

Appendixes and Evidence Tables for this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/multivit/multivit.pdf. 
1 

Executive Summary 

Introduction 

The Johns Hopkins University Evidence-based Practice Center (EPC) reviewed and 

synthesized the published literature on four Key Questions: 

1. What is the efficacy of multivitamin/mineral supplement use in the prevention of chronic 

disease for the general adult population? 

2. What is the safety of multivitamin/mineral supplementation in the general population of 

adults and children? 

3. What is the efficacy of single nutrients or functionally related nutrient pairs in preventing 

chronic disease in the general adult population? 

4. What is the safety of single nutrients or functionally related nutrient pairs in the general 

population of adults and children? 

Multivitamin/mineral supplements are the most commonly used nutritional supplements in 

the United States. Most multivitamin/mineral supplements contain at least 10 vitamins or 

minerals with a wide range of doses. Many individuals use multivitamin/mineral supplements for 

prophylactic or disease-mitigating purposes. 

Chronic disease is estimated to account for 35 million deaths worldwide. Cardiovascular 

disease and cancer comprise a major proportion of chronic diseases in both developed and 

developing countries. Other than cardiovascular disease and cancer, obesity-related diseases such 

as type 2 diabetes, end-stage renal disease, and osteoarthritis are also becoming significant public 

health problems. Many of these chronic diseases share common risk factors and underlying 

pathologic mechanisms that may be modified by nutrients. Examples include reduction of 

oxidative damage by antioxidants, DNA methylation regulated by folate and B vitamins, bone 

metabolism regulated by vitamin D and calcium, and cell differentiation, proliferation, and 

growth regulated by retinol, calcium, and vitamin D. 

The biological effects of a nutrient are heavily dependent on its bioavailability. Key factors 

determining the bioavailability of micronutrients are the chemical form in which the nutrient is 

presented to the intestinal absorptive surface, the presence of other competing chemicals in the 

intestinal lumen, the concentration of food constituents (such as phytates and other chelating 

agents) that bind to the nutrient and make it unavailable for absorption, intestinal transit time, 

and enzyme activity. A nutrient may affect not only the absorption of other nutrients, but also the 

transport, tissue uptake, function and metabolism of other nutrients. Hence, concurrent ingestion 

of several nutrients may result in synergistic, antagonistic, or threshold effects as compared to a 

single nutrient. The efficacy of a single nutrient or multiple nutrients should be considered 

separately unless no interactive or threshold effects can be found. 

The United States Food and Nutrition Board has established the tolerable upper intake levels 

(ULs) for several nutrients. By definition, a UL is the highest level of daily nutrient intake that is 

likely to pose no risk of adverse health effects to almost all individuals in the general population. 

Since the time when ULs were determined, several large-scale randomized controlled trials of 
2 

vitamin/mineral supplementation have been completed. An update of the data on adverse 

effects/events will help to evaluate the appropriateness of the ULs. 

 

Methodology 

 Our EPC established a team and a work plan to develop this evidence report. The project 

consisted of recruiting technical experts, formulating and refining the specific questions, 

performing a comprehensive literature search, summarizing the state of the literature, 

constructing evidence tables, synthesizing the evidence into a report, and submitting the report 

for peer review. The investigative team has strong expertise in nutrition, medicine, chronic 

disease epidemiology, clinical trial methodology, HIV infection, ophthalmology, and 

gerontology. In addition, the investigators have extensive experience in conducting research 

projects specific to vitamins and minerals in the general population, children, and the elderly. 

 We defined multivitamin/mineral supplements as any supplements containing 3 or more 

vitamins and/or minerals without herbs, hormones, or drugs, each at a dose less than the UL 

determined by the Food and Nutrition Board. The general population is defined as communitydwelling individuals who do not have special nutritional need (e.g., not institutionalized, 

hospitalized, pregnant, or clinically deficient in nutrients). For efficacy, we considered data from 

randomized controlled trials. For safety, we considered data from randomized controlled trials 

and observational studies. 

 We used a systematic approach for searching the literature to minimize the risk of bias in 

selecting articles for inclusion in the review. In this systematic approach, we had to be very 

specific about defining the eligibility criteria for inclusion in the review. The systematic 

approach was intended to help identify gaps in the published literature.” 

 To enhance our understanding of the efficacy of multivitamin/mineral supplements in 

preventing chronic disease, we also considered evidence on the efficacy and the safety of 

individual vitamins and minerals that are often included in multivitamin/mineral supplements. 

The individual or functionally-related paired nutrients considered for efficacy issues were 

calcium, folic acid, vitamin B6, vitamin B12, vitamin D, vitamin E, vitamin C, vitamin A, iron, 

zinc, magnesium, vitamin B1, vitamin B2, niacin, calcium/vitamin D, calcium/magnesium, folic 

acid/vitamin B12, and folic acid/vitamin B6. The nutrients considered for safety issues were 

calcium (with or without vitamin D), folic acid, vitamin D, vitamin E, vitamin A, iron, selenium, 

and β-carotene. 

 The following chronic diseases were considered: (a) breast cancer, colorectal cancer, lung 

cancer, prostate cancer, gastric cancer, or any other malignancy; (b) myocardial infarction, 

stroke; (c) type 2 diabetes mellitus; (d) Parkinson’s disease, dementia; (e) cataracts, macular 

degeneration, hearing loss; (f) osteoporosis, osteopenia, rheumatoid arthritis, osteoarthritis; (g) 

non-alcoholic steatorrheic hepatitis, non-alcoholic fatty-liver disease; (h) chronic renal 

insufficiency, chronic nephrolithiasis; and (i) HIV infection, hepatitis C, tuberculosis, and (j) 

chronic obstructive pulmonary disease. 

 
3 

Literature Sources 

 We searched for articles published from 1966 through February 2006 using MEDLINE,®

EMBASE,® and the Cochrane database. Additional articles were identified by searching 

references in pertinent articles, querying experts, and hand-searching the tables of content of 15 

journals published from January 2005 through February 2006. 

Eligibility Criteria 

 An article was included if it had data from a randomized controlled trial that assessed the 

efficacy of multivitamin/mineral supplement use in preventing one or more of the chronic 

diseases listed above. An article was excluded if it met any of the following exclusion criteria: 

(1) not written in English; (2) contained no human data; (3) included only pregnant women; (4) 

only infants; (5) only subjects of age less than or equal to 18 years (if a study included only 

subjects of age less than or equal to 18 years, we included it only if it presented data on the 

safety of a vitamin/mineral supplement) (6) included only patients with particular chronic 

diseases; (7) included only patients receiving treatment for chronic disease or included only 

patients in long-term care facilities; (8) only studied clinical nutritional deficiency; (9) contained 

no useful information applying to the Key Questions; (10) did not address the use of 

supplements; (11) did not address the use of supplements separately from dietary intake; (12) did 

not cover the defined disease endpoints or; (13) was an editorial, commentary, or letter. 

Additionally, an article could be excluded if it applied to Key Question 1 and/or 3 but was not a 

randomized controlled trial or a systematic review and did not address safety issues. However, 

we included observational studies for the Key questions about the safety of vitamin/mineral 

supplements. Differences in opinions regarding abstract inclusion or exclusion were resolved 

through consensus adjudication. 

Article Inclusion/exclusion 

 Each article underwent title review, abstract review, and inclusion/exclusion review by 

paired reviewers. Differences in opinions at abstract and inclusion/exclusion review were 

resolved through consensus adjudication. 

Assessment of Study Quality 

 Each eligible article was reviewed by paired reviewers who independently rated the quality 

of each study with respect to the categories: representation of study participants (4 items), bias 

and confounding (12 items), descriptions of study supplements and supplementation (2 items), 

adherence and follow up (6 items), statistical analysis (6 items), and conflict of interest (1 item). 

Reviewers assigned a score of zero (criterion not met), one (criterion partially met), or two 

(criteria fully met) to each item. The score for each quality category was the percentage of the 

total score available in each category and could range from 0 to 100 percent. The overall quality 

score was the average of the six categorical scores. 

 
4 

Data Extraction 

 Paired reviewers abstracted data on study design, geographical location, study period, 

participants’ eligibility, sample size, recruitment settings, demographic and lifestyle factors of 

participants, prior supplement use, intervention (type, dose, and chemical forms of study 

supplements, and duration, frequency, and timing of study supplement use), and results. Data 

abstraction forms were completed by a primary reviewer, and verified for completeness and 

accuracy by a second reviewer. Differences in opinions were resolved through adjudication. We 

used a systematic approach for extracting data from the studies to minimize the risk of bias in 

how we extracted data from eligible studies. By creating standardized forms for data extraction, 

we sought to maximize consistency in identifying all pertinent data available for synthesis. 

Results 

 The literature search process identified 11,324 citations potentially relevant to the Key 

Questions. We excluded 849 duplicate citations. In the title review process, we excluded 6,863 

citations because they clearly did not pertain to the Key Questions. In the abstract review 

process, we excluded 3,163 citations that did not meet one or more of the eligibility criteria. 

Using the article inclusion/exclusion form, we then excluded an additional 386 articles that did 

not meet one or more of the eligibility criteria. That left a total of 63 articles eligible for 

inclusion in the review of one or more of the Key Questions. 

Results from this systematic review indicated a paucity of data from randomized controlled 

trials that specifically address the efficacy of multivitamin/mineral supplement use in the 

prevention of chronic disease in the general population of the United States. The data were on 

the efficacy of designed combinations of vitamins and minerals; none of the trials used one-a-day 

multivitamins prevailing on the market in the United States. Data on cancer and cardiovascular 

outcomes came from the Linxian General Population Trial in China and the Supplementation en 

Vitamines et Mineraux Antioxydants (SU.VI.MAX) trial in France. The Linxian trial 

documented that supplementation with combined β-carotene, vitamin E and selenium 

supplements at doses 1 to 2 times the United States Recommended Daily Allowance (RDA) for 5 

years had 13 percent to 21 percent reductions in gastric cancer incidence, gastric cancer 

mortality, and total cancer mortality in a poorly nourished Chinese population. The reduction in 

cancer mortality was stronger in women than in men. There were no significant effects on total 

cancer incidence and cerebrovascular mortality. The SU.VI.MAX study in a French population 

documented a 31 percent reduction in overall cancer risk by use of vitamin C, vitamin E, βcarotene, selenium, and zinc at doses 1-2 times the RDAs for 8 years in men but not in women. 

A 12 percent reduction in prostate cancer risk, particularly a 48 percent risk reduction in those 

with normal prostate specific antigen levels at baseline, was found in men receiving active 

supplements compared to men receiving placebo. There was no significant effect of the 

combined antioxidants on ischemic cardiovascular disease incidence. In this trial, men had lower 

serum levels of vitamin C and β-carotene than women at baseline. 

Multivitamin/mineral supplement use for 3 to 6 years had no significant benefits in 

preventing cataract in 3 trials in the United States (also in the United Kingdom in one trial) and 

the Linxian trial. In the Age-Related Eye Disease Study (AREDS), high-dose zinc (10 times the 

RDA) alone or combined with antioxidants (5 to 15 times the RDAs) had beneficial effects on 

age-related macular degeneration only in those with intermediate age-related macular 
5 

degeneration in one or both eyes, or those with advanced age-related macular degeneration in 

one eye. 

 Overall, data on total mortality rates pointed to either no increased risk or lower risk in the 

groups with multivitamin/mineral supplement use. Total mortality was 9 percent lower among 

those who received β-carotene, selenium, and vitamin E in the Linxian trial; there was no sex- or 

age-difference in the relative risks. In AREDS, total mortality was 6 percent higher in the group 

receiving antioxidants compared to the group receiving no antioxidants, but the increase was not 

statistically significant. Among the participants at high risk for age-related macular degeneration, 

total mortality was 13 percent to 20 percent lower in the groups receiving zinc alone or zinc 

combined with antioxidants. In the SU.VI.MAX study, a sex-difference was documented for the 

relative risk of total mortality among those receiving antioxidants and zinc compared to those 

receiving placebo. In the REACT, the total mortality rate was not calculated. There were 9 

deaths in the antioxidant group, whereas 3 deaths occurred in the placebo group. 

 Daily supplementation with β-carotene of 20 mg, 30 mg or 50 mg was not protective against 

malignancies, cardiovascular disease outcomes, diabetes mellitus, cataract or age-related 

maculopathy. Supplementation with β-carotene with or without vitamin A increased the 

incidence of lung cancer in persons with asbestos exposure or in smokers, and was associated 

with increased mortality. To date, there has been no randomized controlled trial that assessed the 

efficacy of vitamin A alone in preventing chronic disease. Studies in selected populations 

(nutritionally inadequate, smokers, or asbestos exposure) showed no benefit of combinations of 

vitamin A and zinc or vitamin A and β-carotene for the prevention of stroke mortality, 

esophageal or gastric cancer incidence, cardiovascular mortality, or all-cause mortality. 

 Vitamin E supplements (synthetic α-tocopherol 50 mg or 300 IU per day, natural vitamin E 

500 IU, or natural source vitamin E, 600 IU per day) have been studied for primary prevention of 

cancer, cardiovascular disease, cataract, and age-related eye disease. The evidence 

predominantly comes from the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) 

study and the Women’s Health Study (WHS). There was a lack of effects of vitamin E in the 

prevention of these diseases, except for a 32 percent reduction in prostate cancer incidence, a 41 

percent reduction in the prostate cancer mortality, and a 22 percent reduction in colorectal cancer 

in smokers in the ATBC study, and decreased cardiovascular deaths (primarily sudden death) in 

the WHS participants, particularly in those aged 65 years or older. The findings on hemorrhagic 

stroke were conflicting between the ATBC trial and the WHS; the former found a higher risk 

with use of low-dose α-tocopherol supplements but the latter found a lower risk with use at a 

high dose. 

 Two previous systematic reviews reported that supplementation with folic acid at a daily 

dose of 0.75 mg or 30 mg, alone or in combination with vitamin B12 and/or vitamin B6 for 5-12 

weeks, had no significant effects on cognitive function in 5 small randomized controlled trials. 

Combined vitamin B2 and niacin supplement use for 5 years had no significant effects on 

cerebrovascular mortality, total mortality, total cancer incidence, esophageal or gastric 

dysplasia/cancer incidence, or esophageal or gastric cancer mortality in a poorly nourished 

population in China. 

 In a study in persons with a history of non-melanoma skin cancer, supplementation with 

selenium of 200 mcg per day had no effect on cardiovascular outcomes, but had protective 

effects on total mortality and incidence of lung, colorectal, and prostate cancers. Another study 

in China found a significantly reduced risk for liver cancer in those who used selenium 

supplements of 200 mcg/day for two years. 
6 

Due to the substantial amount of efficacy data on calcium/vitamin D and osteoporosis, we 

reviewed systematic review articles supplemented with updated data from recent randomized 

controlled trials and data from randomized controlled trials that met our inclusion criteria, but 

were not included in previous systematic reviews. The previous systematic reviews reported that 

supplementation with calcium has short-term (particularly within one year) benefit on retaining 

bone mineral density in postmenopausal women, and a possible effect in preventing vertebral 

fractures. The reviews also indicated that combined vitamin D3 (700-800 IU/day) and calcium 

(1000 mg/day) may reduce the risk of hip and other non-vertebral fractures in populations with 

low levels of vitamin D and/or calcium. Recent published data from the Women’s Health 

Initiative (WHI) trial were consistent with these systematic reviews in showing a 1.06 percent 

higher hip bone density (p<0.02) and a 12 percent non-significant lower risk for hip fracture in 

postmenopausal women after receiving calcium carbonate (500 mg twice a day) and vitamin D3

(200 IU twice a day) for an average of 7 years as compared to women receiving a placebo. In this 

trial, participants were allowed to have self-selected use of multivitamin supplements as well as 

calcium and vitamin D supplements up to 1000 mg and 600 IU per day, respectively, and thus 

the WHI participants had higher intake of calcium (an average of 1150 mg per day) than the 

general population (761 mg per day). The WHI trial found no benefit of calcium and vitamin D 

supplementation in preventing colorectal cancer incidence. 

For data on safety, we identified 10 studies using multivitamin/mineral preparations and 24 

studies using single nutrients. Doses were usually 2 to 10 times the RDA. Overall, there was no 

consistent pattern of increased adverse effects in the active group compared with the placebo 

group, with the exception of changes in skin color, which was common in studies in which βcarotene was part of the multivitamin preparation. In the few studies where mortality was 

compared between active and control groups, no significant adverse effect of 

multivitamin/mineral supplementation on this outcome was found. 

 Supplementation with β-carotene with or without vitamin A increased the incidence of lung 

cancer in persons with asbestos exposure or in smokers. Vitamin A supplementation moderately 

increased serum triglyceride levels. Calcium supplementation increased the risk of kidney stones. 

Vitamin E supplementation was associated with an increased incidence of epistaxis but was not 

associated with an increased risk of more serious bleeding events, such as hemorrhagic stroke. 

Iron supplementation was found to reduce weight gain in iron-sufficient, non-anemic children in 

a small randomized controlled trial. More recent trials have not clarified this issue because they 

targeted deficient populations and/or included other micronutrients in the intervention 

formulation. 

Future Research 

In vitro studies and animal models have helped us to understand the function of nutrients 

under a controlled environment. However, these types of studies often have over-simplified the 

sophistication of the human body. There is a gap in our knowledge of how specific nutrients 

work in vivo to prevent disease. Future research should be directed toward filling the gap by 

developing valid in vivo biomarkers and applying them in the settings of randomized controlled 

trials to examine how nutrients influence the body’s physiological function and pathological 

processes, and how multiple nutrients work in concert to do so. Identifying an optimal dose in 

dose-response studies is critical to guide the design of future large-scale randomized controlled 

trials when the conduct of the trials is considered worthwhile. 
7 

Nutritional research has adopted a reductionist approach that emphasizes the role of 

individual nutrients in physiologic function or disease process. In view of the complex 

pathological processes of chronic diseases, the idea of using a single nutrient or a few nutrients 

to modify disease risk carries considerable optimism. The design and conduct of several largescale randomized controlled trials on antioxidants was derived from epidemiological data that 

showed a lower risk of chronic disease (predominantly cancer and cardiovascular disease) in 

those who had higher circulating levels or dietary intake of some micronutrients. Because of 

residual confounding and measurement errors in dietary assessment, dietary data from 

observational studies can be better examined by patterns of food consumption with a multivariate 

approach, rather than by ranking of specific nutrient intake with a univariate approach. 

We have found that many studies did not report study participants’ self-selected supplement 

use before and during the trial participation, and allowed self-selected supplement use during the 

trial. Similarly, there was a lack of information on other variables that might have modified the 

effects of study supplements. Furthermore, collective study findings also may not apply to every 

individual. Additional research should be done, particularly in existing randomized controlled 

trials, to examine how efficacy may vary by age, time since trial enrollment to diagnosis, selfselected supplement use, dietary patterns, disease history, medication use, and/or genetic 

polymorphisms. 

With many food products being fortified with several nutrients, Americans’ dietary intake of 

certain nutrients may well be above the RDAs. Hence, it is important to study the level of intake 

among consumers and assess how nutrient fortification may influence the public’s health. An 

adverse event reporting system needs to be in place to facilitate this type of research. 

For policy making, research should be conducted to estimate the cost-effectiveness and the 

risk/benefit profile of multivitamin/mineral supplement use or more generally, dietary 

supplement use, in the general population. Such research should also consider subpopulations for 

which these parameters may differ. 
11 

Chapter 1. Introduction 

Purpose 

Multivitamin/mineral supplements are the most commonly used nutritional supplements in 

the United States.1

 Scientific evidence on the efficacy and safety of supplement use will serve as 

the basis for us to identify knowledge gaps and inform the general public’s practice and future 

research. This report synthesizes the published literature on the efficacy and the safety of 

multivitamin/mineral supplements in the prevention of chronic disease for the general population 

of adults, and on the efficacy and the safety of certain commonly-used single vitamin or mineral 

supplements in the general population of adults and children. The content of this report will be 

used by the National Institutes of Health (NIH) in preparing a State-of-the-Science Statement for 

health care providers and the general public. 

Specific Aims 

The specific aims of this review are to synthesize evidence in the literature for addressing the 

following Key Questions: 

1. What is the efficacy determined in randomized controlled trials of multivitamin/mineral 

supplements (defined as 3 or more vitamins and/or minerals without herbs, hormones, or 

drugs), each at a dose less than the tolerable upper intake level (UL) determined by the 

Food and Nutrition Board, in the general adult population*

 for prevention† against the 

development of one or more of the following chronic diseases or conditions‡? 

a. Oncologic: breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric 

cancer, or any other malignancy (including colorectal polyps) 

b. Cardiovascular: myocardial infarction, stroke 

c. Endocrine: type 2 diabetes mellitus 

d. Neurologic: Parkinson’s disease, cognitive decline, memory loss, dementia 

e. Age-related sensory loss: cataracts, macular degeneration, hearing loss 

f. Musculoskeletal: osteoporosis, osteopenia, rheumatoid arthritis, osteoarthritis 

g. Gastroenterologic: non-alcoholic steatorrheic hepatitis, non-alcoholic fatty-liver 

disease 

h. Renal: chronic renal insufficiency, chronic nephrolithiasis 

i. Infectious: HIV infection, hepatitis C, tuberculosis 

j. Pulmonary: chronic obstructive pulmonary disease 

 

* General population is defined as community-dwelling individuals who do not have special nutritional need such as 

those who are institutionalized, hospitalized, pregnant or clinically deficient in nutrients.” 

†

 This review focused on primary prevention using the following definition as a guide. Primary prevention denotes 

an action taken to prevent the development of a disease in a person who is well and does not have the disease in 

question.185 Using this definition, we included studies of supplements that were used in patients with risk factors for 

disease (e.g., type 2 diabetes mellitus or hypertension) to prevent one or more of the listed chronic diseases or 

conditions (e.g., cardiovascular disease). We also included studies of supplements that were used in patients with 

selected precursors of disease (e.g., polyps) to prevent a malignant disorder (e.g., colon cancer). We did not include 

studies of supplements that were used in patients with carcinoma-in-situ or similar malignant conditions. 
12 

2. What is known about the safety of use of multivitamin/mineral supplements (as defined 

in question 1) in the general population of adults and children, based primarily on data 

from randomized controlled trials and observational studies? 

3. What is the efficacy determined in randomized controlled trials of supplementation with 

the single nutrients or functionally related nutrient pairs listed below, each at a dose less 

than the UL determined by the Food and Nutrition Board, in the general adult population 

for prevention against the development of one or more of the chronic diseases or 

conditions listed above for question 1? 

a. calcium b. folic acid c. vitamin B6 d. vitamin B12 

e. vitamin D f. vitamin E g. vitamin C h. vitamin A 

i. iron j. zinc k. magnesium l. vitamin B1 

m. vitamin B2 n. niacin o. calcium/vitamin D 

p. calcium/magnesium q. folic acid/vitamin B12 

r. folic acid/vitamin B6 

4. What is known about the safety of use of the following single nutrients in the general 

population of adults and children, based primarily on data from randomized controlled 

trials and observational studies? 

a. calcium (with or without vitamin D) b. folic acid 

c. vitamin D d. vitamin E e. vitamin A 

f. iron g. selenium h. β-carotene 

Use of Multivitamin/mineral Supplements in the 

United States 

Multivitamins are the most commonly used dietary supplements in the United States.1

Multivitamin/mineral pills typically include at least 10 vitamins, and 10 minerals. They generally 

contain 100 percent of the Recommended Daily Allowance (RDA) for those micronutrients for 

which there are recommendations, except for calcium and certain other minerals, which are too 

bulky to include more than a fraction of the RDA. Recently, variation in the formulation of 

multivitamin/mineral supplements has occurred. Many of these supplements contain two to six 

times the RDA. Often, formulations of B vitamins are 10 to 20 times the RDA. According to the 

National Health and Nutrition Examination Survey (NHANES) 1999-2000, 35 percent of adults 

reported use of multivitamin/mineral supplements in the month prior to the survey.1

Commercials have widely promoted dietary supplements. In 2005, 20.3 billion dollars were 

spent on purchases of dietary supplements in the United States.2

 Many individuals use 

vitamins/minerals supplements for prophylactic or disease-mitigating purposes. Whether longterm use is efficacious and safe warrants rigorous scientific evaluation. 
13 

Chronic Disease 

Chronic disease is estimated to account for 35 million deaths worldwide.3 Cardiovascular 

disease and cancer comprise a major proportion of chronic diseases in both developed and 

developing countries.4

 Other than cardiovascular disease and cancer, obesity-related diseases 

such as type 2 diabetes, end-stage renal disease, osteoarthritis and non-alcoholic steatorrheic 

hepatitis are also becoming significant public health problems.5,6 The prevalence and incidence 

of these diseases may rapidly increase in the near future in the United States because the 

prevalence of obesity has increased from 23 percent to 30 percent during the 1990s.7 At the same 

time, the population is gradually aging, and age-related degenerative diseases/conditions claim 

enormous health and economic tolls. Age-related cataract is the leading cause of blindness, 

accounting for about 42 percent of all blindness globally.8 Approximately one in five people over 

age 65 live with age-related macular degeneration, and adults with advanced macular 

degeneration have a markedly reduced quality of life and need for assistance with activities of 

daily living.9

 The incidence of dementia also increases exponentially with age.10 Alzheimer 

disease accounts for more than half of dementia cases.11

Common Pathologic Mechanisms of Chronic Diseases 

The etiology of most chronic diseases is multifaceted. However, many chronic diseases share 

common risk factors and underlying pathologic mechanisms. Cigarette smoking/tobacco use, 

sedentary lifestyle, unhealthy (high calorie, low fruit/vegetable intake) diet, and obesity are well 

established as major risk factors of several chronic diseases. Cigarette smoke is a rich source of 

oxidants (free radicals and reactive oxygen, nitrogen and chlorine species), whereas a diet low in 

fruits and vegetables contains a low amount of antioxidants. Substantial evidence from in vitro

experiments, animal models and epidemiological observational studies suggests that oxidative 

stress, a result of an imbalance between oxidative and reductive potential in favor of the former, 

may play an important role in the initiation, promotion, and progression of cardiovascular 

disease (in particular, ischemic heart disease and stroke), cancer, and several degenerative 

diseases/conditions, such as age-related cataract, age-related macular degeneration and cognitive 

decline.12-19 Oxidative damage to lipids by free radicals initiates and propagates chain reactions 

that may be intercepted by antioxidants or otherwise lead to development of atherosclerosis and 

mutagenesis.12,20 Oxidative damage to DNA causes formation of DNA adducts, double strand 

breaks, single strand breaks, aberrations and instability of chromosomes, and genomic instability, 

all of which may result in mutagenesis and carcinogenesis.21 Oxidative damage to proteins may 

affect enzyme expression and impair critical cellular signaling, leading to alterations in cell 

function.22 

It is well known that sedentary lifestyle, excessive caloric intake, and lack of physical 

activities lead to obesity, and obese individuals have higher levels of inflammation, a key process 

of host responses to infections and an important risk factor of cardiovascular disease and many 

cancers and chronic conditions.23,24 Inflammatory responses can induce the generation of free 

radicals and reactive species that cause oxidative stress and further exacerbate disease 

processes.25 

In addition to oxidative damage and inflammation, one-carbon metabolism has been 

implicated to be important in several chronic diseases, particularly cardiovascular disease, renal 

failure, neurological dysfunction, and cancer. An important step in one-carbon metabolism is the 
14 

synthesis/metabolism of methionine. Methionine is a precursor of S-adenosylmethionine (SAM), 

a universal methyl donor to DNA, RNA, protein, phospholipids, neurotransmitters and 

hormones. Hypermethylation in the promoter regions of tumor suppressor genes and 

chromosome aberrations due to global hypomethylation may lead to oncogenesis.26,27 In 

methionine synthesis, an intermediate molecule is homocysteine, which has been found to be 

associated with increased risk of coronary artery disease, stroke, peripheral vascular disease, 

cognitive impairment, dementia, depression, osteoporotic fractures, and functional decline.28 

 Other pathways by which chronic disease develops may or may not be modifiable by 

vitamins/minerals. Examples of these factors include but are not limited to genetic susceptibility, 

growth factors, and capacity of detoxification. 

 

Possible Mechanisms of Action of Vitamins and Minerals in 

Chronic Disease Prevention 

Multivitamin/mineral supplements often contain vitamin A, β-carotene, vitamin B1 

(thiamine), vitamin B2 (riboflavin), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), 

vitamin C, vitamin D, vitamin E, folic acid, niacin, calcium, iron, zinc, magnesium, and 

selenium. These nutrients have numerous biological effects and have garnered considerable 

research interest in their potential as chemo-preventive agents for the prevention of chronic 

disease. 

As described previously, a common process of chronic disease is oxidative damage by free 

radicals or reactive species. Multiple systems work in concert to protect the human body from 

oxidative damage. Endogenous enzymatic antioxidants, such as copper- and zinc-, or 

manganese-containing superoxide dismutase, selenium-dependent glutathione peroxidase, and 

catalase, can catalyze radical- and peroxide-quenching reactions. Nonenzymatic antioxidants 

include but are not limited to vitamin C, vitamin E, bilirubin, urate, flavanoids, and certain 

carotenoids (e.g., β-carotene and lycopene). In addition, metal-binding proteins can quench iron 

and copper ions which, if free, can catalyze oxidative reactions.29 

Folate, vitamin B6, and vitamin B12 influence methylation by supplying methyl groups and 

are essential for nucleotide synthesis, DNA synthesis, and DNA repair.30 Folate and B vitamins 

maintain normal brain function through the methylation of neurotransmitters, phospholipids and 

myelin.31 They are also essential in homocysteine metabolism because irreversible 

transsulfuration and the re-methylation of homocysteine rely on coenzymes derived from vitamin 

B6, vitamin B12, and folate. A previous meta-analysis indicated that daily supplementation with 

folic acid of 0.5-5 mg and vitamin B12 of approximately 0.5 mg would reduce blood 

homocysteine concentrations by up to one-third, whereas vitamin B6 did not have a significant 

additional effect.32 However, whether a reduction in homocysteine leads to decreased risk for 

clinical outcomes awaits evidence from randomized controlled trials. 

In addition to anti-oxidation and regulation of methylation, vitamins and minerals may have 

inhibitory effects on inflammation (γ-tocopherol, zinc, and vitamin A) and angiogenesis (αtocopherol, vitamin A, vitamin C, vitamin D). Some may also regulate cell differentiation, 

proliferation, and apoptosis (vitamin A, α-tocopherol, vitamin D, calcium) and enhance 

immunity (vitamin A, zinc, vitamin E, vitamin C, calcium).33-40 Vitamin C may be useful in the 

prevention or management of osteoarthritis through collagen synthesis,41 and vitamin D may 

prevent the progression of osteoarthritis by impairing bone’s response to the pathophysiological 
15 

process of the disease.42 Magnesium and calcium are important in regulating blood pressure.43,44

Calcium may also have beneficial effects on cholesterol levels and body weight, and may shield 

the contact of carcinogen with bowel mucosa by forming insoluble chemical complexes with bile 

acid and fat.45,46 Several meta-analyses have addressed the effects of calcium and/or vitamin D 

supplementation on bone density, osteoporosis, fractures, and falls.47-52 The evidence has led the 

Food and Drug Administration (FDA) to authorize health claims in the labeling of calcium 

supplements for the benefits in osteoporosis prevention. The 2004 United States Surgeon 

General’s Report on Bone Health and Osteoporosis has clearly stated the importance of calcium 

and vitamin D in maintaining healthy bones and preventing osteoporosis.53 However, intake of 

vitamin D and calcium from food source has been generally inadequate in American adults; only 

4 percent of individuals of age greater than 51 years meet the Adequate Intake level of vitamin 

D,54 and the average calcium intake in American adults was estimated to be 761mg per day, 

below the Recommended Dietary Allowance for adults (1,000-1,200 mg).55 

Factors that Affect the Efficacy and Safety of Vitamin/mineral 

Supplement Use in Chronic Disease Prevention 

Perturbation of metabolism and other physiologic function often occurs in persons with 

established chronic disease. Accordingly, evaluation of the efficacy and safety of 

multivitamin/mineral supplement use should be made separately for primary versus secondary 

prevention. In addition to individuals’ health status, several factors may affect the efficacy and 

the safety of vitamin and/or mineral supplement use in chronic disease prevention, such as 

individuals’ nutritional status, bioavailability of nutrients, nutrient-nutrient interaction, chemical 

forms and doses of supplements, timing and duration of supplement use, among others. 

Age, sex, race, genetic susceptibility, geographic location, smoking, diet, physical activity, 

obesity, and sunlight exposure are important factors because they affect individuals’ baseline 

nutritional levels and may modify the efficacy and safety of supplement use. Geographical 

location is also relevant because dietary intake of selenium depends on the selenium content of 

the soil where plants are grown or animals are raised. In addition, ecological studies have linked 

areas with increased selenium levels to lower rates of lung, colorectal, bladder, esophageal, 

pancreas, breast, ovarian, and cervical cancers.56 

After a nutrient is ingested, its biological effects are heavily determined by the 

bioavailability, i.e., the absorbable fraction that affects the biological effects of the nutrient by 

modulating the amount of the nutrient entering the body. Key factors determining the 

bioavailability of a micronutrient are the chemical form in which the nutrient is presented to the 

intestinal absorptive surface, the presence of other competing chemicals the concentration of 

food constituents (such as phytates and other chelating agents) that bind to the nutrient and make 

it unavailable for absorption, intestinal transit time, and enzyme activity. For example, synthetic 

vitamin E has approximately 50 percent the bioavailability of natural vitamin E, and use of αtocopherol can reduce the bioavailability of other forms of vitamin E,57 after competing for the 

uptake into very low-density lipoproteins (VLDL) by α-tocopherol transfer protein in the liver. 

Hence, factors influencing the bioavailability of a nutrient are important to consider when 

assessing the effects of multiple micronutrient preparations. 

One nutrient may affect the absorption, transport, tissue uptake, function and metabolism of 

other nutrients. Accordingly, the concurrent ingestion of several nutrients may result in 

synergistic, antagonistic, or threshold effects as compared to a single nutrient. Hence, the 
16 

efficacy of a single nutrient vs. multiple nutrients should be considered separately unless no 

interactive or threshold effects can be found. Examples of nutrient-nutrient interactions include 

vitamin B12 and selenium modification of host’s responses to inadequate dietary intake of folic 

acid. An excessive intake of folic acid may obscure vitamin B12 deficiency.58 Zinc regulates the 

absorption, transport and utilization of vitamin A.59 Calcium and vitamin D are inter-related 

metabolically in bone and intestine. 

 The chemical form of a nutrient may also determine its effects. For example, rather than an 

antioxidant effect, α-tocopheryl succinate has anti-proliferative effects in in vitro settings. Doses 

of supplements and duration of use are directly relevant to the efficacy, particularly for lipid 

soluble vitamins that can be accumulated in the tissue for a long-term. 

The Tolerable Upper Intake Levels of Daily Nutrient Intake 

The United States Food and Nutrition Board established tolerable ULs for several nutrients. 

By definition, a UL is the highest level of daily nutrient intake that is likely to pose no risk of 

adverse health effects to almost all individuals in the general population.60 A UL is determined 

by the following steps: (1) hazard identification based on in vitro experiments, animal studies, 

and/or human studies, (2) dose-response assessment to identify the no-observed-adverse-effect 

level (NOAEL) or lowest-observed-adverse- effect level (LOAEL), which is then weighed with 

an uncertainty factor (UF) to derive the UL. In the case where toxicity data are unavailable from 

children, an extrapolation from the ULs determined for adults is made based on body weight 

difference. The strength of the evidence for determining a UF varies and therefore the choice of a 

UF has leeway of subjectivity. The UL of vitamin E for adults is determined primarily based 

upon its hemorrhagic effects in rats.60 The UL of iron, zinc, and selenium was determined based 

on gastrointestinal symptoms, reduced copper status, and hair and nail brittleness and loss, 

respectively.60 Since the time when ULs were determined, several large-scale randomized 

controlled trials of vitamin/mineral supplementation have been completed. An update on the data 

regarding adverse effects will help to evaluate the appropriateness of ULs. 

Federal Regulation of Vitamin/mineral Supplements 

The United States FDA regulates dietary supplements under the Dietary Supplement Health 

and Education Act (DSHEA) of 1994 which states that supplements containing ingredients 

marketed prior to the enactment of DSHEA are not subject to pre-market burden on proof of 

safety. Many vitamins and minerals, such as vitamin A, vitamin B, vitamin C, vitamin D, 

vitamin E, calcium, and magnesium, with established nutritional function, fall into this category 

and have been grandfathered as Generally Recognized As Safe (GRAS).61,62 However, the 

determination of GRAS was primarily based on experts’ opinions or a history of safe use before 

January 01, 1958 when the Food Additives Amendment to Food, Drug, and Cosmetic Act was 

enacted. A lack of high-quality data before 1958 is conceivable when an adverse event reporting 

system was not in place. 
17 

Conceptual Framework 

Figure 1 demonstrates the conceptual framework used to guide this systematic review, 

focusing on primary prevention of chronic disease. Chronic disease endpoints are the outcomes 

of interest. A biomarker endpoint is considered if the biomarker is a marker of disease 

progression or the biomarker is reported as an adverse effect of supplement use. Bone mineral 

density, cognitive function, and fasting glucose were considered as biomarker endpoints for 

efficacy in this review. The framework acknowledges that vitamin and mineral supplements have 

many biologic effects that could help to prevent chronic disease outcomes. The framework also 

acknowledges potential adverse effects of vitamin and mineral supplements. 
18 
19 

Chapter 2: Methods 

 The NIH Office of Medical Applications of Research (OMAR) requested an evidence report 

to review and synthesize the evidence on multivitamin/mineral supplements and prevention of 

chronic disease. Our Evidence-based Practice Center established a team and a work plan to 

develop the evidence report. The project consisted of recruiting technical experts, formulating 

and refining the specific questions, performing a comprehensive literature search, summarizing 

the state of the literature, constructing evidence tables, synthesizing the evidence and submitting 

the report for peer review. 

Recruitment of Technical Experts and Peer Reviewers 

 At the beginning of the project, we recruited a panel of internal and external technical experts 

to give input on key steps including the selection and refinement of the questions to be 

examined. The panel included two internal technical experts from the Johns Hopkins University 

who have strong expertise in various aspects of the efficacy and/or safety of 

multivitamins/minerals and evidence-based medicine, and external experts who have strong 

expertise in nutritional research (see Appendix Aa

). In addition to this panel of technical experts, 

we recruited a few additional experts to serve as peer reviewers of the evidence report, as 

described further in the section on Peer Review.

Key Questions 

 We worked with the technical experts and representatives of OMAR and the Agency for 

Healthcare Research and Quality (AHRQ) to develop the Key Questions that are presented in the 

Specific Aims section of Chapter 1 (Introduction). We expanded the preliminary questions to 

include functionally related nutrient pairs, tuberculosis, hepatitis C, and pulmonary disease, and 

limited the questions involving efficacy to randomized controlled trials. The Key Questions 

focus on the efficacy of multivitamins/minerals (and specific single nutrients and functionally 

related pairs) in the prevention of chronic diseases and conditions as well as the safety of 

multivitamin/minerals and specific nutrients. 

Literature Search Methods 

 Searching the literature included the steps of identifying reference sources, formulating a 

search strategy for each source, and executing and documenting each search. Additionally, we 

searched for medical subject heading (MeSH) terms that were relevant to the specific nutrients 

and diseases specified in Key Question 1 to help develop the search strategy. We used a 

systematic approach for searching the literature to minimize the risk of bias in selecting articles 

for inclusion in the review. In this systematic approach, we had to be very specific about defining 

the eligibility criteria for inclusion in the review. The systematic approach was intended to help 

 

a Appendixes cited in this report are provided electronically at: http://www.ahrq.gov/clinic/tp/multivittp.htm
20 

identify gaps in the published literature. We used a systematic approach for extracting data from 

the studies to minimize the risk of bias in how we extracted data from eligible studies. By 

creating standardized forms for data extraction, we sought to maximize consistency in 

identifying all pertinent data available for synthesis. 

Sources 

Our comprehensive search plan included electronic and hand searching. Beginning in August 

of 2005 we ran searches of the following databases: MEDLINE®, EMBASE,® and the Cochrane 

database including Cochrane Reviews and The Cochrane Central Register of Controlled Trials 

(CENTRAL). These searches were updated to include all articles published up until November 1, 

2005. The FDA Adverse Event Reporting System (AERS) was researched. AERS covers drug 

adverse events and does not include reports on supplements. A similar reporting system exists 

for reporting adverse events associated with supplements; the Center for Food Safety and 

Applied Nutrition (CFSAN). CFSAN does not have a searchable database. 

 Hand searching for possibly relevant citations took several forms. Our experts identified 15 

journals that were thought to be most likely to contain relevant studies (see Appendix Ba

). We 

scanned the table of contents of each issue of these journals for relevant citations from January 

2005 through February 2006. For the second form of hand searching, reviewers received eligible 

articles and flagged references of interest for the team to compare to the existing database. We 

used SRS® 3.0 (TrialStat! Corporation, Ottawa, Ontario, Canada), a Web-based software package 

developed for systematic review data management, to track the article flagging. 

Search terms and strategies 

 Search strategies, specific to each database, were designed to enable the team to focus 

available resources on articles most likely to be relevant to the Key Questions, given that an 

enormous body of literature exists on vitamins and minerals. Initially, we developed a core 

strategy for MEDLINE, accessed via PubMed, based on an analysis of the MeSH terms and text 

words of key articles identified a priori. The PubMed strategy formed the basis for the strategies 

developed for the other electronic databases (see Appendix Ca

). 

Organization and tracking of literature search 

 The results of the searches were downloaded and imported into ProCite® version 5 (ISI 

ResearchSoft, Carlsbad, CA). From ProCite, the articles were uploaded to SRS 3.0. We used the 

duplication check feature in SRS 3.0. This feature allowed us to scan for exact article duplicates, 

author/title duplicates, and title duplicates. Additionally, this database was used to store citations 

in portable document format (PDF) and to track the search results at title review, abstract review, 

article inclusion/exclusion, and data abstraction levels (Figure 2). A list of excluded articles is 

presented in Appendix Da

. 

 

a Appendixes cited in this report are provided electronically at: http://www.ahrq.gov/clinic/tp/multivittp.htm
21 

Title Review 

 After the electronic databases were searched, citations were downloaded into ProCite, and 

uploaded to the SRS 3.0 tracking system. The study team scanned all titles. Two independent 

reviewers conducted title scans in a parallel fashion. For a title to be eliminated at this level, both 

reviewers had to indicate that it was ineligible. If the two reviewers did not agree on the 

eligibility of an article, it was automatically promoted to the next level (see Appendix Ea

, Title 

Review Form). The title review phase was designed to capture as many studies as possible 

reporting on the efficacy of single nutrients, related nutrient pairs, and multivitamins/minerals in 

the primary prevention of chronic diseases and conditions as well as the safety of 

multivitamins/minerals and a specified set of nutrients. All titles that were thought to address the 

above efficacy and or safety issues were promoted to the abstract review phase. 

Abstract Review 

Inclusion and exclusion criteria 

 The abstract review phase was designed to identify studies reporting on the efficacy of single 

nutrients, related nutrient pairs, and multivitamins/minerals in the primary prevention of chronic 

diseases and conditions as well as the safety of multivitamins/minerals and a specified set of 

nutrients. Investigators determined whether studies involving efficacy were randomized 

controlled trials and applied to primary prevention as previously defined in the Specific Aims 

section of Chapter 1. Investigators were instructed that articles relating to safety did not need to 

be randomized controlled trials. This review was primarily interested in safety studies on 

multivitamin/mineral supplements as well as a defined set of single nutrients for which 

reasonable concerns exist regarding potential adverse effects in the doses used. All articles with 

abstracts meeting these criteria were kept for further review. Abstracts were reviewed 

independently by two investigators, and were excluded if both investigators agreed that the 

article met one of the following exclusion criteria: (1) not written in English; (2) contained no 

human data; (3) included only pregnant women; (4) only infants; (5) only subjects of age less 

than or equal to 18 years (if a study included only subjects of age less than or equal to 18 years, 

we included it only if it presented data on the safety of a vitamin/mineral supplement) (6) 

included only patients with particular chronic diseases; (7) included only patients receiving 

treatment for chronic disease or included only patients in long-term care facilities; (8) only 

studied clinical nutritional deficiency; (9) contained no useful information applying to the Key 

Questions; (10) did not address the use of supplements; (11) did not address the use of 

supplements separately from dietary intake; (12) did not cover the defined disease endpoints or; 

(13) was an editorial, commentary, or letter. Additionally, an article could be excluded if it 

applied to Key Question 1 and/or 3 but was not a randomized controlled trial or a systematic 

review and did not address safety issues. (see Appendix E, Abstract Review Form). Differences 

in opinions regarding abstract inclusion or exclusion were resolved through consensus 

adjudication. At this level of inclusion/exclusion, the reviewers were also asked to identify which 

 

a Appendixes cited in this report are provided electronically at: http://www.ahrq.gov/clinic/tp/multivittp.htm
22 

nutrient(s) each article addressed as well as the Key Questions the article might apply to if the 

article was eligible. 

Article Inclusion/Exclusion 

 Because of the broad array of potentially eligible articles obtained at the abstract review 

phase, full articles initially selected for review underwent another independent parallel review by 

investigators to determine if they should be included for full data abstraction. At this phase of 

review, investigators determined which of the Key Questions each article addressed, and what 

type of protocol was used in the study (see Appendix E, Article Inclusion/Exclusion Form). If 

articles were still deemed to have applicable information, they were included in the final article 

review. Differences in opinions regarding article inclusion or exclusion were resolved through 

consensus adjudication. 

Article Review/Data Abstraction 

 The purpose of the article review was to confirm the relevance of each article to the research 

questions, to determine methodological characteristics pertaining to study quality, and to collect 

evidence that addressed the research questions. Articles eligible for full review could address one 

or more of the Key Questions. If reviewers determined that an article addressed both efficacy and 

safety, multiple data abstraction forms were used. We used a systematic approach for extracting 

data from the studies to minimize the risk of bias in how we extracted data from eligible studies. 

By creating standardized forms for data extraction, we sought to maximize consistency in 

identifying all pertinent data available for synthesis. 

 Each article underwent double review by study investigators for full data abstraction and 

assessment of study quality. For all data abstracted from studies, we used a sequential review 

process. In this process, the primary reviewers completed all data abstraction forms. The second 

reviewer confirmed the first reviewer’s data abstraction forms for completeness and accuracy. 

Reviewer pairs were formed to include personnel with both clinical and methodological 

expertise. A third reviewer re-reviewed a random sample of articles marked as “ineligible” by 

the first two reviewers to ensure consistency in the classification of the articles. Reviewers were 

not masked to the articles’ authors, institution, or journal. In most instances, data were directly 

abstracted from the article. If possible, relevant data were also abstracted from figures. 

Differences in opinion were resolved through consensus adjudication. For assessments of study 

quality, each reviewer independently judged study quality and rated items on quality assessment 

forms. (see Appendix E, Data Abstraction Review Forms) 

 For all articles containing original data, reviewers extracted information on general study 

characteristics such as study design, study period and follow up, study participants, sample size, 

and prior supplement use (see Appendix E, Data Abstraction Review Forms). Data abstracted to 

the “Arm” forms (see Appendix E, Data Abstraction Review Forms) included: placebo or 

intervention; nutrients studied; chemical form; dose; units; frequency of use; timing of use; and 

duration of use. 

 For studies addressing efficacy (Key Question 1 and/or 3), an outcomes form for efficacy 

(see Appendix E, Data Abstraction Review Forms) was filled out to obtain the information on 

study outcomes and adverse effects, and the results from subgroup analyses. Additionally, a 
23 

specific study quality form was filled out (quality forms were filled out independently) to assess: 

representativeness of the study population; bias and confounding; description of study 

supplements/supplementation; adherence and completeness of follow up; statistical analysis; and 

conflict of interest (see Appendix E, Data Abstraction Review Forms). 

 Reviewers used an outcomes form to abstract data from articles addressing safety (Key 

Questions 2 and/or 4) on adverse effects/events and criteria for causality (see Appendix E, Data 

Abstraction Review Forms). 

 We also abstracted data from systematic reviews that specifically applied to our Key 

Questions. This included systematic reviews of calcium and/or vitamin D only, and reviews of 

studies other than calcium and/or vitamin D only (see Appendix E, Data Abstraction Review 

Forms). 

 All information from the article review process was entered into the TrialStat database by the 

individual completing the review. Reviewers entered comments into the system whenever 

applicable. The TrialStat database was used to maintain and clean the data, as well as to create 

detailed evidence tables and summary tables (see Appendix F and Summary Tables). 

Data abstracted to assess the efficacy of multivitamin/mineral 

supplements and single nutrients (and related pairs of nutrients) in 

the primary prevention of chronic diseases/conditions 

(Key Questions 1 and 3) 

Articles were reviewed to obtain information on (1) study characteristics, (2) study 

participants, (3) study supplements, and (4) study results. Specific abstracted data on study 

characteristics were: study name and abbreviation (if available), types of study design, study 

period, chronological follow up period, median/mean follow up duration, eligibility criteria for 

trial enrollment, sample size, study site, and recruitment setting. The inclusion of the item on 

recruitment setting was intended to capture the source population from which the study 

population was established. Specific abstracted data on participants’ characteristics were: age, 

sex, race, smoking, alcohol, and body mass index (BMI). These factors were considered by the 

team members to be important confounding variables. Other characteristics reported in the article 

were also abstracted. Specific abstracted data on study supplements were: control (placebo, no 

dietary supplements or no standard care, standard care, nutritional/dietary education) and 

intervention arms (list of nutrients). The chemical form, total dose per ingestion, dose unit, and 

frequency, timing and duration of use of study supplements were abstracted. For clinical 

endpoints, data abstracted were: outcome measures, number of events, person years, incidence 

rates, and estimates of efficacy (relative risk, odds ratio, hazard ratio) along with the 

corresponding 95% confidence intervals. For biomarker endpoints such as bone mineral density, 

central and dispersion statistics of the biomarker measurements were abstracted. 

Data abstracted to assess the safety of multivitamins/minerals and 

single nutrients (selenium, iron, β-carotene, vitamin A, vitamin E, folic 

acid, and calcium (with or without vitamin D)) (Key Questions 2 and 4) 

Articles with safety data were reviewed to obtain information on (1) study characteristics, (2) 

study participants, (3) randomized groups, and (4) study results. Specific abstracted data on study 
24 

characteristics, study participants and study supplements were the same as those for Key 

Questions 1 and 3. Specific abstracted data on study results were: the types of adverse 

effects/events, whether the adverse effects/events occurred, numbers of adverse events, and 

estimates of associations along with the corresponding 95% confidence intervals. For biomarker 

endpoints, central and dispersion statistics of the biomarker measurements were abstracted. 

Plausibility of causality was considered using the following criteria: temporal relationship, lack 

of alternative causes, dose-response, relationship, evidence of increased circulating levels of the 

nutrient under investigation, and response to re-challenge. 

 

Data abstracted from previous systematic reviews on vitamin D and 

calcium 

Several systematic reviews have been published to address the efficacy of vitamin D and/or 

calcium in the prevention of bone loss, osteoporosis and fractures. The most recent review article 

was published in 2005. In addition, the University of Ottawa Evidence-based Practice Center 

will soon release a systematic review that focuses on vitamin D, including the effect of 

supplemental doses of vitamin D on bone density and fracture and fall risk. Since the studies on 

vitamin D and/or calcium have been reviewed so recently, we reviewed the available systematic 

reviews on this subject. Data from systematic review articles were abstracted regarding: (1) the 

aim of the review, (2) exclusion criteria, (3) search strategies (databases, search terms), (4) range 

of publication dates of reviewed articles, (5) number of trials in the review, (6) total numbers of 

trial participants in vitamin D and/or calcium group and in the placebo groups, (7) range of 

follow up periods, (8) range of proportions of participants lost to follow up, (9) trial participants’ 

characteristics (age, women, race/ethnicity groups), (10) inclusion of primary prevention trials 

alone or a mixture of primary and secondary prevention trials, (11) chemical forms of vitamin D 

and calcium, and (12) aggregate results of bone mineral density/content. 

Data abstracted from previous systematic reviews on nutrients other 

than vitamin D and calcium 

We also abstracted the following data from published systematic reviews on nutrients other 

than vitamin D and calcium: (1) the aim of the review, (2) exclusion criteria, (3) search strategies 

(databases, search terms), (4) range of publication dates of reviewed articles, (5) number of trials 

in the review, (6) total numbers of trial participants in vitamin/mineral group and in the placebo 

groups, (7) range of follow up periods, (8) range of proportions of participants lost to follow up, 

(9) trial participants’ characteristics (age, women, race/ethnicity groups), (10) inclusion of 

primary prevention trials alone or a mixture of primary and secondary prevention trials, (11) 

chemical forms of nutrients included in the review, and (12) aggregate estimates of efficacy 

along with the corresponding 95% confidence intervals and p-values. Efforts were made to 

abstract data from primary prevention trials included in systematic reviews that reviewed 

evidence from both primary and secondary prevention trials. 
25 

Quality Assessment 

Article quality was assessed differently for different types of studies: efficacy studies 

(randomized controlled trials only); safety studies; and systematic reviews. The dual, 

independent review of article quality judged articles on several aspects of each study type’s 

external and internal validity. Quality assessment of studies addressing efficacy included: (1) the 

representativeness of the study population (description of the study population and where it was 

drawn, and how well the participants’ characteristics were described); (2) bias and confounding 

(whether this was controlled for in the study design and reported on in the study); (3) description 

of supplements/supplementation; (4) description of adherence to study protocols and follow up 

(flow of patients through the study over time, loss to follow up, and participant withdrawal); (5) 

statistical analysis; and (6) conflict of interest. 

Quality assessment of studies addressing safety considered: (1) temporal relationships 

between timing of supplement use and adverse events (how this was reported); (2) dose-response 

relationship; (3) whether adverse effects disappeared after supplement use ceased; (4) serum 

levels of supplements; (5) whether an alternative cause for the adverse event was investigated: 

and (6) whether the adverse event re-occurred if the supplement was used again. 

The quality of each systematic review was assessed using a different set of criteria: (1) 

whether the question being addressed by the review was clearly stated; (2) comprehensiveness of 

search methods used and described in the report; (3) whether inclusion/exclusion criteria were 

clearly defined and appropriate; (4) whether analyses were conducted to measure variability in 

efficacy; (5) whether study quality was assessed and done appropriately (using validated 

instruments); (6) whether differences in how outcomes were reported and analyzed across studies 

were taken into consideration; (7) whether the study methodology was reproducible; and (8) 

whether conclusions were supported by the data presented. 

For each study, we assigned a rating of high, medium or low quality for each domain of 

study quality based on whether the score for that domain was designated High (80-100%), 

Medium (50-79%), or Low (0-49%) quality. 

Data Synthesis 

 For each Key Question, we created a set of detailed evidence tables containing all 

information extracted from eligible studies. The investigators reviewed the tables and eliminated 

items that were rarely reported. Investigators used the resulting versions of the evidence tables to 

prepare the text of the report and selected summary tables. 

Data Entry and Quality Control 

 Initial data were abstracted by investigators and entered directly into Web-based data 

collection forms using; SRS® 3.0 (TrialStat! Corporation, Ottawa, Ontario, Canada). After a 

second reviewer reviewed data, adjudicated data were re-entered into Web-based data collection 

forms by the second reviewer. Second reviewers were generally more experienced members of 

the research team, and one of their main priorities was to check the quality and consistency of the 

first reviewers’ answers. In addition to the second reviewers checking the consistency and 

accuracy of the first reviewers, a senior investigator examined all reviews to identify problems 
26 

with the data abstraction. If problems were recognized in a reviewer’s data abstraction, the 

problems were discussed at a meeting with the reviewers. In addition, research assistants used a 

system of random data checks to assure data abstraction accuracy. 

Grading of the Evidence 

 At the completion of our review, we graded the quantity, quality and consistency of the best 

available evidence addressing Key Questions 1 and 3 by adapting an evidence grading scheme 

recommended by the GRADE Working Group.63 We applied evidence grades to bodies of 

evidence on each type of nutrient for each major type of outcome. We considered the strength of 

the study designs with randomized controlled trials considered best, followed by non-randomized 

controlled trials, observational studies, and case reports. We considered at least two randomized 

controlled trials reporting on a specific outcome to constitute a body of evidence pertaining to 

that outcome. If an outcome was evaluated by at least two randomized controlled trials as well as 

observational studies and case reports, our evidence grade was based only on the randomized 

controlled trials evaluating that outcome. If an outcome was evaluated by one or no randomized 

controlled trials, our evidence grade was based on the single randomized controlled trial in 

addition to the best available non-randomized controlled trial or the best available observational 

studies (cohort studies considered best, followed by cross-sectional studies and studies with prepost observational design). We reported the number of studies within the category of best 

available evidence to assess the quantity of evidence. We also assessed the quality and 

consistency of the best available evidence, including assessment of limitations to individual 

study quality (using individual quality scores), certainty regarding the directness of the observed 

effects in studies, precision and strength of findings, and availability (or lack thereof) of data to 

answer the Key Question. We classified evidence bodies pertaining to each Key Question into 

four basic categories: (1) “high” grade (indicating confidence that further research is very 

unlikely to change our confidence in the estimated effect in the abstracted literature); (2) 

“moderate” grade (indicating that further research is likely to have an important impact on our 

confidence in the estimates of effects and may change the estimates in the abstracted literature); 

(3) “low” grade (indicating further research is very likely to have an important impact on 

confidence in the estimates of effects and is likely to change the estimates in the abstracted 

literature); and 4) “very low” grade (indicating any estimate of effect is very uncertain). 

Peer Review 

 Throughout the project, feedback was sought from the technical experts through ad hoc 

and formal requests for guidance. A draft of the completed report was sent to the technical 

experts and peer reviewers, as well as to the representatives of the NIH and AHRQ. In response 

to the comments of the technical experts and peer reviewers, revisions were made to the evidence 

report, and a summary of the comments and their disposition has been submitted to AHRQ. 
27 

Chapter 3. Results 

Overall Results of the Literature Search 

The literature search process identified 11,324 citations potentially relevant to the Key 

Questions (see Figure 2). We excluded 849 duplicate citations. In the title review process, we 

excluded 6,863 citations because they clearly did not pertain to the Key Questions. In the 

abstract review process, we excluded 3,163 citations that did not meet one or more of the 

eligibility criteria (see the list in the Methods chapter). Using the article inclusion/exclusion 

form, we then excluded an additional 386 articles that did not meet one or more of the eligibility 

criteria. That left a total of 63 articles eligible for inclusion in the review of one or more of the 

Key Questions. 

Key Question 1 

What is the Efficacy Determined in Randomized Controlled Trials of Multivitamin/mineral 

Supplement Use (Defined as 3 or More Vitamins and/or Minerals Without Herbs, Hormones, or 

Drugs), Each at a Dose Less Than the UL Determined by the Food and Nutrition Board, in the 

General Adult Population for Prevention Against the Development of one or More Chronic 

Diseases or Conditions? 

Introduction 

Multivitamin/mineral supplements have been used by many as a simple means to ensure 

adequate intake of several essential micronutrients in the hope for prophylactic benefits. Typical 

multivitamin/mineral supplements on the market contain about 10 vitamins and 10 minerals, 

such as vitamin A, vitamin C, B vitamins, vitamin E, folic acid, vitamin D, calcium, magnesium, 

zinc, iron among others. The following section summarizes the evidence from randomized 

controlled trials on the efficacy of multivitamin/mineral supplement use in the prevention of 

chronic disease. 

Results of literature search for Key Question 1 

Our literature search identified 11 articles from randomized controlled trials that addressed 

the efficacy of multivitamin/mineral supplements in the primary prevention of cancer, 

cardiovascular disease, cataract and age-related macular degeneration. Data for other diseases 

were lacking (Table 1). These studies used designed vitamin/mineral combinations, but not the 

one-a-day type of multivitamin supplements available on the United States market. 

The 11 articles documented results from 5 randomized controlled trials published from 1993 

to 2005, including (1) the Linxian General Population Trial in China,64 65 66 67 68, (2) the 

Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study in France,69 70 (3) 

the Multi-center Ophthalmic and Nutritional Eye-Related Macular Degeneration Study 

(MONMD) in United States veterans,71 (4) the Roche European American Cataract Trial 
28 

(REACT) in the United States and United Kingdom,72 and (5) the Age-Related Eye Disease 

Study (AREDS) in the United States.73

 

Design of randomized controlled trials 

The Linxian General Population Trial (referred to as “Linxian Trial” henceforth) was a 

fractional factorial trial designed to determine the efficacy of 8 vitamin/mineral combinations in 

cancer prevention in 29,584 adults of ages 40 to 69 years from 4 Linxian communes64 where the 

rates of esophageal cancer were high. Users of any vitamins were ineligible for trial 

participation. Vitamin/mineral supplements were combinations of the following: (A) retinol 5000 

IU and zinc 22 mg, (B) riboflavin 3 mg and niacin 40 mg, (C) vitamin C 120 mg and 

molybdenum 30 μg, and (D) β-carotene 15 mg, α-tocopherol 30 mg, and selenium 50 μg. The 

combinations were AB, AC, AD, BC, BD, CD, ABCD, and placebo. The dose of each nutrient 

ranged from 1 to 2 times the United States RDAs. The follow up period was 1986 to 1991. At the 

end of the trial, 3,249 participants had eye exams,65 and 391 participants had esophageal/gastric 

endoscopy examinations68 (Appendix Fa

, Evidence Tables 1a-1c). 

The SU.VI.MAX study was designed to determine the efficacy of a daily supplement of 

antioxidants (vitamin C 120 mg, vitamin E 30 mg, β-carotene 6 mg, selenium 100 μg, and zinc 

20 mg) for the primary prevention of cancer and ischemic cardiovascular disease in 13,017 

French adults (7,876 women of age 35 to 60 years, and 5,141 men of age 45 to 60 years).69

Regular users of any of the vitamins/minerals provided in the study were ineligible for trial 

participation. The follow up period was 1994 to 2002. Women had higher baseline serum βcarotene levels than men. Women also had slightly higher baseline serum levels of vitamin C but 

lower levels of zinc and selenium. Information on self-selected supplement use was not provided 

(Appendix F, Evidence Tables 1a-1c). 

The MONMD study was aplacebo-controlled trial conducted in 1992 to evaluate nutritional 

status in 71 United States veterans with dry age-related macular degeneration (AMD) and to 

assess the efficacy of multivitamin/mineral supplement use for 18 months on the progression of 

AMD and potential side effects. The daily multivitamin/mineral supplements included βcarotene 20,000 IU, vitamin E 200 IU, vitamin C 750 mg, citrus bioflavonoid complex 125 mg, 

quercitin 50 mg, biberry extract 5 mg, rutin 50 mg, zinc picolinate 12.5 mg, selenium 50 mcg, 

taurine 100 mg, n-acetyl cysteine 100 mg, l-glutathione 5 mg, vitamin B2 25 mg, and chromium 

100 mcg. The study excluded people who had used vitamins in the year prior to enrollment.74

The instruments used to measure cataract transparence were changed during the study period, but 

the examiners were not well instructed on how to use the new instruments71 (Appendix F, 

Evidence Tables 1a-1c). 

REACT assessed the efficacy of a mixture of antioxidant supplements in preventing cataract 

progression among 297 individuals in Boston, United States and Oxford and Bradford, United 

Kingdom.72 Regular users of any vitamin supplement were also excluded. Participants took a 

placebo or combined β-carotene (6 mg, in the form of beadlets), vitamin C (250 mg), and all-rac 

α-tocopherol acetate (200 mg) 3 times per day with meals. The follow up period was 1990 to 

1995. (Appendix F, Evidence Tables 1a-1c). 

The AREDS study was an 11-center trial that assessed the efficacy of zinc (80 mg zinc oxide 

and 2 mg cupric oxide) and antioxidants (vitamin C 500 mg, vitamin E 400 IU, and β-carotene 

 

a Appendices cited in this report are provided electronically at: http://www.ahrq.gov/clinic/tp/multivittp.htm
29 

15 mg) in the development and progression of age-related lens opacities and visual acuity loss in 

the United States.73,75 Participants were classified into 4 AMD categories according to the size 

and the extent of drusen and retinal pigment abnormality in each eye, the presence of 

manifestations of advanced AMD, and visual acuity. Persons in AMD category 1 (n= 1,117) 

were assigned to antioxidant or placebo, whereas persons in AMD categories 2 to 4 (n=3,640) 

were assigned to placebo, antioxidants, zinc, or combined antioxidants and zinc. The follow up 

period was 1992 to 2001. The major limitations were the option of multivitamin use (by 66% of 

the participants) and self-selected use of non-study supplements (20% of participants) that 

contain at least one of the study nutrients (Appendix F, Evidence Tables 1a-1c). 

Similarity and heterogeneity in study design among trials 

The Linxian trial was conducted in a Chinese population that was nutritionally inadequate 

whereas SU.VI.MAX was conducted in an apparently healthy French population. The Linxian 

trial and the REACT study excluded any vitamin use without specifying how recent the use was. 

The MONMD study excluded persons with supplement use during the year prior to enrollment. 

In contrast, AREDS provided Centrum® to 66 percent of the study participants, in addition to 

study supplements, and SU.VI.MAX allowed use of supplements other than those under study. 

The Linxian trial and the SU.VI.MAX study used doses of 1-2 times RDAs. In contrast, 

MONMD used vitamins C and B2 at doses that were more than 10 times the RDAs; AREDS 

used high doses of vitamin E and zinc (10 times the RDA), and a moderate dose of vitamin C (6 

times the RDA); REACT used a high dose of vitamin E. All trials employed a parallel-arm 

design except for the Linxian trial that used a fractional factorial design. A total of 47,289 

individuals were included in this review section (Appendix F, Evidence Tables 1a-1c; Table 2). 

Study quality 

 Inclusion/exclusion criteria were clearly defined in most trials. Quality of these trials was 

good in terms of randomization, double masking, ascertainment of trial endpoints, adherence, 

and use of intention-to treat approach in statistical analyses. However, there was a lack of 

descriptions as to whether concealment of allocation sequence was done, and whether observers 

independently evaluated trial outcomes. There was a paucity of data on prior supplement use, 

concomitant supplement use, and medication use that may have had effects on the efficacy of 

study supplements. None of the trials reported success of blinding and the extent of unintended 

crossover. Only the AREDS and REACT studies provided information on numbers and reasons 

for withdrawals and percents of loss-to-follow-up (Table 3). 

Cancer 

The Linxian trial examined incidence of and mortality for all cancer, esophageal cancer, 

stomach cancer (cardia and noncardia), esophageal/gastric cardia, and other cancers.64 After 5.25 

years of follow up, no significant risk reduction by supplement use was observed for these 

endpoints. The only exceptions were the reductions in gastric cancer incidence (relative risk 

(RR) 0.84, 95% confidence interval (CI) (0.71-1.00)), cancer mortality (RR 0.87, 95% CI 0.75-

1.00), especially stomach cancer mortality (RR 0.79, 95% CI 0.64-0.99) in the groups receiving 
30 

β-carotene, vitamin E and selenium compared to the groups receiving other vitamin/mineral 

combinations,64 and a lower non-cardia stomach cancer mortality in those receiving retinol and 

zinc (RR 0.59, 95% CI 0.37-0.93).64 Reduction in cancer mortality was greater in women than in 

men and among those of age less than 55 years in this trial (RR 0.79, 95% CI 0.64-0.98) vs. RR 

0.93, 95% CI 0.77-1.12), and (RR 0.71, 95% CI 0.55-0.92) vs. RR 0.94, 95% CI 0.80-1.11), 

respectively).67 In the substudy where participants underwent endoscopy examination, there was 

no significant effect of β-carotene, vitamin E and selenium supplement use on worse overall 

diagnoses of esophageal and gastric cancer or combined cancer and dysplasia prevalence, 

although the odds ratios were in the protective direction 68 (Appendix F, Evidence Tables 1b-1e). 

The SU.VI.MAX study reports no benefit on overall cancer incidence by the antioxidant 

supplement use in women (RR 1.04, 95% CI 0.85-1.29), but a 31 percent risk reduction (RR 

0.69, 95% CI 0.53-0.91) in men.69 As a result, there was a statistically significant interactive 

effect of sex and randomized group on total cancer incidence (p=.02). Women were younger than 

men in this trial, and generally had a healthier lifestyle as evident by higher serum β-carotene 

and vitamin C and fewer smokers. Among men, a moderate reduction in prostate cancer risk was 

observed in the antioxidant supplement group (RR 0.88, 95% CI 0.60-1.29). Further stratification 

analysis showed differential efficacy by baseline prostate specific antigen (PSA) level with a risk 

reduction among men with normal baseline PSA (≤3 μg/L) (hazard ratio (HR) 0.52, 95% CI 

0.29-0.92), but not among men with elevated PSA (HR 1.54, 95% CI 0.87-2.72)70 (Appendix F, 

Evidence Table 1d, Figures 3 and 4). 

Cardiovascular disease 

The Linxian trial reported a non-significant lower risk of stroke mortality with the greatest 

risk reduction (RR 0.91, 95% CI 0.76-1.07) observed in those receiving β-carotene, selenium, 

and α-tocopherol with or without other study nutrients,66 particularly in those receiving the 

combination of β-carotene, selenium, α-tocopherol, retinol and zinc (RR 0.71, 95% CI 0.50-1.00) 

as compared to the counterpart. There was no sex difference in the risk reduction. Hemorrhagic 

and ischemic stroke was not distinguished but other sources showed that approximately twothirds of the strokes were ischemic in this population76 (Appendix F, Evidence Tables 1b-1e). 

In the SU.VI.MAX study, no significant difference in ischemic cardiovascular disease 

incidence was noted between randomized groups. There was no interaction between sex and 

randomized groups. The cardiovascular events in women were only 22.6 percent of the events in 

men69 (Appendix F, Evidence Table 1d, Figure 5). 

Total mortality 

 In the Linxian trial, total mortality was lower among those who received β-carotene, 

selenium, and vitamin E, but not other nutrient combinations (RR 0.91, 95% CI 0.84-0.99).66 In 

the AREDS study, total mortality was 6 percent higher in the group receiving antioxidants 

compared to the group receiving no antioxidants, but the increase was not statistically 

significant.64,73,75 When limited to those participants with AMD categories 2, 3, and 4, total 

mortality was 19 percent and 13 percent lower in the groups receiving zinc alone or zinc 

combined with antioxidants respectively.73 A sex difference in the relative risk for total mortality 

was documented in the SU.VI.MAX study (RR 0.63, 95% CI 0.42-0.93 in men and RR 1.03, 

95% CI 0.64-1.63 in women)69, but no sex or age differences were noted in the Linxian trial67 In 
31 

the REACT, 9 deaths occurred in the antioxidant group, whereas 3 deaths occurred in the 

placebo group. Further examination on the causes of death revealed that the deaths in the 

antioxidant group were due to esophagitis, sudden death, aneurysm, pulmonary fibrosis, cancer 

and coronary thrombosis (Appendix F, Evidence Table 1e, Figure 6). 

Cataract and age-related macular degeneration 

In the Linxian trial, there was no effect of combined vitamin E, selenium and β-carotene on 

nuclear cataract, cortical cataracts, or posterior subcapsular cataracts65 (Appendix F, Evidence 

Table 1d). 

In the MONMD study, distance acuity declined in the placebo group, but was unchanged in 

the multivitamin group (p=.03). The multivitamin group also had better M print acuity and fewer 

scotoma in left eyes in the multivitamin group (p=.07), after 12 months. There was no significant 

difference between randomized groups in refraction, metamorphopsia and Lens Opacities 

Classification System (LOCS) II readings on nuclear color, nuclear opalescence, and posterior 

subcapsular opacities. There was an unanticipated cortical cataractogenic effect for right eyes in 

the multivitamin group.71 (Appendix F, Evidence Tables 1d). 

In the REACT, the primary outcome was the difference between baseline and the last visit in 

percentage pixel opaque (IPO) in the anteriorly-focused, retroillumination image. Secondary 

outcomes were posterior subcapsular cataract, nuclear cataract, cortical cataract, and nuclear 

color. At the end of the second year, there was a small positive effect on percent IPO in both the 

United States and United Kingdom groups. After the third year, the positive effects were greater 

in the United States group (percent pixel opaque = 0.389 vs. 2.517 in the vitamin vs. placebo 

group, p=.0001), but not the United Kingdom group. Unfavorable changes in all secondary 

outcomes were smaller in the vitamin group than the placebo group, but none was statistically 

significantly different72 (Appendix F, Evidence Table 1d). 

In the AREDS study on cataract, outcome measures were cataract surgery, changes in 

photographic grade of nuclear, cortical and posterior subcapsular opacities, and visual acuity loss 

(≥15 letters). After 6 years of follow up, no appreciable difference was found in any of the 

outcomes between antioxidant and placebo groups73 (Appendix F, Evidence Table 1d). 

In the AREDS study, outcomes were rates of progression to advanced AMD and visual 

acuity. After an average follow up period of 6.3 years, the odds ratio (OR) (99% CI) of 

developing advanced AMD was 0.75 (0.55-1.03), 0.80 (0.59-1.09), and 0.72 (0.52-0.98) among 

individuals with zinc, antioxidants, and combined zinc and antioxidant supplementation as 

compared to individuals in the placebo group. Excluding individuals in AMD category 2 

(extensive small drusen, nonextensive intermediate size drusen or pigment abnormalities), the 

OR (99% CI) of developing advanced AMD was 0.71 (0.52-0.99), 0.76 (0.55-1.05), and 0.66 

(0.47-0.91) among individuals with zinc, antioxidants, and combined zinc supplementation and 

antioxidant supplementation, and the OR(99% CI) of having moderate visual acuity loss was 

0.73 (0.54-0.99) in the group with antioxidants plus zinc, but not statistically significant for other 

supplementation groups75 (Appendix F, Evidence Table 1d). 
32 

Summary 

 There is a paucity of data on the efficacy of multivitamin/mineral supplement use in the 

prevention of chronic disease in the general United States population. Limited data from the 

Linxian trial suggest 13 percent to 21 percent reductions in gastric cancer incidence, gastric 

cancer mortality, and cancer mortality by use of β-carotene, vitamin E and selenium supplements 

of doses 1 to 2 times RDAs. Results of total cancer incidence in the SU.VI.MAX trial in France 

were sex-dependent with a 31percent lower risk in men who received vitamin C, vitamin E, βcarotene, selenium, and zinc at doses near RDAs, but no risk reduction in women who appeared 

to have had higher fruit/vegetable intake. The antioxidants used in SU.VI.MAX did not confer 

benefit in preventing ischemic cardiovascular disease, whereas use of β-carotene, selenium, αtocopherol, retinol, and zinc supplements in the Linxian trial had a moderate reduction (30%) in 

stroke mortality. Generalizability of these findings for the United States population is uncertain 

in view of the French paradox and the general nutritional inadequacy of the Linxian population. 

Multivitamin/mineral supplement use for 3 to 6 years had no significant benefits in preventing 

cataract. Zinc (of dose 10 times thhe RDA) alone or in combination with antioxidants had 

beneficial effects on AMD only in those with intermediate AMD in one or both eyes, or those 

with advanced AMD in one eye. Overall, the quality of individual articles was “medium” (Table 

3). Taking into consideration the quantity, quality, and consistency of evidence, we concluded 

the strength of evidence on the efficacy of multivitamin/mineral supplementation was rated as 

“very low” for primary prevention of cancer and cardiovascular disease, and "low" for cataract 

and age-related macular degeneration (Table 4). 

Key Question 2 

What is Known About the Safety of Use of Multivitamin/mineral Supplements (As Defined In Key 

Question 1) in the General Population of Adults and Children, Based Primarily on Data From 

Randomized Controlled Trials and Observational Studies? 

Issues to consider 

Because the most recent revisions of recommended nutrient intakes, the 1997-2004 dietary 

reference intakes (DRIs), include for the first time an upper level of intake, this concept has been 

used as a benchmark to assess the ‘safety’ of micronutrient intake. However, it is important to 

point out that the UL was designed to identify risk, not safety. Risk is a probabilistic, biological, 

objective indicator of the potential adverse effect resulting from a defined intake level. The risk 

associated with a given intake level is expected to be similar for comparable human populations. 

Safety, on the other hand, is a social, cultural and intellectual construct, and reflects the risk that 

a given society is willing to tolerate. This threshold varies in different cultures and societies, and 

can change over time. The distinction is of relevance for our review since, in the absence of 

standardized methods to assess risk associated with nutrient intakes, studies report these adverse 

or unexpected events in a variety of ways, in some cases reflecting more a subjective selfassessment of ‘safety’, and in others a more specific assessment of risk based on objective 

indicators, such as laboratory tests. 
33 

Very few studies have been specifically designed to assess the risk associated with different 

intake levels of single or multiple micronutrients. Nevertheless, many randomized controlled 

trials include a data collection component aimed at monitoring safety, thus providing information 

on adverse events in active and control groups. These data typically include a variety of 

endpoints, from spontaneous or elicited self-reported symptoms or events, exit surveys in 

participants withdrawing from the study, or objective measurements such as blood or urine tests 

or clinical examination. It should be noted that most randomized controlled trials reviewed in 

this evidence report used one or more nutrients at doses above the UL defined by the current 

DRIs. Besides randomized controlled trials, additional insight on risk associated with specific 

nutrients can be obtained from other types of studies, including case series and case reports, 

usually of very small sample size (often single case reports). Not surprisingly, many case reports 

describe the effects of very high intake levels or of unusual host conditions, thus limiting their 

generalizability. 

The basic conditions that enhance the quality of a study in terms of determining the main 

health effects also apply to adverse effects: temporal association, adequate exposure, doseresponse relationship, biological plausibility, and specificity, etc. In the case of safety, reversal of 

effects upon withdrawal may also enhance the solidity of the findings. 

Review of data on the safety/risk of multivitamin/mineral supplements 

We identified 8 articles that reported the adverse effects of multivitamin/mineral 

preparations. The 8 articles were published from 4 randomized controlled trials and 3 case 

reports.72-75,77-81 We considered the following criteria when assessing adverse effects: (1) 

randomized allocation of treatment, (2) adequate sample size, (3) well-defined population, (4) 

defined dose and total intake of the nutrient(s) of interest, and (5) adequate duration of exposure. 

We used the following criteria for assessing causality: temporal relationship, lack of alternative 

causes, dose-response relationship, evidence of increased circulating levels of the nutrient under 

investigation, and response to re-challenge. 

Doses were usually 2 to 10 times the RDA. For example, typical daily dosage for vitamin E 

doses ranged from 200 to 600 IU, vitamin A from 10,000 to 20,000 IU, and vitamin C from 75 to 

750 mg. Overall, we found no consistent pattern of increased adverse events in the active group 

compared with the placebo group, with the exception of changes in skin color, which was 

common in studies in which β-carotene was part of the multivitamin preparation (Appendix F, 

Evidence Tables 2a-2d). 

The REACT study evaluated the effects of an antioxidant vitamin combination (750 mg 

vitamin C, 600 mg vitamin E, and 18 mg β-carotene), given daily for 3 years. The frequency of 

reported side effects did not differ between intervention and control groups72 (Appendix F, 

Evidence Tables 2a-2d). 

In the AREDS trial,73 an antioxidant combination (400 IU vitamin E, 500 mg vitamin C, 15 

mg β-carotene) and/or 80 mg zinc and 2 mg Cu, was given to healthy adults with early signs of 

lens opacity. The only significant effect of the antioxidant supplement was yellowing of the skin

(Appendix F, Evidence Tables 2a-2d). A similar study enrolling patients with incipient macular 

degeneration,75 and using a similar antioxidant combination, also found a higher percent of 

yellowing of the skin in the active group (8.3% vs. 6.0%, p<0.008). 

 The MONMD trial assigned 39 patients with macular degeneration to an antioxidant 

combination, with follow up of 18 months.74 No adverse effects were reported, except for “a few 
34 

cases of diarrhea,” which the authors attributed to the high ascorbic acid content of the 

preparation. 

In a 2 by 4 factorial feasibility trial in Yunnan Province, China, where the incidence of lung 

cancer was extremely high, participants received combinations of retinol 25,000 IU, β-carotene 

50 mg, α-tocopherol 800 IU and selenium 400 μg each day, and there were no excessive adverse 

effects reported for the active supplement groups. Symptoms such as broken nails and skin 

yellowing were generally improved in the groups receiving active supplements.78 

In the 3 trials66 73 69 of multivitamin supplements where mortality rates were compared 

between active and control groups, no adverse effects of supplementation on the outcomes were 

found. In fact, two trials reported lower mortality in the groups receiving multivitamin/mineral 

supplements. 66 69 Few if any studies met all or even a few of the causality criteria (Appendix F, 

Evidence Table 1e). 

Key Question 3 

What is the Efficacy Determined in Randomized Controlled Trials of Supplementation with 

Single Nutrients or Functionally Related Nutrient Pairs, Each at a Dose Less than the UL 

Determined by the Food and Nutrition Board, in the General Adult Population for Prevention 

Against the Development of One or More Chronic Diseases or Conditions 

 Our literature search identified data from randomized controlled trials that assessed the 

efficacy of β-carotene, vitamin A combined with β-carotene or zinc, vitamin E, folic acid with or 

without vitamin B12 or vitamin B6, selenium, and vitamin D with or without calcium in the 

primary prevention of cardiovascular disease, cancer, cataract, age-related macular degeneration, 

cognitive function, bone mineral density, falls or fractures. Using our search strategies, we did 

not identify data on the efficacy of vitamin C, iron, magnesium, vitamin B2, niacin, or 

calcium/magnesium supplement use in the primary prevention of chronic disease. 

β-Carotene 

Introduction 

β-carotene is a major dietary carotenoid and the most abundant carotene found in nature. In 

the 1980s, several large clinical trials had been launched to determine the role of β-carotene in 

chronic disease prevention. The following section summarizes the evidence. 

Results of the literature search 

We identified 22 articles from randomized controlled trials that assessed the efficacy of βcarotene in the prevention of cancer, cardiovascular disease, diabetes mellitus, or age-related 

maculopathy. The 22 articles were published from 6 trials, the Alpha-tocopherol β-carotene 

Cancer Prevention Study (ATBC), the Βeta-Carotene and Retinol Efficacy Trial (CARET), the 

Nambour Skin Cancer Prevention Trial (NSCP), the Skin Cancer Prevention Study (SCP), the 

Physician’s Health Study (PHS), and the Women’s Health Study (WHS).82-87 

Design of randomized controlled trials 

The ATBC was a 2 by 2 factorial trial of synthetic all-rac-α-tocopherol acetate (50% powder, 

50 mg per day) and synthetic β-carotene (10% water-soluble beadlets, 20 mg per day) 
35 

supplementation in 29,133 Finnish smokers aged 50 to 69 years.88 Users of vitamin E, vitamin A, 

and/or β-carotene in excess of predefined doses were excluded. The follow up period was 1985 

to 1993. Post-intervention follow up of cancer incidence and cause-specific mortality was 

performed from 1993 to 1999 for cancer incidence and cause-specific mortality and up to 2001 

for total mortality.89 Gastrointestinal endoscopy was performed on 1,344 men with gastritis after 

a median supplementation time of 5.1 years90 (Appendix F, Evidence Tables 3a-3c).

The CARET study consisted of two pilot studies conducted in 1985 to 1988 followed by a 

large trial conducted from 1988 to 1991 in the United States. The first pilot study, the Asbestos 

Workers Pilot Study for CARET, involved 816 men with a history of asbestos exposure. 91 The 

second pilot study, the Smokers Pilot Study, involved 1029 men and women with a history of 

cigarette smoking.92 The full CARET study was conducted in 18,314 high-risk men and women 

who had a history of asbestos exposure or smoking. Participants were randomly assigned to 

receive either β-carotene 50 mg and retinyl palmitate 25,000 IU per day or placebo. Prior βcarotene supplement users were excluded.93 The follow up period was 1985 to 1995. Post-trial 

follow up of cancer incidence and mortality was performed until the end of 200194 (Appendix F, 

Evidence Tables 3a-3c). 

The NSCP trial was a 2 by 2-factorial trial of β-carotene 30 mg per day and daily sunscreen 

among 1,621 adult Australians of age 20 to 69 years.84 No exclusion or prior supplement use was 

reported. The follow up period was 1992 to 1996 (Appendix F, Evidence Tables 3a-3c). 

The SCP was a trial with a parallel-arm design conducted in 1,729 adults of age 85 years or 

less who had at least one biopsy-proven basal cell or squamous cell skin cancer at baseline. 

Participants were randomized to receive placebo or β-carotene (50 mg per day) during the trial.85 

No exclusion or prior supplement use was reported. The follow up period was 1983 to 1993 

(Appendix F, Evidence Tables 3a-3c). 

The PHS was a 2 by 2 factorial trial of β-carotene (50 mg every other day) and aspirin 

conducted among 22,071 apparently healthy male physicians, aged 40-84 years, in the United 

States. Vitamin A supplement users were ineligible for trial enrollment. The follow-up period 

was 1982 to 1995 95 (Appendix F, Evidence Tables 3a-3c). 

The WHS was a 2 by 2 by 2 factorial trial conducted in 39,876 female health professionals in 

the United States aged 45 years or older to determine whether alternate daily use of aspirin (100 

mg), β-carotene (50 mg), and vitamin E (600 IU) can prevent cancer and cardiovascular 

disease.87 β-carotene supplementation was terminated after a median treatment duration of 2.1 

years (range 0 to 2.7 years), primarily because of the null findings from the PHS.95 Users of 

vitamin A, β-carotene, or vitamin E were ineligible for trial enrollment. Nearly 40 percent of the 

trial participants reported to have multivitamin supplement use at baseline. The follow up period 

of this trial was 1992 to 2004 (Appendix F, Evidence Tables 3a-3c). 

Similarity and heterogeneity in study design among trials 

 Except for the ATBC and NSCP that were conducted in Finland and Australia, respectively, 

the 4 other trials included in this review were conducted in the United States. Except for the SCP 

and NSCP, prior users of β-carotene and/or vitamin A supplements were excluded. The range of 

follow up was 4 to 10 years. The range of daily doses was 20 mg to 50 mg. The ATBC, PHS, 

WHS, and NSCP used a factorial design with α-tocopherol, aspirin, aspirin with/without vitamin 

E, and sunscreen, respectively, as the other intervention, whereas SCP and CARET adopted a 

parallel-arm study design. A total of 112,564 individuals were included in this review section. 

They were heterogeneous populations that ranged from high-risk people with a history of 
36 

asbestos exposure and cigarette smoking (ATBC, CARET) to male physicians (PHS), female 

health professionals (WHS), and adults in a high sun exposure area in Australia (Appendix F, 

Evidence Tables 3a-3c). 

Study quality 

 The general strengths of the randomized clinical trials were large sample size, double 

masking and randomization, high adherence to treatment, and ascertainment of clinical 

outcomes. Adherence was not reported in the CARET study, although β-carotene treatment was 

shown to raise the median serum β-carotene levels to 12 times the baseline levels.93 The success 

of blinding the study was not reported in the NCSP,84 WHS,96 and SCP.85 The study population 

was incompletely described in the SCP.85 Most of these studies did not report on participants’ 

prior use of supplements (Table 3). 

 

Results 

 Cancer. In the ATBC study, compared to those who did not receive β-carotene, participants 

receiving β-carotene had a higher lung cancer incidence and lung cancer mortality (RR 1.18, 

95% CI 1.03-1.36; RR 1.08, 95% CI 1.01-1.16, respectively),97,98 but no increased risk for gastric 

cancer,90 pancreatic cancer,99 colorectal adenomas,100 prostate cancer 101 or colorectal cancer 102

In the 6-year post-trial follow up, the relative risk of lung cancer was 1.06 (95% CI 0.94-1.20) 

for β-carotene recipients versus non-recipients. The supplementation had a late effect on 

colorectal cancer (RR 1.88; 95% CI 1.28-2.76) 4 years after the end of supplementation, but no 

late effect on other cancer outcomes.103 (Appendix F, Evidence Tables 3b-3e, Table 5).

In the PHS, β-carotene supplementation increased the risk of thyroid cancer (RR 9.5, 95% 

CI 2.2-40.7), and bladder cancer (RR 1.5, 95% CI 1.0-2.2), but had no effect on other malignant 

neoplasms95,104 or non-melanoma skin cancer86 (Appendix F, Evidence Table 3d, Table 5). 

In the CARET study, the combination of β-carotene and vitamin A supplementation 

increased the incidence of lung cancer (RR 1.28, 95% CI 1.04-1.57)93,105 and the effects persisted 

6 years after the trial terminated, especially among women.94 β-carotene supplementation had no 

effects on cancers such as leukemia, mesothelioma, bladder cancer, breast cancer, prostate 

cancer, colorectal cancer, head and neck cancer, or lymphoma105 (Appendix F, Evidence Table 

3d, Table 5). 

In the SCP, β-carotene supplementation had no effect on cancer deaths85 (Appendix F, 

Evidence Table 3d, Table 5). 

In the WHS, β-carotene supplementation had no impact on the incidence of cancer96

(Appendix F, Evidence Table 3d, Table 5). 

In the NSCP trial, β-carotene supplementation had no impact upon the incidence of basal cell 

carcinoma or squamous cell carcinoma after 4 years of follow up84 (Appendix F, Evidence Table 

3d, Table 5). 

Cardiovascular disease. The ATBC study participants who received β-carotene had a nonsignificant higher incidence of angina and stroke mortality during the trial,106,107 and had higher 

mortality for a wide spectrum of cardiovascular disease during the post-trial follow up103

(Appendix F, Evidence Table 3d, Table 5).

Participants receiving β-carotene and vitamin A in CARET had a non-significant increased 

risk of cardiovascular death after a mean follow up of 4 years (RR 1.26, 95% CI 0.99-1.61),93 but 

the risk was lower (RR 1.02) 6 years after supplementation was terminated.94 

Participants in the WHS study had a non-significant higher risk for stroke (RR 1.42, 95% CI 
37 

0.96-2.10), but lower risk for myocardial infarction (RR 0.84, 95% CI 0.56-1.27)96 (Appendix F, 

Evidence Table 3d, Table 5). 

In the PHS, β-carotene supplementation had no effects on incidence of type 2 diabetes 

mellitus,108 incidence of myocardial infarction, stroke and all important cardiovascular events, or 

cardiovascular mortality95 (Appendix F, Evidence Table 3d, Table 5). 

Cataract and age-related macular degeneration. In the ATBC trial, β-carotene 

supplementation had no effect on age-related cataract or age-related maculopathy109,110 

(Appendix F, Evidence Table 3d, Table 5).

Total mortality. β-carotene supplementation was associated with an 8 percent, 7 percent, and 

5 percent increased risk of total mortality in the ATBC, WHS and SCP studies, 

respectively.85,96,97 Only the increase in the ATBC trial reached statistical significance (p=0.02). 

In the post-trial follow up on total mortality (8 years of follow up) of the ATBC trial, the relative 

risk of total mortality in the groups receiving β-carotene compared to the corresponding placebo 

groups was 1.07 (95% CI 1.02-1.12)103 (Appendix F, Evidence Table 3e, Table 5). 

Summary 

In summary, β-carotene was associated with increased risk of lung cancer incidence and 

mortality in persons who were heavy smokers or who were regularly exposed to asbestos. βcarotene supplementation did not reduce risk of other chronic disease outcomes, including 

cardiovascular disease, diabetes mellitus, cataract, and maculopathy. Taking into consideration 

the quantity, quality, and consistency of evidence, we concluded that the overall strength of 

evidence regarding the effects of β-carotene on the incidence of cancer and cardiovascular 

disease was “moderate” and on the prevalence of cataract or age-related maculopathy was “very 

low” (Table 6).

Vitamin A 

Introduction 

The following section summarizes the evidence from randomized controlled trials on the 

efficacy of vitamin A supplement use in the prevention of chronic disease. 

Results of the literature search 

Our literature search identified no data on the efficacy of vitamin A alone in the prevention 

of chronic disease. We identified 9 eligible articles that addressed the efficacy of pre-formed 

vitamin A, combined with zinc or β-carotene, in preventing chronic disease. Three articles were 

from the Linxian trial in China64-66 in which retinyl palmitate and zinc was combined as one type 

of supplementation, and 5 articles were from the CARET in the United States92-94,103,105 in which 

retinyl palmitate and β-carotene were combined as one type of supplementation. 

Design of randomized controlled trials 

The designs of the Linxian and CARET trials were described in a previous section of the 

Results chapter, Design of Randomized Controlled Trials, for Key Question 1 and Design of 

Randomized Controlled Trials for Key Question 3, β-carotene, respectively (Appendix F, 

Evidence Tables 3a-3c). 
38 

Results 

In the Linxian trial, combined vitamin A and zinc had no impact on reducing deaths from 

stroke,66 mortality,64 or esophageal or gastric dysplasia or cancer.111 

CARET used a combination of β-carotene and retinyl palmitate which increased the 

incidence of lung cancer (RR 1.28, 95% CI 1.04-1.57), mortality related to lung cancer (RR 1.46, 

95% CI 1.07-2.00) and cardiovascular disease (RR 1.26, 95% CI 0.99-1.61).93 The risk for 

cardiovascular disease was lower (RR 1.02) 6 years after supplementation was terminated.94

Total mortality was higher in the group receiving retinyl palmitate and β-carotene at the end of 

the trial (RR 1.17, 95% CI 1.03-1.33) 93, but leveled off in a post-trial follow up for 6 years (RR 

1.08, 95% CI 0.99-1.17)94 (Appendix F, Evidence Tables 3d-3e). 

Summary 

Available evidence from two studies in selected populations (nutritionally inadequate or 

exposure to asbestos and/or cigarette smoke) suggests no benefit of combinations of vitamin A 

and zinc or vitamin A and β-carotene for cancer or cardiovascular disease prevention. Because 

no trial has been conducted to assess the efficacy of vitamin A alone in the prevention of the 

chronic diseases listed in the Key Question 1, we drew no conclusion for vitamin A by itself. 

Vitamin E 

Introduction

Vitamin E is the second most commonly used dietary supplement in the United States.1 The 

following section reviews the evidence on the efficacy of vitamin E supplementation in the 

prevention of chronic disease. 

 

Results of literature search

Our literature search identified 16 articles (including articles containing post-trial data) that 

provided evidence on the efficacy of vitamin E supplements in the prevention of chronic disease. 

These articles were generated from 4 randomized controlled trials, the ATBC trial, the WHS, the 

Primary Prevention Project (PPP), and the Vitamin E, Cataract, and Age-Related Maculopathy 

Trial (VECAT). The predominant source of evidence (from 12 articles, including articles 

containing post-trial data) on this topic stems from the ATBC trial. 

Design of randomized controlled trials 

The designs of the ATBC trial and the WHS were described in a previous section of the 

Results chapter, Design of Randomized Controlled Trials, on β-carotene (Appendix F, Evidence 

Tables 3f-3h). 

The PPP was a randomized controlled, open-labeled, 2 by 2 factorial trial designed to 

investigate the efficacy of vitamin E (synthetic, 300 IU per day) and aspirin (100 mg per day) for 

cardiovascular disease prevention.112 Participants were 4,495 men and women age 50 years or 

older with at least one of the major well-accepted risk factors for cardiovascular disease. Longterm vitamin E users were ineligible. At the end of the trial, the percent of participants lost to 

follow up was 13.6 percent in the vitamin E group. (Appendix F, Evidence Tables 3f-3h). 

The VECAT was designed to evaluate whether daily vitamin E supplements reduced the risk 

of age-related cataracts in 1,193 Australians who were 55 to 80 years old upon entry into the 

study and who had early or no cataract. Trial participants were randomized to receive 500 IU per 
39 

day of natural vitamin E or placebo for 4 years. Approximately 27 percent of the trial 

participants had prior supplement use. The percent of participants lost to follow up was 25 

percent, and among those who were retained in the trial, 12 percent ceased taking study 

supplements113 (Appendix F, Evidence Tables 3f-3h). 

Similarity and heterogeneity among trials

The participants in these trials had distinct characteristics, being female health professionals 

in the United States (WHS), male smokers in Finland (ATBC), or Italians who might have 

followed a Mediterranean diet (PPP). A total of 74,697 individuals were included in these trials 

with 87 percent being ATBC or WHS participants. Accordingly, approximately 27 percent of 

these trial participants were assigned to also take aspirin and 20 percent were assigned to also 

take β-carotene supplements. Vitamin E supplements used in these studies included synthetic 

form, natural source, and natural vitamin E at doses ranging from 50 IU per day in synthetic 

form to 600 IU per day of natural source (Appendix F, Evidence Tables 3f-3h). 

 

Study quality 

Inclusion/exclusion criteria were clearly defined in most trials. The quality of these trials was 

good with respect to randomization, double masking, ascertainment of trial endpoints, adherence, 

and use of an intention-to treat approach in statistical analyses (see Table 3, Assessment of 

Quality of Studies). There was a lack of descriptions as to whether concealment of allocation 

sequence was performed and whether there was an unintended crossover. The WHS and PPP 

trials collected data on lifestyle factors and medication use. None of the trials reported success of 

blinding and the extent of unintended crossover. Most trials provided no information on numbers 

and reasons for withdrawals and percent lost to follow up. 

Results. 

Cancer. In the ATBC trial, synthetic α-tocopherol of 50 IU per day had no benefit on the 

incidence of lung cancer and gastric neoplasm,90,98 lung cancer mortality, or pancreatic cancer 

mortality,97,99 but increased colorectal adenoma incidence (RR 1.66, 95% CI 1.19-2.32)100. 

Questions have been raised whether the finding on colorectal adenoma was due to increased 

rectal bleeding by α-tocopherol supplementation, leading to the increased diagnosis of polyps. In 

contrast to these findings, men who received α-tocopherol supplements had a non-significant 

protective effect on colorectal cancer development (RR 0.78, 95% CI 0.55-1.09)102 and had a 32 

percent and 41 percent reduction in the incidence of, and the mortality from prostate cancer 

respectively.101 The reduction was evident for clinical prostate cancer but not for latent cancer. In 

the post-trial follow up, the protective effect of α-tocopherol against prostate cancer was 

attenuated (RR 0.88, 95% CI 0.76-1.03). The moderate protective effects of α-tocopherol on 

colorectal cancer during the trial was no longer evident in the 6-year post-trial follow up, and αtocopherol had no late effects on other cancers.103

In the WHS study, vitamin E of 600 IU on alternate days did not affect the risk of developing 

total invasive cancer, breast cancer, lung cancer, and colon cancer, or the risk of cancer death87

(Appendix F, Evidence Table 3i, Table 7). 

Cardiovascular disease. In the ATBC trial, all-rac-α-tocopheryl acetate of 50 IU per day had 

a borderline effect in reducing the incidence of angina (RR 0.91 comparing alpha-tocopherol 

with or without beta-carotene to no alpha-tocopherol with or without beta-carotene; RR 0.97 

comparing alpha-tocopherol alone to placebo), decreased the risk of cerebral infarction (RR 0.86, 
40 

95% CI 0.75-0.99), and increased the risk of subarachnoid hemorrhage (RR 1.50, 95% CI 0.97-

2.32) and fatal subarachnoid hemorrhage (RR 1.81, 95% CI 0.49-1.32).106 A similar increased 

risk in hemorrhagic stroke persisted during the post-trial follow up.103

In the PPP, 107 the evidence was inconclusive due to small numbers of events and premature 

stopping of the trial; there was a non-significant increased risk for main cardiovascular endpoints 

(cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) (RR 1.07, 95% CI 

0.74-1.56), but a lower risk for total cardiovascular events or diseases (RR 0.94, 95% CI 0.77-

1.16)112 (Appendix F, Evidence Table 3i, Table 7). 

In the WHS, use of vitamin E, 600 IU every other day had no effects on fatal and non-fatal 

myocardial infarction and fatal and non-fatal stroke, but reduced total cardiovascular death (RR 

0.76, 95% CI 0.59-0.98).87,96 There was no effect of vitamin E supplementation on hemorrhagic 

stroke (RR 0.92, 95% CI 0.61-1.38)87 (Appendix F, Evidence Table 3i, Table 7). 

Serum lipid levels. Shekelle etal. conducted a systematic review of the effects of vitamin E 

on the prevention and treatment of cardiovascular disease.114 The review, published in April 

2004, was part of a larger evidence report on the effects of vitamin C, vitamin E, and coenzyme 

Q10 on cardiovascular outcomes.115 The review included an examination of the effects of 

vitamin E on lipid levels. The search strategy was comprehensive and retrieved English and nonEnglish studies from multiple electronic databases. Additional studies were obtained by handsearching reference lists from key articles and by consulting experts in the field. Multiple 

synonyms for vitamin E and for clinical trials were used in the initial search, but only 

randomized trials in humans using clinical or important surrogate outcomes were included in the 

report. Two independent evaluators using a standardized form extracted study data, and quality 

was assessed using the Jadad scale. Both primary and secondary prevention trials were 

evaluated. Meta-analyses were performed whenever groups of studies were judged to be 

sufficiently similar (Appendix F, Evidence Table 3i, Table 7). 

The Shekelle review included 84 eligible trials of the effect of vitamin E on cardiovascular 

outcomes. However, only four of the trials were primary prevention studies, and these were 

deemed to be too heterogeneous (with respect to the type of intervention) to permit meta-analysis 

to be performed. The individual results of these 4 studies (ATBC,116 PPP,117 SCP,118 and 

Linxian119) were presented by the authors in narrative form. With respect to lipid lowering, the 

authors stated that “the 2 large primary prevention trials (ATBC and Linxian) reported clinically 

insignificant (but statistically significant) changes in (lipid) outcomes,” and that “there is no 

evidence that vitamin E alone or in combination has a clinically or statistically significant 

favorable or unfavorable effect on lipids.” In their meta-analyses of all primary and secondary 

prevention trials on the lipid effects of vitamin E compared to placebo, they found effect sizes 

that were not significant for total cholesterol (effect size -0.07, 95% CI -0.31 to 0.08), lowdensity cholesterol (effect size -0.07, 95% CI -0.24 to 0.10), or high-density lipoprotein (effect 

size 0.01, 95% CI -0.21 to 0.22).116 A negative effect size would indicate a favorable effect of 

treatment (Appendix F, Evidence Table 3i, Table 7). 

Cataract and age-related macular degeneration. The evidence concerning vitamin E 

supplements and cataract is compatible with no effect. In the VECAT trial,113 the relative risk of 

cataract in the vitamin E group versus the placebo group was 1.0 for any cataract (95% CI 0.8-

1.4). The relative risk for specific types of cataract were 0.9 for cortical cataract (95% CI 0.5-

1.6), 1.1 for nuclear cataract (95% CI 0.8-1.5), and 0.5 for posterior subcapsular cataract (95% 

CI 0.2-1.1)113 (Appendix F, Evidence Table 3i, Table 7). 
41 

In the ATBC trial, lens opacity was measured at the end of the trial in a random sample of 

1,828 participants.109 The results showed that participants randomized to the α-tocopherol group 

were not different from the non-α-tocopherol group with respect to the risk of having nuclear 

cataract (OR 0.8, 95% CI 0.4-1.4), cortical cataract (OR 0.9, 95% CI 0.6-1.4), or posterior 

subcapsular cataract (OR 0.9, 95% CI 0.4-1.8)109(Appendix F, Evidence Table 3i, Table 7). 

The same approach was used in the ATBC trial to assess the association between αtocopherol and the end-of-trial prevalence of age-related maculopathy.110 The prevalence of agerelated maculopathy was higher among those assigned to receive α-tocopherol supplements than 

in the placebo group (32% versus 25%), showing no evidence of a beneficial affect of αtocopherol110(Appendix F, Evidence Table 3i, Table 7). 

Total mortality. The relative risk for total mortality in the vitamin E supplement users 

compared to non-users was 1.04 (95% CI 0.93-1.16), 1.02 (95% CI 0.95-1.09), and 1.07 (95% 

0.61-1.90) in the WHS, the ATBC, and the PPP, respectively. In the post-intervention follow up 

on mortality (8 years of follow up) of the ATBC trial, the relative risk of total mortality in αtocopherol users compared to non-users was 1.01 (95% CI 0.96-1.05).103 Investigators in the 

WHS reported that “the main causes of death, apart from cardiovascular and cancer deaths, were 

pulmonary diseases (32 vitamin E, 22 placebo) and violent deaths, excluding suicide (9 vs. 6). 

None of these causes of deaths was significantly related to vitamin E.” 87 The relative risk of 

cardiovascular death and cancer death in the WHS was 0.76 (95% CI 0.59-9.98) and 1.12 (95% 

CI 0.95-1.32), respectively.87 The VECAT documented 31 deaths (20 in vitamin E; 11 in 

placebo), and the authors reported “no consistent or unusual patterns were identified among the 

specific causes of death recorded”113 (Appendix F, Evidence Table 3j, Table 7). 

Summary 

Vitamin E supplements have been studied for efficacy in the primary prevention of cancer, 

cardiovascular disease, cataract, and age-related macular degeneration. There was a lack of 

effects of vitamin E supplement use in the prevention of these diseases, except for a 32 percent 

reduction in prostate cancer incidence, a 41 percent reduction in the prostate cancer mortality, 

and a 22 percent reduction in colorectal cancer in the ATBC trial. The findings on hemorrhagic 

stroke were conflicting between the ATBC trial and WHS trial in that the former found a higher 

risk with use of low-dose α-tocopherol supplements but the latter found a lower risk with use of a 

high dose. Taking into consideration the quantity, quality, and consistency of evidence on the 

efficacy of vitamin E in preventing chronic disease, we concluded that the overall strength of 

evidence is "very low" for cancer, "low" for the relationship to cardiovascular disease, 

and "moderate" for cataract (Table 6). 

Folic acid and B vitamins 

Introduction 

The co-prevalence of dementia and low circulating levels of micronutrients among the 

elderly has led to the research interest in vitamin supplementation as a means to prevent 

dementia. In various observational studies, low circulating levels of folate and vitamin B6 have 

been associated with poor cognitive function, dementia, and Alzheimer’s disease120-124 and 

hyperhomocysteinemia.125,126 The essential role of folate and the B vitamins in homocysteine 

metabolism has been used to explain the possible role of these vitamins in dementia. 
42 

Results of literature search

Our search revealed two systematic reviews on single or paired vitamin supplementation with 

B vitamin(s) or folic acid for primary or secondary prevention of dementia and cognitive decline, 

and 4 articles from 1 trial that addressed vitamin B2 and niacin in the prevention of chronic 

disease. The systematic reviews were from the Cochrane Collaboration. The review on folic acid 

with or without vitamin B12 was comprised of 4 randomized controlled trials. The review of 

vitamin B6 was comprised of 2 randomized controlled trials. The trial on vitamin B2 and niacin 

was the Linxian trial. No studies were found to assess the efficacy of single or paired B vitamins 

or folic acid supplementation for prevention of other chronic diseases. 

Design of Systematic Reviews 

Malouf et al. systematically reviewed the literature to “assess the efficacy of vitamin B6 

supplementation in reducing the risk of developing cognitive impairment by older healthy 

people, or improving cognitive functioning of people with cognitive decline and dementia,”127

and to “examine the effects of folic acid supplementation, with or without vitamin B12, on 

elderly healthy and demented people in preventing cognitive impairment or retarding its 

progress.”128 The search strategy, data collection and analysis methods were similar in both 

reviews. Trials were identified from a broad database by a predefined search strategy by the 

Dementia and Cognitive Improvement Group. Outcomes were measured as changes in 

continuous rating scales from baseline where available. When the same rating scales were used 

across trials, the weighted mean difference was presented for pooled trials. A standardized mean 

difference was reported for different rating scales. Weighted estimates for odds ratio were used 

for binary outcomes. When duration varied greatly and the range was considered too great to 

combine, a separate meta-analysis was conducted for smaller time periods. If there was evidence 

of heterogeneity of treatment effect between trials, either only homogeneous results were pooled 

or a random effect model was used. There was no pooled outcome measure presented due to 

heterogeneity of study participants and supplements. 

Study quality

Design and quality of the meta-analyses on folic acid and vitamin B6 were similar. Strengths 

of these systematic reviews include: clarity of review question, description and completeness of 

search strategy, and reproducibility of review. Limitations were due primarily to heterogeneity 

among studies reviewed. The authors presented standardized outcomes of cognition when 

possible. No attempt was made to summarize outcome measures because of the great variation in 

trials included. 

The review on vitamin B6 supplementation 127 reviewed 2 randomized controlled trials for 

primary prevention. 128,129 The authors attempted to minimize heterogeneity of study subjects by 

extracting data on older subjects. Follow up time varied from 5 to 12 weeks. Dosages of B6 

supplementation varied from 20 to 75 mg per day. Among the different trials, there were wide 

disparities in dosages of folic acid (750 mcg to 15 mg) and vitamin B6 (20 to 75 mg). 

The review on folic acid130 reviewed 4 randomized controlled trials for primary and 

secondary prevention.128, 131-133 The authors attempted to minimize heterogeneity of study 

subjects by extracting data on older subjects at the expense of decreasing sample size. Despite 

this, there was considerable heterogeneity in study population. One study for primary prevention 

involved only women.128 The remaining 3 studies131-133 were secondary prevention trials. Dosage 

of folic acid varied widely from 750 mcg to 15 mg per day. Two studies combined vitamin B12 
43 

with the folic acid supplementation and these results were combined together with those 

receiving folic acid alone. 

Results. 

Cognitive decline. Although the meta-analysis by Malouf found improvement in biochemical 

indicators of vitamin B6, no measurable improvement in cognition was found after short-term 

supplementation with vitamin B6. Although folic acid with vitamin B12 was effective in 

reducing serum homocysteine levels, the authors concluded that these limited studies did not 

support folic acid supplementation for prevention of cognitive decline. 

Summary 

There is limited evidence to suggest no benefit of vitamin B6, vitamin B12, or folic acid 

supplementation for primary prevention of cognitive decline. Taking into consideration the 

quantity, quality, and consistency of evidence on the efficacy of folic acid, vitamin B6 and 

vitamin B12 in preventing chronic disease, we concluded that the overall strength of evidence is 

“low” for folic acid with or without vitamin B12 and “moderate” for vitamin B6 (Table 6). 

Vitamin B2 and niacin 

Introduction 

The following section summarizes the evidence on the efficacy of vitamin B2 and niacin 

supplement use in the prevention of chronic disease. 

Results of the literature search 

Our literature search identified 4 eligible articles from the Linxian General Population Trial 

that addressed the efficacy of vitamin B2 (3mg per day) and niacin (vitamin B3, 40 mg per day) 

in preventing cancer, cardiovascular disease or cataract. 64-66, 111 Data on other chronic diseases 

were lacking. 

 Design of randomized controlled trial 

The design of the Linxian trial was described in a previous section of the Results chapter, 

Design of Randomized Controlled Trials, for Key Question 1 (Appendix F, Evidence Tables 3k3o). 

Results.

Cancer, cardiovascular disease and total mortality. In the Linxian trial, combined vitamin 

B2 and niacin had no impact on reducing deaths from stroke,66 mortality,64 or esophageal or 

gastric dysplasia or cancer.111 (Appendix F, Evidence Tables 3k-3o) 

Cataract. A lower prevalence of nuclear cataracts was observed in those who received 

riboflavin and niacin, and there was no difference between randomized groups in cortical 

cataracts.65 However, a 2.64-fold increased prevalence in posterior subcapsular cataract was 

documented for the groups receiving riboflavin 3 mg and niacin 40 mg compared to the groups 

not receiving riboflavin and niacin65 (Appendix F, Evidence Tables 3k-3o). 
44 

Summary 

Data on the efficacy of vitamin B2 and niacin supplement use in the primary prevention of 

chronic disease are sparse and the only study was conducted in a nutritionally deprived Chinese 

population found no benefit of combined vitamin B2 and niacin for primary prevention of 

cancer, cardiovascular mortality, or cataracts. 

Selenium 

Introduction 

Selenium functions as an antioxidant since it is essential to the antioxidant enzyme 

glutathione peroxidase.129 Because selenium is involved in the biosynthesis of testosterone, 

another proposed mechanism involves its role in the endocrine and immune system. 130,131

Selenium has also been theorized to function on the molecular level by changing carcinogen 

metabolism, inhibiting protein synthesis or specific enzymes, and stimulating apoptosis.132 The 

following section summarizes the evidence on the efficacy of selenium supplement use in 

chronic disease prevention. 

Results of literature search 

Our literature search identified 6 articles that provided evidence on the efficacy of selenium 

supplements in the prevention of cancer, cardiovascular disease. These publications were 

generated from 2 different trials, the Nutritional Prevention of Cancer (NPC) trial and another 

study. We included the NPC trial of patients with a history of non-melanoma skin cancer because 

the study reported on the risk of cancer other than non-melanoma skin cancer, and nonmelanoma skin cancer is not a precursor of other cancers. 

Design of randomized controlled trials 

The NPC trial was a double-blind, placebo-controlled multi-center cancer prevention trial in 

1,312 men and women to test the efficacy of selenium supplementation (200 mcg supplied as 

500 mg high-selenium yeast tablets) in reducing chronic disease, specifically cancer.133-135 Trial 

participants had a history of either 2 or more basal cell carcinomas (BCC) or one squamous cell 

carcinoma (SCC) of the skin within the prior year. Prior supplement users were eligible for 

enrollment. The primary outcome of interest was occurrence of a new non-melanotic skin cancer. 

Secondary endpoints included incidence of lung, colorectal, and prostate cancers, total mortality 

and cancer mortality. The total blinded treatment period was from September 1983 until January 

1996. Interim analysis was published in 1996 on data from the full cohort of 1312 participants 

through December. 1993133,134 Analyses at the end of the full, blinded treatment period in 1996 

were published on total cancer outcomes, 136 prostate cancer, 137 and lung cancer.135 Later 

analyses excluded 62 patients who had baseline blood tests more than 4 days after 

randomization.135-137 Interim analysis for prostate cancer was performed on 974 male 

participants, accounting for a 2-year lag effect.134 Re-analysis of prostate cancer data at the end 

of full, blinded treatment was done on 927 participants without a history of prostate cancer 

before randomization, using those individuals with a valid baseline blood draw less than 4 days 

after randomization. 137 By the end of the blinded study in 1996, 35.9 percent of participants 

were on supplementation, 16.6 percent were off supplementation, but continuing follow up, 22.1 

percent were censored for dermatological endpoints but not other endpoints, and 24.8 percent 

had died. We did not include one study with melanotic skin cancer recurrences in the NPC trial 
45 

because it addressed secondary prevention. Full text of the articles on cardiovascular disease and 

colorectal cancer were published after the cutoff date of our review138 Another study by Yu et al. 

was conducted in Qidong County, China and published in 1991.139 (Appendix F, Evidence 

Tables 3k-3o). 

Similarity and heterogeneity among trials 

Participants in the NPC trial were recruited from dermatology clinics and had non-melanotic 

skin cancer without recent treatment for internal malignancy. Participants in the study by Yu etal. 

were selected to be at high risk for liver cancer because of a family history of cancer in addition 

to living in an area of China that has high rates of liver cancer. Both studies used 200 mcg per 

day of selenium as a yeast tablet. 

Study quality 

In the NPC Study, the study population, inclusion and exclusion criteria, flow of patients, 

outcome reporting and statistical analyses were well described. Well designed aspects of the 

study included: random assignment of patients, placebo control, confirmation of outcomes, 

efforts at blinding, assessment of adherence, appropriate handling of losses to follow up, 

reporting of statistical analyses, and intention-to-treat analysis. However, there was inadequate 

information reported regarding excluded patients, prior supplement use, prior and concurrent 

medication use, success of blinding, independent ascertainment of outcomes, unintended crossover rates, description of supplements, and statistical power.133 The study was initially designed 

to look at incidence of non-melanoma skin cancer, and other cancer endpoints were designated 

secondary outcomes 7 years after commencement of the trial. 

The study by Yu et al. had inadequate data reporting on almost all aspects of the study with 

the exception of a fair description of supplements and assessment of adherence to supplements 

by biomarkers (Table 3). 

Results. 

Cancer. Initial interim analysis of the NPC trial through 1993 found that the selenium group 

had a significantly lower total cancer mortality (RR 0.5, 95% CI 0.31-0.8), total cancer incidence 

(RR 0.63, 95% CI 0.47-0.85), and significantly lower incidence of lung, colorectal, and prostate 

cancers (RR 0.56, 95% CI 0.31-1.01; RR 0.39, 95% CI 0.17-0.90; RR 0.35, 95% CI 0.18-0.65, 

respectively).133 Cancer endpoints from the full trial period through 1996 were analyzed and had 

a mean follow up of 7.9 years. Selenium continued to reduce the risk of all cancers (HR 0.75, 

95% CI 0.58-0.97) and prostate cancer (HR 0.51, 95% CI 0.29-0.87), lung cancer (HR 0.70, 95% 

CI 0.40-1.21) and colorectal cancer (HR 0.46, 95% CI 0.21-1.02), although the findings on lung 

cancer and colorectal cancer were not statistically significant.135,137

An interim reanalysis of 843 male patients with prostate specific antigen levels less than 4 

ng/ml, taking into account a 2-year treatment lag, found that the selenium group had a significant 

reduction in prostate cancer (RR 0.37, p-value 0.002).134 Subgroup analyses showed that the 

effect of selenium on prostate cancer was greatest in those with a baseline prostate specific 

antigen level less than 4 ng/ml (RR 0.35, 95% CI 0.13-0.87)137 (Appendix F, Evidence Tables 

3k-3o). 

In the 2-year intervention trial with selenized yeast by Yu et al., the incidence of primary 

liver cancer was significantly less (p<0.05) in selenium supplemented subjects (10 of 1444; 
46 

0.69%) compared to control subjects (13 of 1030; 1.26%)139 (Appendix F, Evidence Tables 3k3o) (Appendix F, Evidence Tables 3k-3o). 

Cardiovascular disease. Only the NPC study reported cardiovascular outcomes in the context 

of selenium supplementation, and there was no effect on cardiovascular disease (HR 1.03, 95% 

CI 0.78-1.37), stroke (HR 1.02, 95% CI 0.63-1.65), or cardiovascular mortality (HR 1.22, 95% 

CI 0.76-1.95) for primary prevention in those without prior cardiovascular disease.133, 140

(Appendix F, Evidence Tables 3k-3o). 

Total mortality. Total mortality in the NPC study was reduced by 21 percent in the group 

receiving selenium (HR 0.79, 95% CI 0.61-1.02) as compared to placebo133 (Appendix F, 

Evidence Tables 3o). 

Summary 

Evidence on the role of selenium in cancer prevention is limited, but suggests some benefit in 

prevention of total and prostate cancer, with the greatest benefit in men with a normal baseline 

prostate specific antigen level. Selenium did not significantly reduce the risk of lung or 

colorectal cancer. The only well-designed randomized controlled study supporting selenium 

supplementation for cancer prevention was done in a population with non-melanotic skin cancer. 

Taking into consideration the quantity, quality, and consistency of evidence on the 

efficacy of selenium in preventing chronic disease, we concluded that the overall strength of 

evidence is "moderate" (Table 6). 

Calcium and vitamin D 

Introduction 

Supplementation with calcium, vitamin D, or both has been recommended for primary 

prevention of osteoporosis. Physiologically, calcium supplementation corrects for suboptimal 

intake or decreased intestinal absorption of calcium. Left uncorrected, secondary 

hyperparathyroidism develops, leading to accelerated bone resorption and ultimately to increased 

risk for fractures. Supplemental vitamin D optimizes intestinal calcium absorption, and it also 

improves neuromuscular function and reduces the recurrences of fractures. 151 

 Improvement in bone mineral density (BMD) is a marker for stronger bones and is 

predictive of fracture reduction.150 However, fracture is the major clinical outcome of 

osteoporosis. 

Due to the substantial amount of efficacy data on calcium/vitamin D and osteoporosis, we 

reviewed systematic review articles supplemented with data from recent randomized controlled 

trials. We also used data from randomized controlled trials meeting our inclusion criteria, that 

were not included in previous systematic reviews. 

Results of literature search

Our search for evidence that supplemental calcium and/or vitamin D prevents 

osteoporosis/fractures/falls revealed 7 articles from 6 recent systematic reviews, authored by 

Shea et al.,47,50 Mackerras and Lumley,52 Papadimitropoulos et al.,49 Avenell et al.,143 and 

Bischoff-Ferrari et al.144,145 Two articles on osteoporosis and colorectal cancer from the 

Women’s Health Initiative study (WHI)146 were released as we prepared this report. We also 

identified three small relevant randomized controlled trials 147-149 that were not included in 

previous systematic reviews. Using our search strategies, we identified no additional randomized 
47 

controlled trials for the efficacy of calcium with or without vitamin D supplement use in the 

primary prevention of other chronic diseases. In 2005, AHRQ awarded a contract to the 

University of Ottawa’s EPC to conduct a systematic review of the efficacy of vitamin D on bone 

density and fracture risk, but that review was not available in time for inclusion in the evidence 

report. 

All of this literature met our criteria for calcium and vitamin D formulations and doses. For 

calcium, the doses were less than 2.5 grams per day, the adult UL recommended by the Food and 

Nutrition Board (Appendix F, Evidence Tables 3p-3r). With regard to vitamin D, our interest 

was in over-the-counter supplements, but some systematic reviews included studies using 

formulations available only by prescription. Therefore, in summarizing these previous reviews, 

we extracted the relevant data reported for non-prescription vitamin D3 (cholecalciferol) and 

vitamin D2 (ergocalciferol) used in doses not exceeding the UL, 2000 IU per day (Appendix F, 

Evidence Tables 3p-3r). 

Calcium 

Design of systematic reviews. Three articles from 2 systematic reviews 47,50,52 examined the 

efficacy of calcium on BMD. Two of the reviews 47,50 by Shea etal. presented identical data, so 

only the more recent article 47 was used. Shea etal. analyzed randomized controlled trials 

published from 1978 to 1998 investigating skeletal effects of calcium supplementation in postmenopausal women. The randomized controlled trials addressed fractures in 5 trials (n = 638) 

and BMD in 15 trials (n=1826) of 1 to 4 years duration in women whose mean age ranged from 

46 to 72 years. The Mackerras review 52 evaluated 8 randomized controlled trials from 1987 to 

1995. However, Mackerras etal. had a different focus, concentrating on year-by-year BMD 

changes in a younger group of postmenopausal women (n = 1386, mean age 51 to 66 years) 

(Appendix F, Evidence Tables 3p and 3q). 

Quality of reviews. The strengths of the Shea review were: attention to methodologic detail 

(e.g., contacting authors for details of randomization and blinding) and assessment of 

heterogeneity of BMD results across studies with various subgroup analyses (e.g., losses to 

follow up, time after menopause). A major limitation of the Shea review (and also that of 

Mackerras whose papers were all included in the Shea review) was that conclusions were 

compromised by problems inherent in the original studies. These problems included small 

sample size, large losses to follow up, and significant heterogeneity of study populations and 

interventions (e.g., the variable use of vitamin D in addition to calcium in treated and control 

subjects) (Appendix F, Evidence Tables 3p and 3q). 

Strengths of the Mackerras review were: strict attention to precision and quality control 

issues involving bone density measurements that are often overlooked (e.g., excluded a study 

that changed densitometers mid-study); rigorous analysis of BMD data (e.g., did not pool 

measurements from different anatomical sites and measured BMD change year by year rather 

than averaging total change over the treatment period); and subgroup analyses to evaluate effects 

of calcium on bone density independent of other potential effectors, especially vitamin D and 

exercise. An important weakness of the Mackerras review, in addition to those mentioned above, 

was lack of discrimination against poorly randomized trials. Mackerras etal. did not contact 

investigators for missing information. 

Design of randomized controlled trials. The WHI published 2 articles comparing the effect of 

calcium and vitamin D with placebo for primary prevention of fractures 146 and colorectal cancer 
48 

152 in healthy postmenopausal women. A subgroup of 2431 women had BMD measured at 

annual visits 3, 6, and 9. 

Storm et al.149 compared the effect of calcium supplementation versus dietary calcium intake 

or placebo on seasonal (i.e. winter) bone loss in healthy, older postmenopausal women (n = 60, 

age greater than 65 years). 

Meier et al.147 compared the effect of calcium and vitamin D versus no treatment on seasonal 

bone loss in healthy, German, community dwellers (Appendix F, Evidence Tables 3s and 3t). 

Similarity and heterogeneity among randomized controlled trials. The WHI studies 146,152

selected participants from multiple United States cities. WHI studies allowed personal calcium 

and vitamin D supplementation up to 1000 mg and 600 IU daily respectively and thus had a 

baseline average daily intake of 1150 mg calcium and 365 IU vitamin D as assessed by a food 

frequency questionnaire. Meier 147 did not allow prior or personal use of calcium or vitamin D 

supplements, but did not assess baseline calcium or vitamin D intake at baseline. Storm limited 

calcium intake to less than 800 mg per day as measured by food frequency questionnaire and 

thus had an average baseline calcium intake of 684 mg per day (Appendix F, Evidence Tables 3s 

and 3t). 

Quality of randomized controlled trials. Strengths of the WHI study included: double 

blinded, placebo-controlled study, large sample size, rigorous quality control, reporting of 

baseline characteristics, clearly documented protocol, appropriate analytic methods, few losses to 

follow-up, long follow-up, and central adjudication of outcomes. Weaknesses of the study 

included: possible inadequate ascertainment of all outcomes, lack of adherence to treatment 

regimen, high baseline intake of calcium and vitamin D (though diet and supplement use), and 

inadequate power, all of which may bias this study to the null. 

Strengths of the Storm study149 were the administration of calcium alone without vitamin D, 

double blinding with placebo and treatment group, description of baseline calcium intake, 

description and number of withdrawals, quality control and outcome ascertainment and 

measurement of serum 25-hydroxyvitamin D levels during the study period. Weaknesses 

included small sample size, poor description of adherence assessment, and clarity and 

appropriateness of statistical analyses. 

Strengths of the Meier study147 included randomization with description of baseline 

equivalence of groups. Weaknesses of this study include: lack of placebo-control and double 

blinding, unclear description of inclusion and exclusion criteria, no description of adherence, 

high rate of withdrawals, short supplementation time, and heterogeneity of a relatively small 

sample size of participants. 

Results 

Calcium and bone density. Both Shea et al. and Mackerras et al. reported a small positive 

effect of calcium in preventing bone loss. Shea et al., who averaged BMD changes across the 

entire treatment period, concluded that BMD at four different sites was consistently 1.5 to 2.0 

percent higher after two years of treatment. In a more rigorous analysis of BMD data, Mackerras 

et al. found that calcium’s effects occurred mainly in the first year. They concluded that BMD 

losses actually occurred in both treated and control groups, but that losses were relatively greater 

in controls (0.5-2.8% from baseline at 10 different sites) than in treated groups (with 

corresponding losses of only 0.1-1.1%). 

The WHI146 found significant cumulative dose-responsive difference in total hip BMD 

between patients treated with 1000 mg calcium and 400 IU vitamin D and placebo-treated 

patients, but no significant difference in spine BMD. 
49 

Storm et al. found that supplemental calcium alone (1000 mg per day) prevented seasonal 

bone loss of the greater trochanter (associated with a 25% decrease in serum 25-hydroxyvitamin 

D levels) and significantly increased BMD of the femoral neck by 3 percent from baseline. In 

contrast, seasonal bone loss occurred in placebo-treated women who had a 3 percent loss of 

BMD in the greater trochanter and 0.3 percent loss in the femoral neck after 2 years. Dietary 

calcium treated subjects (average 1000 mg per day) had a 1.5 percent loss in greater trochanter 

BMD and 1.8 percent loss in the femoral neck BMD. (Appendix F, Evidence Table 3r). 

Meier et al. found that 500 mg calcium and 500 IU vitamin D supplementation significantly 

increased lumbar (+0.8%, p=.04) and femoral BMD (+0.1%, p=.05) compared to the previous 

year without any supplementation, which was significantly different (p=.03 for lumbar spine, and 

p=.05 for femoral bone) from the control group, which had a decrease in lumbar and femoral 

BMD147 (Appendix F, Evidence Table 3u). 

Calcium and fractures. Shea et al. found in calcium-treated individuals, a trend toward 

reduction of vertebral fractures (RR 0.79, 95% CI 0.55-1.13). There was no significant effect of 

calcium on non-vertebral fractures. Fracture results were consistent across studies but the 

strength of the conclusion was limited by the small study populations and short follow up periods 

(Appendix F, Evidence Table 3r). 

Intention-to-treat analysis of the WHI study 146 found that calcium plus vitamin D 

supplementation did not significantly decrease the incidence of hip fracture (HR 0.88, 95% CI 

0.72-1.08), clinical spine fracture (HR 0.90, 95% CI 0.74-1.10) or total fractures (HR 0.96, 95% 

CI 0.91-1.02) (Appendix F, Evidence Table 3u). 

Calcium and colorectal cancer. A secondary outcome of the WHI trial was colorectal cancer. 

152 Intention to treat analysis found that calcium plus vitamin D supplementation did not 

significantly decrease the incidence of invasive colon cancer (HR 1.08, 95% CI 0.86-1.34). 

 Summary. The studies showed a consistent small effect of calcium on prevention of BMD 

loss (approximately 2%) over a period of 2 or more years in postmenopausal women. The effects 

occurred mainly in the first year. Calcium supplementation prevented the seasonal bone loss 

associated with wintertime drops in vitamin D levels. Based on very limited data, Shea also 

raised the possibility that calcium may reduce vertebral, but not non-vertebral, fractures. 

(Appendix F, Evidence Tables 3r and 3u). 

Vitamin D 

Four articles from 3 systematic reviews, 49, 143-145 and one article from the WHI 146 addressed 

the effect of vitamin D on fractures. Vitamin D effects on BMD were also assessed in one of 

these reviews, by Papadimitropoulos et al.,49 as well as in the WHI study and 2 small randomized 

controlled trials.147,148

Design of Systematic reviews. The most comprehensive of the systematic reviews, the 

Avenell study, 143 investigated the effects of vitamin D with or without calcium on fractures. 

Avenell et al. analyzed 38 randomized controlled trials; 12 of these (from 1983-2005) are 

pertinent to our review because they involved treatment with vitamin D3, 400-800 IU per day, in 

about 35,000 men and women, age 65 or more. Included among the 12 trials is the large 

Porthouse primary prevention trial (n=3454 women)150which employed a treatment regimen of 

vitamin D3 (800 IU/day) and calcium (1000 mg/day). The other 26 trials were not considered in 

this review because they used active hydroxylated metabolites of vitamin D (Appendix F, 

Evidence Tables 3p and 3q). 
50 

 Of the two systematic reviews by Bischoff-Ferrari et al., the first 145 explored anti-fracture 

efficacy of vitamin D with or without calcium in older persons (8 trials, n = 9820, mean age 75 

to 85 years), whereas the second 144 tested the effects of vitamin D3 on fall prevention in a similar 

but smaller population (3 trials, n = 613). 

 The Papadimitropoulos review, limited to older postmenopausal women (mean age 72 to 84 

years), evaluated 25 randomized controlled trials, 10 of which we included in our review because 

they employed vitamin D3 in doses of 300-2000 IU/day. Of the 10 trials, 6 measured BMD 

changes (n = 956), and 4 evaluated fracture prevention (n = 5780) (Appendix F, Evidence Tables 

3p and 3q). 

Quality of Reviews. The strengths of the Avenell et al. review included its large size and 

comprehensive nature that allowed independent assessment of the anti-fracture effects of vitamin 

D and calcium, administered separately and in combination. Also important were assessments of 

methodological quality for each reviewed trial (revealing a range of quality from poor to 

satisfactory). A weakness of the Avenell et al. study was lack of information on dropouts from 

both treatment and control arms of some studies, possibly causing inaccurate estimates of 

outcome events by the intention to treat analysis. Similar to Avenell et al., a strength of the 

Papadimitropoulos review was the assessment of methodologic quality of each eligible study. In 

addition, a priori hypotheses concerning study design, population, intervention, and 

methodologic quality were developed in an attempt to identify reasons for differences in results 

across studies. Nevertheless, both the Avenell and Papadimitropoulos reviews suffered from 

marked heterogeneity across the included studies. 

A strength of the Bischoff-Ferrari fracture prevention review 145 was the consistency of 

treatment across studies with regard to vitamin D3 doses, but a problem was that calcium was 

also used with some patients, possibly obscuring the effects of vitamin D alone. Other problems 

were the small number of trials analyzed and the absence of specific large relevant studies.150,151

Similar issues of scope and variability in treatment regimens apply to Bischoff-Ferrari’s review 

on fall prevention (Appendix F, Evidence Tables 3p and 3q). 144 

Design of randomized controlled trials. The WHI study assessed the efficacy of vitamin D3

(400 IU/day) with calcium (1000 mg/day) for primary prevention of fractures in healthy 

postmenopausal women (n = 36,282, mean age 63 years).146 BMD was followed at annual visits 

3, 6, and 9 in a subgroup (n = 2431) (Appendix F, evidence tables 3s-3u). 

Meier etal. (519) compared the effect of supplemental vitamin D3 (500 IU/day) plus calcium 

(500 mg/day) with no treatment for prevention of wintertime BMD losses in health German men 

and women (n=55, age range 34-75 years). 

Hunter etal. 148 compared the effect of vitamin D (800 IU cholecalciferol/day) with placebo 

in a twin-control on change in BMD in healthy postmenopausal women living in the United 

Kingdom over 2 years (Appendix F, Evidence Tables 3s and 3t). 

Similarity and heterogeneity among randomized controlled trials. Most studies included 

primarily postmenopausal women. Only Meier et al.147 included men in addition to 

postmenopausal women. There was wide variation in baseline calcium and vitamin D intake and 

exposure. The WHI studies 152,146 selected participants from multiple United States cities. Two 

studies were conducted in areas of northern latitude, Germany,147 and the United Kingdom, with 

presumably less sunlight exposure. WHI studies allowed personal calcium and vitamin D 

supplementation up to 1000 mg and 600 IU daily respectively and thus had a baseline average 

daily intake of 1150 mg calcium and 365 IU vitamin D as assessed by a food frequency 

questionnaire. Hunter 148 did not allow vitamin D or calcium supplementation, but participants 
51 

had daily baseline calcium and vitamin D intakes of 1050 mg and 135 IU respectively. Meier et 

al. 147 did not allow prior or personal use of calcium or vitamin D supplements, but did not assess 

baseline calcium or vitamin D intake at baseline. Treatment intervention regimens also varied 

among the different studies. Three studies used both calcium and vitamin D.146,147,152 One study 

used only vitamin D.148 Vitamin D formulation was cholecalciferol146,147,152 with dosage ranging 

from 400 to 500 IU daily (Appendix F, Evidence Tables 3s and 3t). 

Quality of randomized controlled trials. Strengths of the WHI study included: double 

blinded, placebo-controlled study, large sample size, rigorous quality control, reporting of 

baseline characteristics, clearly documented protocol, appropriate analytic methods, few losses to 

follow-up, long follow-up, and central adjudication of outcomes. Weaknesses of the study 

included: possible inadequate ascertainment of all outcomes, lack of adherence to treatment 

regimen, high baseline intake of calcium and vitamin D (though diet and supplement use), and 

inadequate power, all of which may bias this study to the null. 

Strengths of the Meier study 147 include randomization with description of baseline 

equivalence of groups. Weaknesses of this study include: lack of placebo-control and double 

blinding, unclear description of inclusion and exclusion criteria, no description of adherence, 

high rate of withdrawals, short supplementation time, and heterogeneity of a relatively small 

sample size of participants. 

Hunter et al. 148 described inclusion/exclusion criteria, flow of patients, and baseline 

equivalence of patients well. Other strengths of the study included double blinding, placebocontrol, and assessment of adherence. Small size of the study, nearly 20 percent withdrawal rate, 

and high baseline intake of calcium and vitamin D may have limited the power of the study. 

Results. 

Bone mineral density. The Papadimitropoulos review also analyzed BMD effects of vitamin 

D. Treatment with vitamin D3 between 300 and 2000 IU/day caused only marginal positive 

effects of the vitamin D and calcium intervention (increases by about 1% in the femoral neck in 

year 5 and in the lumbar spine in year 1). 

The WHI146, found a mean difference in total hip BMD of 0.59 percent (p<.001) at 3 years, 

0.86 percent (p<.001) at 6 years, and 1.06 percent (p=.01) at 9 years between those treated with 

calcium and vitamin D and placebo group. There was no significant difference in BMD in the 

spine. 

Hunter et al.148 did not find any significant difference in spine or hip BMD between those 

treated with vitamin D alone and control. 

Meier et al.147 found calcium and vitamin D supplementation significantly increased lumbar 

BMD (+0.8%, p=.04) and femoral BMD (+0.1%, p=.05) compared to the previous year without 

any supplementation, which was significantly different (p=0.03 for lumbar spine, and p=0.05 for 

femoral bone) from the control group that had a decrease in lumbar and femoral BMD 

(Appendix F, Evidence Tables 3r and 3u) 

Fractures. The review by Avenell et al. included data from primary prevention trials as well 

as secondary prevention trials. They reported that vitamin D alone did not prevent hip, vertebral, 

or any non-vertebral fractures, and that vitamin D (700-800 IU per day) plus calcium (1000 

mg/day) reduced hip fractures (RR 0.81, 95% CI 0.68-0.96) and non-vertebral fractures (RR 

0.87, 95% CI 0.78-0.97), but the combination was no more effective than calcium alone. There 

was no effect on vertebral fractures. Subgroup analysis indicated that the effects on hip and nonvetabral fracture were primarily reported from studies of the incidence of fracture (3 trials, 

n=4242; RR 0.75, 95% CI 0.62-0.91 for hip fracture; RR 0.83, 95% CI 0.72-0.95 for non-
52 

vertabral fracture), but not recurrence of fracture (4 trials, n=6134; RR 1.02, 95% CI 0.71-1.47 

for hip fracture; RR 0.93, 95% CI 0.79-1.10 for non-vertebral fracture). Another subgroup 

analysis showed that the effects on hip fracture were primarily reported from studies in 

institutionalized groups (2 trials, n=3853, RR 0.75, 95% CI 0.62-0.92), but not in communitydwelling groups (5 trials, n=6523, RR 1.01, 95% CI 0.70-1.44), whereas the effects on nonvertabral fracture were similar between the two types of populations (RR 0.85 and 0.89, 

respectively). Baseline mean serum 25-OH vitamin D levels (measured in 9 of the studies) were 

generally quite low (≤ 15 ng/mL), but levels after vitamin D supplementation were not available. 

In the Papadimitropoulos review, fracture results were similar to those of Avenell et al. 

Comparable treatment regimens of vitamin D3 and calcium were associated with a nonsignificant trend in reduction of non-vertebral fractures (RR 0.78, 95% CI 0.55 – 1.09). 

(Appendix F, Evidence Table 3r). 

In contrast, both of the reviews by Bischoff-Ferrari et al. showed definitive positive effects of 

vitamin D3, with or without calcium, on fracture reduction and prevention of falls. Analysis of all 

the fracture results revealed heterogeneity that was resolved by pooling studies into separate 

high-dose (700-800 IU/day) and low dose (≤ 400 IU/day) subgroups. Studies using the high-dose 

regimen showed reductions in the pooled relative risk of hip fracture (RR 0.74, 95% CI 0.61-

0.88) and of non-vertebral fracture of (RR 0.83, 95% CI 0.70-0.98). In a similar analysis of the 

effect of vitamin D on falls, supplementation with 800 IU/day with or without calcium had a 

pooled odds ratio for prevention of falls of 0.78 (95% CI 0.64-0.92) (Appendix F, Evidence 

Table 3r). 

Incidence of fractures was the primary outcome of interest in the WHI study.146, Intention-totreat analysis found that calcium plus vitamin D supplementation did not significantly decrease 

the incidence of hip fracture (HR 0.88, 95% CI 0.72-1.08), clinical spine fracture (HR 0.90, 95% 

CI 0.74-1.10) and total fractures (HR 0.96, 95% CI 0.91-1.02) in the total trial participants. A 

subgroup analysis of women who took at least 80 percent of study medication showed a 

significant risk reduction in hip fracture (HR 0.71, 95% CI 0.52-0.97) (Appendix F, Evidence 

Table 3u). 

Colorectal Cancer. A secondary outcome of the WHI trial was colorectal cancer.152 Intention 

to treat analysis found that calcium plus vitamin D supplementation did not significantly 

decrease the incidence of invasive colorectal cancer (HR 1.08, 95% CI 0.86-1.34) (Appendix F, 

Evidence Table 3u).

Summary. The majority of published literature on calcium and vitamin D are studies in 

postmenopausal women. Review of this evidence supports improvement in BMD with calcium 

with or without vitamin D supplementation for postmenopausal women. The evidence 

also indicates that calcium supplementation was associated with a non-significant trend toward 

decreasing the risk of vertebral fractures. The greatest benefit of calcium supplementation was 

found to occur in the first year of use. There is a paucity of data on the effect of vitamin D alone 

on BMD. Vitamin D combined with calcium prevented hip fracture and non-vertebral fracture 

with the greatest benefit seen in populations with a low baseline intake of calcium and/or vitamin 

D. A high dose of vitamin D (700-800 IU per day) with or without calcium prevented hip 

fracture, non-vertebral fracture and falls. Taking into consideration the quantity, quality, and 

consistency of evidence on the efficacy of vitamin D and calcium, we concluded that the overall 

strength of evidence is “low" for calcium to prevent loss in BMD, vitamin D to prevent loss in 

BMD, and for vitamin D to prevent fractures, "very low" for calcium to prevent fractures, and 
53 

"high" for combined calcium and vitamin D to prevent BMD loss, hip fracture or non-vertebral 

fracture (Table 6). 

Key Question 4 

What is Known about the Safety of Use of the Following Single Nutrients in the General 

Population of Adults and Children, Based Primarily on Data From Randomized Controlled 

Trials and Observational Studies? 

Calcium and vitamin D 

In a recent Cochrane review,48 it was concluded that studies are too different (exposure time, 

doses, etc) to draw general conclusions regarding the safety of calcium supplements. A case 

report of nephropathy with calcified lesions in a patient consuming 1g/day of calcium lactate 

appears to be the result of the combined use of high dose ascorbic acid (6,000mg/day) plus 

laxatives that led to chronic hypokalemia.79

 The calcium-vitamin D arm of the WHI study 146 administered 1g of calcium carbonate and 

400 IU of vitamin D daily to 18,000 postmenopausal women for 7 years. The study reported an 

increased risk for kidney stones in the active group (HR 1.17). No other significant differences 

among the study groups were observed, including gastrointestinal symptoms. 

 Long-term consumption of 1g or more per day of calcium may increase risk of kidney stones. 

It is not clear whether this finding can be generalized to premenopausal women or to men. 

Vitamin A 

Randomized controlled trials 

A number of studies compared retinol or β-carotene supplementation with placebo. 

The CARET trial in smokers 93 administered 25,000 IU per day of vitamin A and 30 mg per day 

of beta-carotene for 5 years, and reported no adverse effects other than yellowing of the skin in 

0.3 percent of people in the active group. In this study,153 the active group also exhibited a 

modest but significant rise in serum triglycerides. This increase remained stable after the first 

year of follow up, i.e., it was non-progressive (Appendix F, Evidence Tables 4a-4d). 

Another study in healthy adults aged 18-54 years77 compared the effects of 15,000 IU per day 

of vitamin A (4500 RE) with a group receiving only 75 IU per day, for 5 years. The only relevant 

finding was an increase in serum triglycerides in the high-dose group, from 1.0 at baseline to 

1.30 at year 3 and 1.18 at year 5. There was no effect on liver enzymes, and no increase above 

defined maximal plasma retinol levels (3.49 μmol/L) (Appendix F, Evidence Tables 4a-4d). 

Observational studies 

 The possibility that high intakes of retinol increase the risk of hip fractures, particularly in 

postmenopausal women, has been raised by one observational study that tracked 35 77-year-old 

women for 18 years. 154 This study reported an increased risk of hip fractures in persons at the 

higher quartile of total retinol intake. However, there was no significant difference in fracture 

risk between users and non-users of multivitamin or vitamin A supplements. These provided 

around 25 percent of the total daily retinol intake, or around 400-500μg RE/day. There was no 
54 

association between hip fractures and β-carotene intake, either total, from foods, or from 

supplements. 

 Another, 9-year observational study in 34,000 postmenopausal women found no significant 

correlation between food or supplemental retinol intake and hip or all-type fractures.155

Cross-sectional studies 

 A cross-sectional study in 178 Swedish women156 reported a significant negative correlation 

between dietary retinol intake and BMD. The authors attributed this finding to the very high 

retinol intake in Nordic countries, associated with the common use of cod liver oil and the 

fortification of milk with vitamin A. The potential contribution of vitamin supplements was not 

reported in this study. Another more recent cross-sectional assessment of 11,000 women enrolled 

in the WHI cohort 157 found no correlation between diet-only or total retinol intake and BMD. 

Blood retinol levels, measured in a subsample, were not correlated with BMD either. Similarly, 

an analysis of data from the NHANES III survey found no correlation between serum retinyl 

ester concentrations and BMD.158 

 In terms of the possible effects of total daily vitamin intake, a conservative interpretation of 

the limited human data may be warranted, because of the biological plausibility of a negative 

effect of excess vitamin A on bone. However, the data specifically linking vitamin A 

supplements or multivitamins containing retinol to fracture risk are very limited and insufficient 

to draw a definitive conclusion at this time. 

Vitamin E 

 The VECAT study administered 500 IU of vitamin E per day to 1200 volunteers (50-88 years 

of age) for 4 years. 113 No difference in adverse events or mortality was identified between active 

and placebo groups. 

Another study administered vitamin E to healthy adults, but is not discussed here because of 

its low sample size (n=42 total, divided in 4 arms), short follow up (6 weeks), and lack of 

outcome data relevant to this report. 

In the WHS,87 participants received 600 IU of vitamin E every other day. No excess adverse 

effects were identified in the active group, except for marginally significant increased epistaxis. 

Authors attributed this to a chance finding, since there was no other evidence of an adverse effect 

on bleeding (coagulation time, hemorrhage, hemorrhagic stroke, etc). The PPP study112

administered 300 mg/d for 3.6 years, to people more than 65 yrs of age. Only bleeding and 

mortality were monitored, and no significant differences in these outcomes were found between 

active and control groups (Appendix F, Evidence Tables 4e-4g). 

β-carotene 

 The beta-carotene arm of the WHI study 96 administered 50 mg/day of beta-carotene to about 

20,000 women for 2 years. The only adverse effect associated with treatment was yellowing of 

the skin. 

 Another randomized controlled trial 84 followed about 400 adults for 4 years, administering 

30 mg/day of beta-carotene or placebo. This study did not report specific events associated with 

the beta-carotene arm, but the number of withdrawals associated with self-reported adverse 

effects of the supplement was 65 in the active group and 64 in the placebo group. 
55 

The PHS administered 50 mg of beta-carotene on alternate days to about 11,000 participants 

for almost 12 years. The only significant adverse effects reported were yellowing of the skin 

(1700 in active vs. 1500 in placebo) and minor gastrointestinal symptoms, such as belching (275 

in active vs. 124 in placebo) (Appendix F, Evidence Tables 4a-4d). 

 

Selenium 

 One randomized controlled trial administered 200 μg/day of selenium for 4.5 years to 1300 

patients with a history of skin cancer. 133 More participants complained of gastrointestinal 

symptoms in the active group than in the placebo group (21 vs. 14). There were no differences in 

plasma selenium levels between those reporting symptoms and those who did not (Appendix F, 

Evidence Tables 4h-4j). 

Iron 

 The possible adverse effect of iron supplementation in healthy children is an issue receiving 

intense scrutiny at this time. An early report from a small randomized trial in 40 iron-sufficient, 

non-anemic children showed a significant reduction in weight gain over 4 months in 

supplemented (3mg/kg/day) children compared to placebo 159. More recent trials have not fully 

clarified this issue, because they targeted deficient populations and/or included other 

micronutrients in the intervention formulation (Appendix F, Evidence Tables 4h-4j). 
56 
57 

Chapter 4. Discussion 

The biological effects of vitamins and minerals have sparked enormous scientific enthusiasm 

in examining their potential as agents for preventing a variety of chronic diseases and conditions. 

Over the past four decades, there have been more than 355,000 peer-reviewed articles addressing 

one or more of the nutrients that often are included in multivitamin/mineral supplements. The 

evidence accumulated to date primarily concerns vitamin/mineral supplement use in relation to 

the prevention of cancer, cardiovascular disease, and bone health, and less frequently, eye 

disease and cognitive function. In this context, the nutrients that have been studied the most 

include multivitamins, β-carotene, vitamin E, folic acid/vitamin B6/vitamin B12, calcium, 

vitamin D, and to a lesser extent, selenium. 

In 2003, the United States Preventive Services Task Force released a report concluding that 

the evidence is insufficient to recommend for or against the use of supplements of vitamins A, C, 

or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cancer or 

cardiovascular disease. The Task Force also concluded that β-carotene supplementation provides 

no benefit in the prevention of cancer or cardiovascular disease in middle-aged and older 

adults.160 In addition to providing an update on the available evidence, this evidence report goes 

beyond the scope of the United States Preventive Services Task Force review to have included 

systematic reviews and original studies on the efficacy of multivitamin/mineral supplement use 

in the prevention of chronic diseases and conditions, in addition to cancer and cardiovascular 

disease, in the general adult population, and on the safety of multivitamin/mineral supplements, 

vitamin A, vitamin D with or without calcium, vitamin E, folic acid, β-carotene, selenium, and 

iron supplementation in the general population of adults and children. 

Summary of the Key Findings 

Results from this systematic review indicate a relative paucity of data that specifically 

address the efficacy of multivitamin/mineral supplement use in the prevention of chronic disease 

in the general population of the United States. The data were on the efficacy of designed 

combinations of vitamins and minerals; none of the trials used the one-a-day multivitamins (of 

approximately 100% of the RDAs) prevailing on the market. The Linxian trial suggests that 

supplementation with combined β-carotene, vitamin E and selenium supplements at doses 1 to 2 

times the RDA for 5 years had 13 percent to 21 percent reductions in gastric cancer incidence, 

gastric cancer mortality, and total cancer mortality in a nutritionally deprived Chinese 

population. The reduction in cancer mortality was stronger in women than in men, and in persons 

of age 55 or younger. There were no significant effects on total cancer incidence and 

cerebrovascular mortality. The SU.VI.MAX study in a French population documented a 31 

percent reduction in overall cancer risk by use of 5 antioxidants (vitamin C, vitamin E, βcarotene, selenium, and zinc) for 8 years in men but not in women, and a 12 percent reduction in 

prostate cancer risk, particularly a 48 percent risk reduction in those with normal prostate 

specific antigen levels at baseline. There was no significant effect of the combined antioxidants 

on ischemic cardiovascular disease incidence. In this trial, men had lower serum levels of 

vitamin C and β-carotene than women at baseline. Multivitamin/mineral supplement use for 3 to 

6 years had no significant benefits in preventing cataract in 3 trials in the United States (with one 

trial also in United Kindom) and the Linxian trial. High-dose zinc combined with antioxidants 

had beneficial effects on age-related macular degeneration only in those with intermediate age-
58 

related macular degeneration in one or both eyes, or those with advanced age-related macular 

degeneration in one eye. 

 Overall, total mortality data pointed to either no increased risk or lower risk in the groups 

with multivitamin/mineral supplement use. Total mortality was 9 percent lower among those 

who received β-carotene, selenium, and vitamin E in the Linxian trial; there was no sex- or agedifference in the relative risks. In the AREDS study, total mortality was 6 percent higher in the 

group receiving antioxidants compared to the group receiving no antioxidants, but the increase 

was not statistically significant. Among the participants at high risk for age-related macular 

degeneration, total mortality was 13 percent to 20 percent lower in the groups receiving zinc 

alone or zinc combined with antioxidants.64,75 In the SU.VI.MAX study, a sex-difference was 

documented for the relative risk of total mortality among those receiving antioxidants and zinc 

compared to those receiving placebo. In the REACT, total mortality rate was not calculated. 

Nine deaths occurred in the antioxidant group, whereas 3 deaths occurred in the placebo group. 

The deaths in the antioxidant group were caused by esophagitis, sudden death, aneurysm, 

pulmonary fibrosis, cancer, and coronary thrombosis. 

 Daily supplementation with β-carotene of 20 mg, 30 mg or 50 mg was not protective against 

malignancies, cardiovascular disease outcomes, diabetes mellitus, cataract or age-related 

maculopathy. Supplementation with β-carotene with or without vitamin A increased the 

incidence of lung cancer in persons with asbestos exposure or in cigarette smokers, and was 

associated with increased mortality in some trials. To date, there has been no randomized 

controlled trial that assessed the efficacy of vitamin A alone in preventing chronic disease. 

Studies in selected populations (nutritionally inadequate, asbestos exposure, or smokers) showed 

no benefit of combinations of vitamin A and zinc or vitamin A and β-carotene for the prevention 

of stroke mortality, esophageal or gastric cancer incidence, or cardiovascular or all-cause 

mortality. 

 Vitamin E supplements (synthetic α-tocopherol 50 mg or 300 IU per day, or natural source, 

600 IU per day) have been studied for primary prevention of cancer, cardiovascular disease, 

cataract, and age-related eye disease. The evidence predominantly comes from the ATBC and 

WHS studies.68,87,90,96,98-100,107 There was a lack of effects of vitamin E in the prevention of these 

diseases, except for a 32 percent reduction in prostate cancer incidence, a 41 percent reduction in 

the prostate cancer mortality, and a 22 percent reduction in colorectal cancer in heavy smokers in 

the ATBC, and decreased cardiovascular deaths (primarily sudden death) in the WHS 

participants, particularly in those aged 65 years or older. The findings on hemorrhagic stroke 

were conflicting between the ATBC trial and the WHS; the former found a higher risk with use 

of low-dose α-tocopherol supplements but the latter found a lower risk with use at a high dose. 

 Two previous systematic reviews reported that supplementation with folic acid at daily 

doses of 0.75 mg or 30 mg, alone or in combination with vitamin B12 and/or vitamin B6 for 5-12 

weeks, had no significant effects on cognitive function in 5 small randomized controlled trials. 

Combined vitamin B2 and niacin supplement use for 5 years had no significant effects on 

cerebrovascular mortality, total mortality, total cancer incidence, and esophageal or gastric 

dysplasia/cancer incidence and esophageal or gastric cancer mortality in a poorly nourished 

population in China. 

 In a study in persons with a history of non-melanoma skin cancer, supplementation with 

selenium of 200 mcg per day had no effect on cardiovascular outcomes, but had protective 

effects on total mortality and incidence of lung, colorectal, and prostate cancers. Another study 
59 

in China found a significantly reduced risk for liver cancer in those who used selenium 

supplements of 200 mcg/day for two years. 

Due to the substantial amount of efficacy data on calcium/vitamin D and osteoporosis, we 

reviewed systematic review articles supplemented with data from recent randomized controlled 

trials and data from randomized controlled trials meeting our inclusion criteria that were not 

included in previous systematic reviews. The previous reviews reported that supplementation 

with calcium has short-term (particularly within one year) benefit on retaining bone mineral 

density in postmenopausal women, and a possible effect in preventing vertebral fractures. The 

reviews also indicated that combined vitamin D3 (700-800 IU/day) and calcium (1000 mg/day) 

may reduce the risk of hip and other non-vertebral fractures in populations with low levels of 

vitamin D and/or calcium. Recent published data from the WHI trial were consistent with these 

systematic reviews in showing a 1.06 percent higher hip bone density (p<.02) and a 12 percent 

non-significant lower risk for hip fracture in postmenopausal women after receiving calcium 

carbonate (500 mg twice a day) and vitamin D3 (200 IU twice a day) for an average of 7 years as 

compared to women receiving a placebo. In this trial, participants were allowed to have selfselected use of multivitamin supplement as well as calcium and vitamin D supplements up to 

1000 mg and 600 IU per day, respectively, and thus had a baseline average daily intake of 1150 

mg calcium and 365 IU vitamin D. Hence, the WHI participants had higher intake of calcium 

than the general population (761 mg per day). The WHI trial found no benefit of calcium and 

vitamin D supplementation in preventing colorectal cancer incidence. 

For evidence on the safety of multivitamin/mineral supplements when used for the purpose 

of preventing chronic disease, we identified 10 studies using multivitamin/mineral preparations 

and 24 studies using single nutrients for primary prevention of chronic disease. Doses were 

usually 2 to 10 times the RDA. Overall, we found no consistent pattern of increased adverse 

effects in the active group compared with the placebo group, with the exception of changes in 

skin color, which was common in studies in which beta-carotene was part of the multivitamin 

preparation. 

Supplementation with β-carotene with or without vitamin A also increased the incidence of 

lung cancer in persons with asbestos exposure or in heavy smokers, and was associated with 

increased mortality. Vitamin A supplementation may moderately increase serum triglyceride 

levels. Calcium supplementation increased the risk of kidney stones. Vitamin E supplementation 

was associated with an increased incidence of epistaxis but was not associated with an increased 

risk of more serious bleeding events, such as hemorrhagic stroke. Iron supplementation was 

found to reduce weight gain in iron-sufficient, non-anemic children in a small randomized 

controlled trial. But more recent trials have not fully clarified this issue, because they targeted 

deficient populations and/or included other micronutrients in the intervention formulation. 

Efficacy of Multivitamin/mineral Supplements 

Between the Linxian trial and the SU.VI.MAX trial, the types of vitamin/mineral 

supplements overlapped and the doses were similar. The efficacy was somewhat different, but 

had similar implications. 64,68-70,111,161,162 While the multivitamin/mineral supplements used in the 

Linxian trial reduced cancer mortality by 21 percent in women and by 7 percent in men, the 

efficacy of the multivitamin/mineral supplementation in the SU.VI.MAX in reducing cancer 

incidence was only evident in men. This sex-dependent efficacy may be accounted for by the 

different nutritional status of the study populations, i.e., generally poor nutritional status in the 
60 

Linxian population and the suboptimal antioxidant status in men compared with women in the 

SU.VI.MAX.69 These findings also corroborated observational studies that suggest benefits of 

fruits and vegetables on cancer prevention. However, they did not suggest that supplementation 

with multivitamins and minerals can replace a balanced, healthful diet to achieve an optimal 

health state because these studies were not designed to address that question. In view of the 

inadequate nutritional intake in the Linxian population and the “French paradox,” the 

generalizability of the findings from the SU.VI.MAX and Linxian trials to the United States 

population is uncertain. 

 For cataract prevention, AREDS was the largest trial with findings internally consistent in 

showing no benefits of multivitamin/mineral supplement use. While the REACT found a 

deceleration in cataract progression in the United States study site, similar benefits were not seen 

in the United Kingdom study site. For the prevention of age-related macular degeneration, the 

AREDS study found benefits of high-dose (10 times RDA) zinc alone or in combination with 

antioxidants in persons with intermediate age-related macular degeneration in one or both eyes, 

or persons with advanced age-related macular degeneration in one eye. The MONMD study was 

conducted in persons with advanced dry age-related macular degeneration. The study suffered 

from missing data and unclear data analysis and presentation, but the authors concluded that the 

antioxidant supplements used in the study stabilized but did not improve dry age-related macular 

degeneration. It appears that benefits of multivitamin/mineral supplements in the 

prevention/management of age-related macular degeneration were limited to persons with 

moderate or advanced age-related macular degeneration. However, such inference was based on 

findings from two trials (n=3,580) with one that was very small (n=71). 

With multivitamin/mineral supplements in wide use by the general public in the United 

States, particularly middle-aged or older individuals, it would be difficult now to recruit trial 

participants for the conduct of large-scale randomized placebo-controlled trials to determine the 

efficacy of multivitamin supplementation in chronic disease prevention. In the AREDS, 55 

percent of study participants had used some vitamins/minerals before enrollment, and 

consequently, the study investigators provided a free brand name multivitamin to 66 percent of 

the study participants. Because many nutrients share common mechanisms of action, selfselected supplement use may attenuate the net efficacy, if any, of the nutritional supplements 

under investigation. This conjecture is supported by the findings that 40 percent of the WHS 

participants had multivitamin/mineral supplement use in addition to study supplements, and 

when limited to non-multivitamin supplement users, the relative risk of major cardiovascular 

disease was 0.88 (95% CI 0.75-1.03), in contrast to a relative risk of 1.02 (95% CI 0.84-1.25) 

among multivitamin supplement users.87 We have found that very few studies reported 

participants’ self-selected supplement use, and most studies allowed use of supplements that 

were not under investigation. This limitation was rarely addressed in the literature. 

Efficacy of β-carotene 

Much research interest has been devoted to elucidating how β-carotene may increase lung 

cancer risk in high-risk individuals. "Antioxidants" have been assumed to exert in vivo antioxidative effects, based on in vitro observations. In fact, the oxidative propensity of a purported 

"antioxidant" depends at least on the concentrations, the redox potential of the molecule, and the 

biological environment the molecule is in (e.g., the oxygen tension and the existence of other 

oxidants/antioxidants). For example, carotenoids may inhibit or enhance apoptosis depending on 
61 

their concentration, concerted action of other oxidants/antioxidants, cell type, and redox status.163

At low oxygen tension, β-carotene may act as an antioxidant, while at high oxygen tension, it 

may behave as a pro-oxidant,164 although a pro-oxidant effect was not corroborated by an in vitro 

experiment on human bronchial epithelial cells.165 While β-carotene has a pivotal role in 

preventing vitamin A deficiency, the general lack of benefits from β-carotene supplementation 

and its potential harms in increasing lung cancer risk among high-risk individuals argue against 

supplementation with β-carotene alone for chronic disease prevention in the general population. 

Efficacy of Vitamin E 

In addition to β-carotene, vitamin E is the most extensively studied single nutrient as a 

chemopreventive agent. Several systematic review articles on vitamin E were identified in our 

literature search.114,166-169 However, in the majority of the previous reviews, primary prevention 

trials were not separated from secondary prevention trials,166,114,168 and when aggregate efficacy 

was calculated, the efficacy of a single nutrient in one intervention arm was not separated from 

the efficacy of multiple nutrients in one intervention arm.166,114,168 A systematic review can give 

misleading results for the efficacy of a single nutrient by including data from trials of multiple 

nutrients in an intervention arm (which is a multivitamin/mineral intervention). This argument is 

based on the rationale that several nutrients share common mechanisms of action, that nutrientnutrient interaction may exist, and that the efficacy of an individual nutrient cannot be 

determined in a trial that includes multiple nutrients in an intervention arm. This argument is also 

substantiated by a systematic review in which the aggregate effect of vitamin E alone on 

cardiovascular death, fatal myocardial infarction, non-fatal myocardial infarction was 

consistently in the protective direction (RR 0.96, 0.97, and 0.72, respectively), but the RR was 

1.03, 1.02, and 0.99 respectively when efficacy was calculated for vitamin E in combination with 

other nutrient(s).114

The general lack of benefits of vitamin E in the primary and secondary prevention of cancer, 

cardiovascular disease, cataract, and age-related macular degeneration was unexpected in view 

of the substantial evidence from experiments, animal studies and epidemiologic studies that 

showed great promise of vitamin E. Natural vitamin E has eight forms, α-, β-, γ-, and δtocopherols and α-, β-, γ-, δ-tocotrienols. Supplements of RRR-α-tocopherol, that is not naturally 

occurring, but derived from methylating γ-tocopherol in vegetable oil, are often commercially 

labeled as “natural source” vitamin E (as used in the WHS87).96 It has been shown that high 

intake of α-tocopherol may enhance the metabolism of other forms of vitamin E.170-171 Because 

γ-tocopherol is the predominant (70%) vitamin E in the typical American diet,172 and because γtocopherol and its metabolite may have biological effects,173,174 it has been hypothesized that 

reductions in circulating γ-tocopherol levels by α-tocopherol supplementation may compromise 

the efficacy of α-tocopherol, if any.175 In the present review, we found that many trials that used 

vitamin E did not report the chemical forms. Presumably, all trials used some esters of αtocopherol because α-tocopherol was the center of research attention in the past, and γtocopherol or mixed tocopherols were only available on the market in recent years. 

Based on data from the PPP and WHS, neither synthetic α-tocopherol of 300 IU per day for a 

short term, 3.6 years, nor natural source α-tocopherol of 600 IU every other day for a long-term, 

10 years, had beneficial effects in the primary prevention of cardiovascular outcomes.87,112 One 

intriguing finding from the WHS was the significantly lower risk of cardiovascular death 

(primarily sudden death), which might have been due to chance alone.87 
62 

Prompted by the findings from the ATBC trial and the NCP trial on the reduced risk for 

prostate cancer,101,133 the National Cancer Institute has launched the Selenium and Vitamin E 

Cancer Prevention Trial (SELECT) to test for the efficacy of daily use of α-tocopherol 

supplements in the primary prevention of prostate cancer in 32,400 men. The SELECT trial uses 

synthetic α-tocopherol of a high dose, 400 IU, and will be closed out in 2013.176

Vitamin/mineral Supplement Use and Total Mortality 

The implications of the impact of vitamin/mineral supplement use on total mortality are 

uncertain. Total mortality is relevant to the context of chronic disease prevention because it may 

provide a clue to potential harms and can be considered as a reference outcome in risk/benefit 

analysis. However, because two of the causality criteria cannot be applied to death outcome (i.e., 

response to re-challenge and response to discontinuation of use), the risk for death should be 

considered based on plausible biological mechanisms and the evidence on the effects of the 

nutrients on specific disorders. With this rationale along with the consideration on the great 

heterogeneity in the study design (i.e., factorial design vs. parallel-arm design), doses of 

supplements, duration of supplement use, and characteristics of study participants, we did not 

attempt to calculate an aggregate estimate for total mortality for the trials that reported such data. 

Instead, we examined the causes of death that might have accounted for the difference in total 

mortality between randomized groups. 

The 9 percent reduced risk of total mortality by multivitamins/minerals in the Linxian trial 

was likely to be driven by the reduction in stomach cancer mortality. Similarly, reduced total 

mortality in men in the SU.VI.MAX may reflect the 31 percent reduction in cancer incidence. 

The higher total mortality by β-carotene supplementation during the conduct of ATBC trial 

was primarily due to lung cancer and cardiovascular disease, whereas the higher total mortality 

in the first 4 years of post-trial follow up was primarily due to a wide spectrum of cardiovascular 

diseases.103 How β-carotene increased the risk of cardiovascular mortality remains unclear. 

A contentious issue regarding vitamin E supplementation is its impact on total mortality. The 

issue was set off by a recent meta-analysis from which an excess of 39 deaths per 10,000 persons 

was reported (95% CI 3 to 74 per 10,000) for trials using vitamin E at doses greater than or equal 

to 400 IU per day.168 In contrast, mortality was reduced (risk difference was –16 per 10,000 (–40 

to 10 per 10,000) for trials using lower doses (less than 400 IU per day).168 This meta-analysis 

had the shortcoming in combining 9 primary prevention trials and 10 secondary prevention trials, 

and combining data from 9 trials using vitamin E alone and data from 10 trials using vitamin E 

combined with other nutrients, including β-carotene which has been linked with an increased risk 

for total mortality. Furthermore, most trials that used high doses were secondary prevention trials 

in persons with various types of diseases and medication use. 

In the present review on vitamin E supplement use for primary prevention, the ATBC and the 

WHS participants comprised 87 percent of the study populations. In the ATBC trial, a 2 percent 

increased risk of total mortality was observed at the end of the supplementation period, but a 4 

percent risk “reduction” was observed in the next 3 years, followed by a 5 percent increase for 

the next 3 years and 0 percent for the next 2 years.103 The overall relative risk of total mortality 

during the 8 years of post-trial follow up was 1.01 (95% CI 0.96 to 1.05) and there was no 

difference in the relative risk of mortality throughout the post-trial follow up period.103 These 

findings suggest no late effects of α-tocopherol supplementation on risk of death in heavy 

smokers. In the WHS,87 the authors reported that “the main causes of death, apart from 
63 

cardiovascular and cancer deaths, were pulmonary diseases (32 vitamin E, 22 placebo) and 

violent deaths, excluding suicide (9 vs. 6). None of these causes of deaths was significantly 

related to vitamin E.” The relative risk of cardiovascular death and cancer death in the WHS was 

0.76 (95% CI 0.59-9.98) and 1.12 (95% CI 0.95-1.32), respectively.87 The VECAT documented 

31 deaths (20 in vitamin E; 11 in placebo), and the authors reported that “no consistent or 

unusual patterns were identified among the specific causes of death recorded.”113 In view of 

these data along with consideration of biological plausibility, we find no convincing evidence to 

suggest vitamin E supplement use increases risk of death per se. 

Timing and Duration of Supplement Use 

Timing and duration of supplement use is an important determinant of the efficacy. However, 

these issues have rarely been addressed in the literature and little is known about the optimal 

time to start and stop supplementation. For the reasons of feasibility and resource constraints, 

most randomized controlled trials have had a follow up period of approximately 5 years, and 

some followed for only 2 years, while a chronic disease may take 10 to 20 years to develop. 

In the ATBC and CARET studies, lung cancer risk was increased by β-carotene alone or by 

combined β-carotene and retinol over 5 to 10 years of supplementation among heavy smokers 

and persons regularly exposed to asbestos, suggesting that the supplementation regimens might 

have accelerated the progression of carcinogenesis in these high-risk groups. 

The CARET study reported a late effect of β-carotene supplementation on lung cancer.94 The 

ATBC trial observed a late effect on colorectal cancer, but not lung cancer.103 These post-trial 

follow up data may provide some clues to how likely the link between β-carotene 

supplementation and increased lung cancer incidence was causal, and how the effects may vary 

with carcinogenesis processes, but the data may also be simply due to chance alone or be subject 

to confounding by trial participants’ changes in supplement use after the closeout of the trial. 

An intriguing finding from the WHS study was that a significantly lower risk of major 

cardiovascular events was limited to women aged 65 or older who received vitamin E 

supplements for 10 years (RR 0.74).87 This finding is not congruent with the oxidative 

hypothesis stating that oxidative damage occurs early in the atherosclerosis process,177 nor with 

the data that showed that early atherosclerotic lesions occurred in adolescents.178,179 In the 

Linxian trial with 5 years of follow up, benefits of α-tocopherol, selenium and β-carotene on 

cancer mortality, cardiovascular mortality and total mortality were more evident in those aged 

less than 55 years.67 The SU.VI.MAX trial found a protective effect of antioxidants on prostate 

cancer incidence among men who had normal prostate specific antigen levels, but not in men 

who had elevated prostate specific antigen levels after 8 years of follow up.70 The benefit on 

prostate cancer by β-carotene supplement use in the ATBC trial was limited to clinical prostate 

cancer but not for latent cancer.101 If cancer development takes more than 10 years to develop, 

these data would seem to have provided paradoxical information on whether antioxidant 

supplements should be used earlier or later in the life span, let alone whether different 

chemopreventive agents may act differently along the carcinogenesis process. Additional data 

from subgroup analyses from trial enrollment to diagnosis with adjustment for potential 

confounding variables such as age in other completed or on-going trials are needed before a clear 

picture can be seen. 
64 

Doses of Vitamin/mineral Supplements 

 The RDA is the average daily dietary intake level sufficient to meet the nutrient requirement 

of nearly all (97 to 98 percent) apparently healthy individuals in a particular age and gender 

group. There is a wide range of doses of vitamins and minerals formulated into over-the-counter 

supplements. The “one-a-day” type of multivitamins/mineral supplements may contain nutrients 

of 100% to 300% of the RDAs for adults. The doses of B vitamins in other multivitamin 

preparations are high; usually 1667% of the RDAs, and up to 6000% of the RDAs. For vitamin 

E, commonly used doses in individual vitamin E or multivitamin supplements are 100, 200, 400, 

and 800 IU which, if of natural form, correspond to 333%, 667%, 1332% and 2640% of the 

RDA for vitamin E. For vitamin C, commonly used doses in individual vitamin C supplements 

or multivitamin supplements are 250 mg, 500 mg, and 1000 mg, which correspond to 

approximately 417%, 833%, and 1667% of the RDA for vitamin C. 

 In this review, only two trials of multivitamin/minerals supplements reported data on cancer 

and cardiovascular outcomes and the benefits on these outcomes were implicated in those who 

had inadequate nutrient intake. The active supplements (combined vitamin E, selenium, and βcarotene; combined vitamin E, selenium, β-carotene, vitamin C and zinc) in these two trials were 

of doses around 100%-200% of the RDAs. Hence, the efficacy of lower or higher doses of the 

nutrients was not known. With respect to prevention of age-related macular degeneration, the 

AREDS study used a high dose of vitamin E (400 IU) and zinc (2 times the UL), and the benefit 

on preventing the progression to advanced age-related macular degeneration appeared to have 

come primarily from the groups receiving zinc. In this study, of nearly 100 comparisons, a few 

adverse effects occurred more often in participants receiving zinc as compared to participants 

receiving no zinc, including more difficulties in swallowing the pill (17.8% vs. 15.3%), more 

hospitalizations due to genitourinary problems (7.5% vs. 4.9%), more “adverse circulatory 

experiences” (0.9% vs. 0.3%) and more anemic individuals (13.2% vs. 10.2%). 

 In the WHI study, participants were allowed to have self-selected use of multivitamin 

supplements, as well as calcium and vitamin D supplements up to 1000 mg and 600 IU per day, 

respectively. Hence, the WHI participants had a baseline average daily intake of 1150 mg 

calcium and 365 IU vitamin D. If women randomized to the calcium supplementation group also 

used their own calcium supplements and multivitamin supplements that contained calcium, a 

daily total intake could have approached the UL, 2500 mg, and led to a higher risk for adverse 

effects such as kidney stone formation. 

Safety Consideration 

As noted previously, the potential adverse effects of multivitamin or single-nutrient 

supplements have not been systematically studied in well-controlled trials. Because of the 

uncertainties regarding design (exposure, doses, etc.) and the ethical constraints, such studies 

may never be carried out. Our assessment of the safety of supplements, therefore, must rely on 

the safety monitoring during randomized controlled trials and on case reports and other 

observational data. 

Since the ULs were defined based on limited data or extrapolations, and generally were 

based on one single indicator of adverse effects, it is not surprising that several trials reported no 

adverse effects after consumption of doses above the UL. These studies may have used 

indicators other than those used to define the UL for that nutrient, or may have had only slight 
65 

increases in an adverse effect that was not significantly different from the placebo group. A few 

adverse effects, because they appear with certain consistency in different trials, may be 

interpreted as common responses in the general population. For example, yellowing of the skin 

with sustained consumption of β-carotene at daily doses of 8 mg or higher has been described in 

most studies using this nutrient. Similarly, increases in serum triglycerides with vitamin A 

supplementation have been reported in several studies. Minor bleeding, particularly epistaxis, 

also appears to be a relatively common effect of vitamin E supplementation. But as noted above, 

there is no evidence that this vitamin results in an increased risk of more serious bleeding events, 

such as hemorrhagic stroke. 

A general conclusion, with the caveats mentioned regarding the limited data available, is that 

consumption of multivitamin supplements for prolonged periods (1 to 8 years) appears to be 

safe. We found no reports of major, life-threatening adverse effects, and no evidence of 

increased mortality in groups consuming multivitamin supplements. A similar general 

conclusion can be reached for single-nutrient supplements. However, the late effects of βcarotene on cardiovascular death in heavy smokers deserve further investigation for the 

underlying mechanisms. In addition, some studies confirmed the adverse effects used to define 

the UL, as for example, gastrointestinal symptoms and/or diarrhea with vitamin C. While the UL 

for this nutrient was set at 2 g per day, some studies have reported these symptoms with doses of 

750 mg per day. It is recognized that the ULs represent a probability of an adverse event in the 

general population, and that that probability (and therefore the UL threshold) may vary across 

subgroups and in different circumstances. 

Limitations 

An enormous volume of literature exists on the effects of multivitamin/mineral supplements 

when seeking to include the literature on all of the single nutrients that are often included in 

multivitamin supplements. To find the most relevant literature on our questions, we had to design 

a search strategy that sacrificed some degree of sensitivity in order to have reasonable 

specificity. Thus, it is possible that the search strategy missed some studies that have potentially 

relevant data. We tried to minimize this problem by performing hand searching of the references 

in key articles and reviews, and by asking our peer reviewers to identify any important studies 

that were missing in the draft report. Clinical experts may question the efficiency of our 

systematic approach to searching the massive volume of literature on multivitamin/mineral 

supplements, but we were concerned about the risk of bias in selecting articles for inclusion in 

the review if we had relied only on experts for identifying eligible studies. 

In addition, for our review of evidence on the efficacy of multivitamin/mineral supplements 

in preventing chronic disease, we focused on randomized controlled trials as the strongest source 

of evidence. We also focused on primary prevention studies because they are the ones most 

relevant to use of multivitamins in the general population of healthy adults. Although we focused 

on randomized controlled trials only for efficacy data, we included observational studies in our 

consideration of the safety of multivitamins/mineral supplements. 

Many of the studies had important methodologic limitations. One particularly important 

limitation is that study groups often were permitted to use vitamin/mineral supplements other 

than the assigned study interventions. Such leeway would have attenuated the observed efficacy 

of study supplements. In addition, most studies did not provide information on trial participants’ 
66 

characteristics, such as medication use, that may have modified the effects of the nutrients of 

interest. 

There is marked heterogeneity of the literature on our key questions, with differences in 

study design (e.g., some of the trials used a factorial design), targeted study population (with 

different cultural/lifestyle and genetic backgrounds), chemical forms and doses of supplements, 

and specific outcome measures. This degree of heterogeneity makes it difficult to synthesize 

results across studies, and generally makes it inappropriate to perform quantitative synthesis (i.e., 

meta-analysis). The differences in study populations are particularly problematic because few 

studies have examined the efficacy of multivitamin/mineral supplements in the general United 

States population, making it difficult to determine whether the results of studies in other 

countries such as China and France can be applied to the United States population. 

There has been inconsistent reporting on the potential adverse effects of the nutrients of 

interest. A significant proportion of data in the literature concerning adverse events came from 

case reports that are subject to serious methodological limitations. As a result, the overall 

strength of the evidence on adverse effects is weak. In addition, the implications of data from 

case reports are uncertain. In a previous systematic review of case reports of adverse effects of 

drugs, it was found that 83 percent of suspected adverse reactions were not further evaluated in 

confirmatory studies, and adverse effect alerts were not systematically incorporated into 

published drug reference information.140

Conclusions 

Limited evidence accumulated to date suggests potential benefits of multivitamin/mineral 

supplements in the primary prevention of cancer in individuals with poor nutritional status or 

suboptimal antioxidant intake. However, the heterogeneity in the study populations upon which 

this evidence is based limits generalization to the United States population. The evidence also 

indicates that multivitamin/mineral supplement use does not have significant effects in the 

primary prevention of cardiovascular disease and cataract, but may confer benefits to slow the 

progression of age-related macular degeneration among persons at high risk for developing 

advanced stages of the disease. 

 We also conclude that regular supplementation with a single nutrient or a mixture of nutrients 

for years has no significant benefits in the primary prevention of cancer, cardiovascular disease, 

cataract, age-related macular degeneration or cognitive decline. A few exceptions, that were 

reported in a single or a few trials, included a decreased incidence of prostate cancer with use of 

synthetic α-tocopherol (50 mg per day) in smokers, a decreased progression of age-related 

macular degeneration with high doses of zinc alone or zinc in combination with antioxidants in 

persons at high risk for developing advanced stages of the disease, and a decreased incidence of 

cancer with use of selenium (200 mcg per day). Supplementation with calcium has short-term 

(particularly within one year) benefit on retaining bone mineral density in postmenopausal 

women, and a possible effect in preventing vertebral fractures. Combined vitamin D3 (700-800 

IU/day) and calcium (1000 mg/day) may reduce the risk of hip and other non-vertebral fractures 

in individuals with low levels of intake. Supplementation with β-carotene increased lung cancer 

risk in persons with asbestos exposure or cigarette smoking. 

 The overall quality and quantity of the literature on the safety of multivitamin/mineral 

supplements is limited. Available data suggest multivitamin/mineral supplement use for 1 to 8 

years is safe. Among the adverse effects reported in randomized controlled trials, a prominent 
67 

one is yellowing of the skin among β-carotene supplementation. Vitamin A supplementation may 

moderately increase serum triglyceride levels. Calcium supplementation may increase the risk of 

kidney stones. Vitamin E supplementation was associated with an increased incidence of 

epistaxis but was not associated with an increased risk of more serious bleeding events. 

Future Research 

In vitro studies and animal models have helped us to understand the function of nutrients 

under a controlled environment. However, these types of studies often have over-simplified the 

sophistication of the human body. There is a gap in our knowledge of how specific nutrients 

work in vivo to prevent disease. Future research should be directed toward filling the gap by 

developing valid in vivo biomarkers and applying them in the settings of randomized controlled 

trials to examine how nutrients influence the body’s physiological function and pathological 

processes, and how nutrients work in concert to do so. Identifying an optimal dose in doseresponse studies is critical to guide the design of future large-scale randomized controlled trials 

when the conduct of the trials is considered worthwhile. 

Nutritional research has adopted a reductionist approach that emphasizes the role of 

individual nutrients in physiologic function or disease process. In view of the complex 

pathological processes of chronic diseases, the idea of using a single nutrient or a few nutrients 

to modify disease risk carries considerable optimism. The design and conduct of several largescale randomized controlled trials on antioxidants was derived from epidemiological data that 

showed a lower risk of chronic disease (predominantly cancer and cardiovascular disease) in 

those who had higher circulating levels or dietary intake of some micronutrients. Because of 

residual confounding and measurement errors in dietary assessment, dietary data from 

observational studies can be better examined by patterns of food consumption with a multivariate 

approach, rather than by ranking of specific nutrient intake with a univariate approach. 

We have found that many studies did not report study participants’ self-selected supplement 

use before and during the trial participation, and allowed self-selected supplement use during the 

trial. Similarly, there was a lack of information on other variables that might have modified the 

effects of study supplements. Collective study findings also may not apply to every individual. 

Additional research should be done, particularly in existing randomized controlled trials, to 

examine how efficacy may vary by age, time since trial enrollment to diagnosis, self-selected 

supplement use, dietary patterns, disease history, medication use, and/or genetic polymorphisms. 

With many food products being fortified with several nutrients, Americans’ dietary intake of 

certain nutrients may well be above the RDAs. Hence, it is important to study the level of intake 

among consumers and assess how nutrient fortification may influence the public’s health. An 

adverse event reporting system needs to be in place to facilitate this type of research. 

For policy making, research should be conducted to estimate the cost-effectiveness and the 

risk/benefit profile of multivitamin/mineral supplement use or more generally, dietary 

supplement use, in the general population. Such research should also consider subpopulations for 

which these parameters may differ. 
68 

Implications 

 The results of this systematic review have important implications for clinical practice and 

public health policy. When people ask about the need for multivitamin/mineral supplements, 

clinical practitioners should be aware that while multivitamin/mineral supplements are unlikely 

to have serious adverse effects, it remains unclear whether multivitamin/mineral supplementation 

is efficacious in preventing cancer, cardiovascular disease, or other major chronic diseases and 

conditions in the general United States adult population. Clinical practitioners may need to take 

into consideration other factors, such as nutritional status, when making recommendations about 

the need for multivitamin/mineral supplements. For public health policy makers, our conclusion 

is that evidence is insufficient to universally recommend or discourage routine use of 

multivitamin/mineral supplements by adults in the general United States population for primary 

prevention of chronic disease. 
69 

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SUMMARY TABLES 

89 

Table 1. Number of articles by key questions and disease categories Numbers within the table may exceed total numbers in each category; nutrients may have more than one effect. KQ = key question; Other nutrients include: Vitamin B2, selenium, zinc, and niacin 

KQ 3 (N= 44) 

KQ 1 

(N = 11) 

KQ 2 

(N = 10) 

β-carotene 

(N = 20) 

Vitamin 

A 

(N = 7) 

Vitamin 

E 

(N = 12) 

Vitamin 

B2 and 

niacin 

(N = 3) 

Selenium 

(N = 6) 

Vitamin D/ 

calcium 

(systematic 

reviews) 

(N= 6) 

Vitamin 

D/ 

calcium 

(RCTs) 

(N=5) 

β-carotene 

(N= 13) 

Cancer 2 14 2 8 1 5 1 Cardiovascular disease 

2 10 2 4 1 2 

Cataract 4 1 1 2 1 Age-related macular degeneration 

2 1 

Bone mineral densisty 

 3 2 

Fracture prevention 

 5 1 

Total mortality 

4 3 2 4 1 1 5 

Hospitalization 2 General illness 

 1 4 

Yellowing of skin 

 5 4 

Anemia 1 1 Genitourinary 1 Circulation 1 2 Gastrointestinal 3 1 Cardiovascular 2 2 Renal 1 Psychiatric 1 
90 

Table 2. Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention 

Study name/ Study design 

Study Site/ year 

Sample Size 

Characteristics of Study Population 

Study design Randomized groups 

Doses (RDA) 

Supplementation Period 

Selfselected supplement use 

Statistically significasignificant findings, Comment 

Linxian General Population Trial 64 66

Fractional factorial trial 

Linxian, China 1986-91 

29,584 age 44-60 

55% women nutritionally deprived low intake of fresh fruits, meat, and other animal products low circulating levels of micronutrients, but overt clinical deficiencies were not common 

Groups of placebo, AB, AC, AD, BC, BD, CD, ABCD where A: Retinol palmitate 10,000 IU + Zinc oxide 45 mg, B: Riboflavin 5.2 mg + Niacin 40 mg, C: Ascorbic acid 180 mg + Molybdenum Yeast complex 30 μg, D: β-carotene 15 mg + Selenium yeast 50 μg + α-tocopherol 60 mg 

≈1-2 x RDAs 

5.25 years Not reported 

(Prior supplement users were ineligible for trial enrollment) 

SIGNIFICANT: (1) In the groups rece

and selenium:gastric cancer inciden 0.84 (0.71-1.00), cancer mortality  0.87 (0.75-1.00), stomach cancer morta 0.79 (0.64-0.99), total mortality  0.91 (0.84-0.99) (2) in the groups recenon-cardia stomach c 0.59 (0.37-0.93) (3) in the groups rece

carotene, vitamin E an

Stroke death  0.71 (0.50-1.00) NON-SIGNIFICANT: (1) No effects of A, B, Total mortality, stroke mortality, esophageal/ gastric ccancer mortality, cancincidence, gastric cancancer incidence, esocancer incidence (2) No effect of D on: Stroke death, esophaesophageal/ gastric cincidence, esophageaesophageal/ gastric c(3) no effects of AB, AABCD on: Stroke deaths (excepmortality 
91 

Table 2. Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention (contin

Study name/ Study design 

Study Site/ year 

Sample Size 

Characteristics of Study Population 

Study design Randomized groups 

Doses (RDA) 

Supplementation Period 

Selfselected supplement use 

Statistically significasignificant findings, Comment 

Linxian General Population Trial – end-of-trial endoscopy survey68

Linxian, China 1991 

391 Mean age: 

53 45% women younger, more men, more smokers, more alcohol use compared to the total trial participants 

Groups of placebo, AB, AC, AD, BC, BD, CD, ABCD where A: Retinol palmitate 10000 IU + Zinc oxide 45 mg, B: Riboflavin 5.2 mg + Niacin 40 mg, C: Ascorbic acid 180 mg + Molybdenum Yeast complex 30 μg, D: β-carotene 15 mg + Selenium yeast 50 μg + α-tocopherol 60 mg 

≈1-2 x RDAs 

Endoscopy done at the end of the trial 

Not reported SIGNIFICANT; 

None NON-SIGNIFICANT: No effects of A, B, C, Dysplasia and cancer stomach cancer in the COMMENT: Overall prevalence of extraordinarily high, 1Small sample size. 
92 

Table 2. Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention (contin

Study name/ Study design 

Study Site/ year 

Sample Size 

Characteristics of Study Population 

Study design Randomized groups 

Doses (RDA) 

Supplementation Period 

Selfselected supplement use 

Statistically significasignificant findings, Comment 

Linxian General Population Trial – end-of trial cataract study65

Linxian, China 1985-91 

5,390 age 45-74 

55% women 

Groups of placebo, AB, AC, AD, BC, BD, CD, ABCD where A: Retinol palmitate 10000 IU + Zinc oxide 45 mg, B: Riboflavin 5.2 mg + Niacin 40 mg, C: Ascorbic acid 180 mg + Molybdenum Yeast complex 30 μg, D: β-carotene 15 mg + Selenium yeast 50 μg + α-tocopherol 60 mg 

≈1-2 x RDAs 

Eye exams done at the end of the trial 

Not reported (Prior supplement users were ineligible for trial enrollment) 

SIGNIFICANT: (1) in the groups receprevalence of nuclear 74, OR (95% CI) = 0.4(2) in the groups rece

prevalence of posteriothose aged 45-74, OR 5.35) NON-SIGNIFICANT: (1) no effects of A, C, prevalence of nuclear and posterior subcaps(2) no effects of B on cataract In those aged 55-64 
93 

Table 2. Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention (contin

Study name/ Study design 

Study Site/ year 

Sample Size 

Characteristics of Study Population 

Study design Randomized groups 

Doses (RDA) 

Supplementation Period 

Selfselected supplement use 

Statistically significasignificant findings, Comment 

12741 62% women 

Mean(SD) age: women: 46.6 (6.6); men: 51.3 (4.7) 

SU.VI.MAX 7.5 years 69,70

Parallelarm design 

France 1994-2002 

5141 (men) 

Mean (SD) age: 51.3 (4.6) 

Vit C 120mg+ vit E 30mg+ β-carotene 6mg+ selenium 100μg+ zinc 20mg vs. Placebo 

≈ 1-2 x RDAs (vitamin E: chemical forms not specified) 

8 years 

Not reported (Regular users of any of the vitamins and minerals provided in the study were ineligible for trial enrollment.) 

SIGNIFICANT: Men: total cancer incidence  0.69 (0.53-0.91) total mortality  0.63 (0.42-0.93) prostate cancer in me

0.52 (0.29-0.92) NON-SIGNIFICANT: Men & women: Ischemic cardio-vascuWomen: cancer incidence, totaMen: Prostate cancer for ththe subgroups by agelevels of β-carotene, vselenium, and zinc no and IGF levels COMMENT: Well-designed Men had lower serum vitamin C at baseline. Cardiovascular event22.6% of the events in Information on prior ouse was not reported
94 

Table 2. Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention (contin

Study name/ Study design 

Study Site/ year 

Sample Size 

Characteristics of Study Population 

Study design Randomized groups 

Doses (RDA) 

Supplementation Period 

Selfselected supplement use 

Statistically significasignificant findings, Comment 

REACT72

Parallelarm design 

US UK 1990-1995 

297 Mean (SD) 

age: UK: 67.55 (8.47) US: 64.2 (8.49) 

β-carotene 18mg + vit C 750mg + all-rac αtocopherol acetate 600 mg, 3 divided doses per day vs. Placebo 

Vit C: 10x RDA for women ≈8x RDA for men all-rac αtocopherol acetate: 40x RDA 

3 years Not reported 

(Regular users of any vitamin supplement were ineligible for trial enrollment.) 

SIGNIFICANT: Anterior % pixel opaqMean (95% CI) Placebaseline 5.0 (1.4), last 8.3 (2.2), Mean change from baSupplement: baseline Mean change from baDifference from placeNON-SIGNIFICANT: Retro data posterior % endpoint): Retro data posterior % anterior pupil diametediameter, nuclear coloposterior subcapsulaCOMMENT: After 3 years, the posthe U.S. group (% pix2.517 in the vitamin vp=0.0001), but not the 
95 

Table 2. Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention (contin

Study name/ Study design 

Study Site/ year 

Sample Size 

Characteristics of Study Population 

Study design Randomized groups 

Doses (RDA) 

Supplementation Period 

Selfselected supplement use 

Statistically significasignificant findings, Comment 

AREDS – cataract73

Parallelarm design 

U.S. (11- center trial) 1992-2001 

4596 Median age: 

56 

β-carotene 15 mg + vit C 500 mg + vit E 400 IU vs. Placebo 

Vit C: 6.6x RDA Vit E: chemical form not specified Zinc: 10x RDA 

6.3 years 55% of trial 

participants who had prior vitamin/ mineral supplement use were enrolled and supplied with Centrum. Additionally, 13% of trial participants chose to take Centrum. 

SIGNIFICANT: None NON-SIGNIFICANT: Total lens event, nucleposterior sub-capsulasevere lens event, losmortality COMMENT: The study had the straspects of the study cwithdrawal, compliancThe major limitations multivitamin use (66% and self-selected use (20% of participants) the study nutrients. Data on how the self-distributed across rancategories were not re
96 

Table 2. Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention (contin

Study name/ Study design 

Study Site/ year 

Sample Size 

Characteristics of Study Population 

Study design Randomized groups 

Doses (RDA) 

Supplementation Period 

Selfselected supplement use 

Statistically significasignificant findings, Comment 

AREDS – agerelated macular degeneration75

2 by 2 factorial design 

 3509 Median age: 

69 

Groups of placebo, A, B, C where A: β-carotene 15 mg + vit C 500 mg + vit E 400 IU B: zinc 80 mg as zinc oxide + copper 2mg as cupric oxide C: β-carotene 15 mg + vit C 500 mg + vit E 400 IU + zinc 80 mg as zinc oxide + copper 2mg as cupric oxide 

 SIGNIFICANT: 

(1) zinc vs. no zinc:Progression to advanparticipants in AMD caOR (99% CI) = 0.79 (Neovascular AMD OR (99% CI) = 0.76 ((2) zinc vs. placebo Progression to advanparticipants in AMD caOR (99% CI) = 0.71 ((3) Antioxidants + zinProgression to advanced AMD categories 3&4; 2&OR (99% CI) = 0.66 (0.4Loss of visual acuity scobaseline(among participaOR (99% CI) = 0.73 (0.5Risk of neovascular AMDcategories 3&4), OR (99NON-SIGNIFICANT: (1) No effects of A or Progression to advanparticipants in AMD caLoss of visual acuity sbaseline(among partic3&4) (2) No effects of A, B, Loss of visual acuity sbaseline (among part2&3&4) Central geographic atcategories 3,4) (3) No effects of A onProgression to advanparticipants in AMD caNeovascular AMD 
97 

Table 2. Summary of randomized controlled trials on multivitamin/mineral supplements and chronic disease prevention (contin

Study name/ Study design 

Study Site/ year 

Sample Size 

Characteristics of Study Population 

Study design Randomized groups 

Doses (RDA) 

Supplementation Period 

Selfselected supplement use 

Statistically signnon-significant Comment 

MONMD71, 74 Parallelarm design 

U.S. 1992 

71 Veterans β-carotene 

20,000IU + vit E 200IU + vit C 750mg + citrus bioflavonoid complex 125mg+ quercitin 50 mg + rutin 50 mg+ biberry extract 5 mg+ zinc picolinate 12.5 mg+ selenium50mcg+ taurine 100mg+ N-acetyl cysteine 100 mg+ l-glutathione 5mg + vit B2 25mg+ Chromium 100 mcg vs. Placebo 

Vitamin E: 6.6x RDA Vit C: 10x RDA for women 8.3x RDA for men Zinc: 0.83xRDA Selenium: 0.71xRDA Vit B2: ≈18xRDA 

18 months Not reported 

(Persons who had vitamin use in the year prior to enrollment were ineligible.) 

SIGNIFICANT: Distance acuity dgroup, but stable (p=0.03). The multivitamin acuity and fewer eyes in the multivwhich occurs afte

NON-SIGNIFICANo significant diffrandomized groumetamorphopsia nuclear color, nucposterior subcapUnanticipated cofor right eyes in tCOMMENT: Instruments used transparence westudy period and well instructed. 

SU.VI.MAX = SUppléments en VItamines et Minéraux AntioXydants; REACT = Roche European American Cataract Trial; AREDS = Age-Study; ARMD = Age-Related Macular Degeneration; MONMD = Multicenter ophthalmic and nutritional age-related macular degeneration 
98 

Table 3. Assessment of the quality of randomized controlled trials on the efficacy of multivitamin/mineral 

supplements and single nutrients in the prevention of chronic diseases and conditions. 

Author, 

year 

Representativenessa Bias and 

Confoundingb Adherence and follow-upc Statistical Analysisd Conflict of Intereste

Multivitamin Studies, Cancer Prevention 

Blot, 199364 Medium Medium Low Low Low

Wang, 

199468 Medium Medium Medium Medium Low 

Meyer, 

200570 High Medium Low High Low 

Hercberg, 

200469 High Medium Medium High High

 Medium Medium Medium Medium Low 

Multivitamin Studies, Cardiovascular disease prevention 

Mark, 

199866 Low Low Low Medium Low

Hercberg, 

200469 High Medium Medium High High

 Medium Medium Low High Medium

 Multivitamin Studies, Eye Disease Prevention 

Sperduto, 

199365 Medium Medium High Medium Low

Chylack, 

200272 High High High High Low

AREDS, 

2001a73 High High Medium High High

AREDS, 

2001b75 High High High High High

Richer, 

199674 Medium Low Medium Low Low 

 High Medium Medium Medium Low 

Vitamin A/ Beta-carotene Studies, Cancer Prevention 

ATBC, 

199497 High Medium Medium High Low

Albanes, 

199698 Medium Medium Low High Low 

Rautalahti, 

199999 High Medium Medium High Low

Varis, 

199890 High Medium Medium High Low

Omenn, 

1996105 Medium Medium Low High Medium 

Omenn, 

199693 Medium Medium Medium High Low 

Green, 

199984 Medium Medium Low High Medium

Greenberg, 

199685 Medium Medium Medium High High 

Cook, 

2000104 Medium Medium Medium Medium Medium

Frieling, 

200086 Medium Medium Low Medium Medium

Hennekens, 

1996 95 Medium Medium Low Medium Low 
99 

 

Table 3. Assessment of the quality of randomized controlled trials on the efficacy of multivitamin/mineral 

supplements and single nutrients in the prevention of chronic diseases and conditions. (continued) 

Author, 

year 

Representativenessa Bias and 

Confoundingb Adherence and follow-upc Statistical Analysisd Conflict of Intereste

Vitamin A/ Beta-carotene Studies, Cancer Prevention (continued) 

Lee, 

199996 High Medium Medium High Medium

Blot, 199364 High Medium Medium Medium Low

 Medium Medium Medium Medium Low 

 Vitamin A/ Beta-carotene Studies, Cardiovascular Disease Prevention 

Rapola, 

1996106 High Medium Medium High Low

Leppalla, 

2000107 High Medium Medium High Low 

Omenn, 

1996105 Medium Medium Low High Medium 

Goodman, 

200494 Medium Medium Medium Medium

 

Medium 

 

Greenberg, 

199685 Medium Medium Medium High High 

 

Liu, 

1999108 Medium Medium Low High Medium

Hennekens, 

1996 95 Medium Medium Low Medium Low 

Lee, 

199996 High 

 

Medium Medium

 

High Medium

Mark, 

199866 Low 

 

Low 

 

Low Medium Low

 63 60 57 76 46 

Vitamin A/ Beta-carotene Studies, Eye Disease Prevention 

Teikari, 

1997109 High Medium Medium Medium Low

Sperduto, 

199365 Medium Medium High Medium Low

 High Medium Medium Medium Low

Vitamin E Studies, Cancer Prevention 

Varis, 

199890 High Medium Medium High Low

Albanes, 

199698 Low Medium Low High Low 

Albanes, 

2000102 High Medium Medium High Low 

ATBC, 

199497 High Medium Medium High Low

Rautalahti, 

199999 High Medium Medium High Low

Heinonen, 

1998101 High 

 Medium 

Medium

 High Medium 

Lee, 

200587 High Medium Medium High High 

 Medium Medium Medium Medium Low 
100 

Table 3. Assessment of the quality of randomized controlled trials on the efficacy of multivitamin/mineral 

supplements and single nutrients in the prevention of chronic diseases and conditions. (continued). 

Author, 

year 

Representativenessa Bias and 

Confoundingb Adherence and follow-upc Statistical Analysisd Conflict of Intereste

Vitamin E Studies, Cardiovascular Disease Prevention 

Rapola, 

1996106 High Medium Medium High Low

Leppalla, 

2000107

Lee, 

200587 High Medium Medium High High 

Lee, 

199996 High Medium Medium High Medium

De Gaetano, 

2001112 Medium Medium Medium High High

Sacco, 

2003181 Medium Medium Low 

 

High High

 Medium Low Medium High Medium

Vitamin E Studies, Eye Disease Prevention 

McNeil, 

2004113 High Medium Medium High Medium 

Teikari, 

1997109 High Medium Medium Medium

 

Low

 High Medium Medium Medium Low 

Other Nutrients, Cancer Prevention 

Clark, 

1996133 Medium Medium Medium High Medium

Clark, 

1998134 Medium Medium Low Medium Low 

Reid, 

2002135 Medium Low 

 

Low Medium Medium 

 

DuffieldLillico, 

2002136

Medium Low Low Medium Low 

DuffieldLillico, 

2002137

Medium Low Low Medium Low 

Blot, 199364 High Medium Medium Medium Low

Yu, 1991139 Low Low Low Low Low

 Medium Low Low Medium Low 

Other Nutrients, Cardiovascular Disease Prevention 

Clark, 

1996133 Medium Medium Medium

 

High 

 

Medium

Mark, 

199866 Low High Low

 Medium 

Low

 Other Nutrients, Eye Disease Prevention 

Sperduto, 

199365 Medium Medium High Medium Low

 Medium Medium High Medium Low 

 

For each study, we assigned a rating of high, medium or low quality for each domain of study quality based on 

whether the score for that domain was designated High (80-100%), Medium (50-79%), or Low (0-49%) quality.
101 

Table 3. Assessment of the quality of randomized controlled trials on the efficacy of multivitamin/mineral 

supplements and single nutrients in the prevention of chronic diseases and conditions. (continued). 

a

 Representativeness: Score was based on a total maximum score of 8 points. This included the authors’ description of setting (2

points), details on inclusion and exclusion criteria (2 points), information on excluded or non-participating individuals (2 points), 

and description of key participant characteristics (2 points). 

b

 Bias and Confounding: Score was based on a total maximum score of 28 points. This included the authors’ description of 

patient assignment (2 points), details on concealment (2 points), description of differences in patient characteristics between

groups (2 points), reporting on prior supplement use (2 points), description of the differences between groups in the prior use of 

supplements (2 points), description of medication use during the study (2 points), details on blinding (2 points) and the success of 

blinding (2 points), confirmation of medical diagnoses by medical chart (2 points), independent interpretation of clinical 

outcomes (2 points), overall blinding (2 points), randomization of arms (2 points), detail of description of study supplements (2 

points), and overall assessment of the adherence to study supplements (2 points). 

c

 Adherence and Follow-up: Score was based on a total maximum score of 12 points. This included the authors’ description of 

flow of participants through each stage (2 points); patient adherence to study supplement use (2 points); description or 

identification of unintended cross-over between randomized groups (2 points); reporting (2 points) and description of 

withdrawals from the study (2 points), identifying if the study stopped earlier than planned (2 points). d

 Statistical Analysis: Score was based on a total maximum score of 12 points. This included the authors’ description of statistical 

tests (2 points), how unintended cross-over (2 points) and loss-to-follow-up (2 points) was handled, reporting of primary 

endpoints (2 points), adjustment for confounders (2 points), reporting of statistical power (2 points). e

 Conflict of Interest: Score was based on a total maximum score of 2 points. This included the authors’ description identifying

the sources of funding (2 points). 
102 

Table 4. Grading of the quality of evidence of the efficacy of multivitamins/minerals in the prevention of chronic disease 

Key Question 1 

Efficacy of Multivitamins/minera

Cancer CVD Cataract 

Quantity of Evidence:Number of studies 

2 (Linxian, 

SU.VI.MAX) 

2 (Linxian, 

SU.VI.MAX) 

4 (REACT, Lin

AREDS, MON

Total number of patients studied 42325 

(12741+29584) 

42325 

(12741+29584) 

10354 (297+45

5390+71) 

Quality and Consistency of Evidence:

Were study designs randomized trials (high quality), nonrandomized controlled trials (medium quality), or observational studies (low quality)? 

4 

(RCTs) 

4 

(RCTs) 

4 

(RCTs) 

Did the studies have serious (-1) or very serious (-2) limitations in quality? (Enter 0 if none) 

-1 -1 0 

Did the studies have important inconsistency? (-1) 0 0 0 Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest? 

-2 -2 -1 

Were data imprecise or sparse? (-1) -1 -1 -1 Did the studies have high probability of reporting bias? (-1) 0 0 0 Did the studies show strong evidence of association between intervention and recruitment outcome? (“strong” if significant relative risk or odds ratio > 2 based on consistent evidence from 2 or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > 5 based on direct evidence with no major threats to validity (+2)) 

0 0 0 

Did the studies have evidence of a dose-response gradient? (+1) 0 0 0 Did the studies have unmeasured plausible confounders that most likely reduced the magnitude of the observed association? (+1) 

+1 +1 0 

Overall grade of evidence (high, medium, low, very low) Very low Very low Low 

CVD = Cardiovascular disease; AMD = Age-related macular degeneration. 
103 

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease Study name/ Design 

Study site/ Year 

Sample size 

Study population (Age, sex, special characteristics) 

Active supplements 

Supplementation period Self-selected supplement use

Statistically statistically findings (list of disea

22071 95,104 12.9 years 104 (mean) 

12 years95 (mean) 

STATISTICABladder canc(RR 1.5, 95% Thyroid canc(RR 9.5, 95% STATISTICAprostate cancancer, lung leukemia, mstomach canall cancer mincidence, mCVD death, 

21884 86 12 years 

(mean) 

STATISTICANone STATISTICANon-melanobasal cell cacarcinoma 

PHS86,95, 104,108

2 by 2 factorial trial of β-carotene 

and aspirin 

USA/ 1982-1995 

21468 108

Age range: 40-84 100% men US male physicians 

β-carotene 50 mg on alternate day 

12 years (mean) 

Vitamin A supplement users were ineligible for trial enrollment. 23% used multivitamin supplements at baseline. 6.4% of the placebo group reported taking βcarotene or 

vitamin A supplements during the trial. 22% of the βcarotene group 

stopped taking the study supplements before the end of the trial. 

STATISTICANone STATISTICAType 2 Diabe
104 

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease (continued) Study name/ Design 

Study site/ Year 

Sample size 

Study population (Age, sex, special characteristics) 

Active supplements 

Supplementation period Self-selected supplement use

Statistically statistically findings (list of disea

WHS 872 by 2 by 2 factorial trial of β-carotene, 

vitamin E and aspirin All data are from 2 posttrial follow-up studies 

USA Supplementation 1993-1996 Follow-up 1993-1996 

39876 Mean age: 54.6 

100% women Female health care professionals 

β-carotene 50 mg on alternate day 

2.1 years β-carotene supplementation was terminated earlier than planned. 40% used multivitamin supplements outside the trial 

Users of individual supplements of vitamin A, vitamin E, or β-carotene 

more than once per week were ineligible for trial enrollment. At the end of termination of the β-carotene component, 87% of the active group reported taking at least two thirds of the study capsules, and 9.9% of the placebo group reported taking β-carotene or vitamin A supplements outside the trial. 

STATISTICANone STATISTICAAll cancers oskin cancer, incidence, tomortality, mystroke, all m

NSCP 842 by 2 factorial trial of sun screen and βcarotene 

Australia 1992-1996 

809 Mean age: 48.8 

56.3% women 

β-carotene 30 mg per day 

4.5 years No reported STATISTICA

None STATISTICABasal-cell cacarcinoma 
105 

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease (continued) Study name/ Design 

Study site/ Year 

Sample size 

Study population (Age, sex, special characteristics) 

Active supplements 

Supplementation period Self-selected supplement use

Statistically statistically (list of disea

29133 99 Mean age: 57.7 

Age range: 50-69 100% men Smokers (5 or more cigarettes per day) 

6.1 years STATISTICA

None STATISTICAPancreatic cpancreatic c

1344 90 Mean age: 58.8 

100% men Low serum pepsinogen; Smokers (5 or more cigarettes per day) 

5.1 years (median) Serum pepsinogen measured in 1989-91 and 1992-93 

STATISTICANone STATISTICAGastric dyspcarcinoid 

1828 109 Mean age: 

64.5-65.1 years 100% men Smokers (5 or more cigarettes per day) 

6.6-6.7 years Ophthalmology exam performed in Nov 1992-March 1993 

STATISTICANone STATISTICANuclear cataposterior subcataract sev

ATBC 90,97,98,101-103,106,107,109,99,100,110 2 by 2 factorial trial of α-tocopherol and β-carotene 

Finland 1984-1993 

941 110 Age 65 or older 

100% men Smokers (5 or more cigarettes per day) 

β-carotene 20 mg per day 

Ophthalmology exam performed in Dec 1992-March 1993 

Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible 

STATISTICANone STATISTICAAge-related 
106 

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease (continued) Study name 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period 

Self-selected supplement use

Statistically sigstatistically no(list of disease

ATBC (continued) 

Finland 1984-1993 

29133 98 Age range: 50-69, 

100% men; Smokers (5 or more cigarettes per day) Stratified by baseline data 

β-carotene 20 mg per day 

6.1 years Users of vitamin 

A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible 

STATISTICALLY Lung cancer (RR 1.16, 95% group, (RR 1.39, 95% aged 65-69; (RR 1.25, 95% smoker 20+ cig(RR 1.23, 95% who always inh(RR 1.17, 95% exposed to asb(RR 1.40, 95% with dietary inta(RR 1.35, 95% drank ethanol >RR (1.33, 95% with baseline se13.1 mg/L STATISTICALLY Lung cancer in subgroups descLung cancer in baseline dietaror retinol, and bretinol. 
107 

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease (continued) Study name 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period 

Self-selected supplement use

Statistically signon-significan(list of disease

22269 106 Median age: 56.9, 

100% men Smokers (5 or more cigarettes per day) With no history of angina 

4.7 years (median) 

STATISTICALLY None STATISTICALLY Incidence of an

29133 97

Mean age: 57.2 100% men Smokers (5 or more cigarettes per day) 

6.1 years (median) 

STATISTICALLY Lung cancer inc(RR 1.18, 95% lung cancer mo(RR 1.08, 95% 

ATBC (continued) 

Finland 1984-1993 

28519 107 Mean age: 57.7 

100% men Smokers (5 or more cigarettes per day) With no history of stroke

β-carotene 20 mg per day 

6 years (median)

Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible 

STATISTICALLY Intracerebral he(RR 1.62, 95% 

STATISTICALLY Incidence of all hemorrhage, anMortality of substroke, intracerecerebral infarcti
108 

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease (continued)Study name 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period Self-selected supplement use

Statistically statistically (list of disea

29133102 STATISTICA

None STATISTICAColorectal ca

29133101

Mean age: 57.1 100% men Smokers (5 or more cigarettes per day) 

6 years (mean) 

STATISTICANone STATISTICAProstate cancancer morta

15618 100 Mean age: 57.0 

100% men Smokers (5 or more cigarettes per day) 

β-carotene 20 mg per day 

6.3 years (mean) 

Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible 

STATISTICANone STATISTICAColorectal ad

ATBC (continued) 

Finland 1984-1993 

Post-trial follow up 29133103 

Age range: 50-69, 100% men Smokers (5 or more cigarettes per day) 

No study supplement use during post-trial follow up 

6 years for cancer incidence and cause-specific mortality 8 years for total mortality 

 STATISTICA

Colorectal ca(RR 1.88, 95Total mortalit(RR 1.07, 95STATISTICALung cancermortality, urocancer, kidnecancer, othedisease mormortality, nomortality 
109 

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease (continued) Study name/ Design 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period 

Self-selected supplement use

Statistically non-signific(list of disea

SCP85 Parallelarm design 

United States 1983-1993 

1720 Mean age: 63.2 

31% women 

β-carotene 50 mg /day 

Median supplementation: 4.3 yrs Follow up: 8.2 years 

No exclusion was made on supplement use 

STATISTICANone STATISTICAAll deaths, ccancer death

18314 105

STATISTICALung cancer (RR 1.36, 95Lung cancer 1.13-2.23) frSTATISTICALeukemia (pcancer, colorcancer, lympbladder canc

CARET 93,105,183 Parallel-arm design 

Seattle, WA; Portland, OR; San Francisco, CA; Baltimore, MD; New Haven CT; Irvine, CA. Pilot study 1983-1988 Main study 1985-1996 

1831493

Mean age: 58 34.3% women smokers or asbestos workers 

Retinyl palmitate 25000 IU + beta-carotene 30 mg Retinol in pilot phase (1985-1988) then retinyl palmitate (1988-1996) 

4 years (mean) Participants 

agreed to have Vitamin A intake<5500 IU/day, and to not use beta-carotene supplements 

STATISTICALung Cance(RR 1.29, 95Total mortalit(RR 1.17, 95Lung cancer (RR 1.46, 95STATISTICAMesotheliomprostate can
110 

Table 5. Summary of randomized controlled trials on beta-carotene and chronic disease (continued) Study name/ Design 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period 

Self-selected supplement use

Statistically non-signific(list of disea

CARET (cont’d) 

 17140 184

year 1996-2001 

Mean age: 62, 35% women 

None Post-trial follow 

up (6 years) 

Participants were asked to stopped taking the study supplements in 1996 

STATISTICALung cancer 1.01-1.43) Lung cancercardiovasculLung cancer total mortalit1.17) 

PHS (Physicians Health Study); WHS (Women's Health Study); NS (Not Specified); ATBC (Alpha-Tocopherol, Beta Carotene Cancer Prevention Tria

and Retinol Efficacy Trial). 
111 

Table 6. Grading of the quality of evidence of the efficacy of single nutrients in the prevention of chronic disease 

Key Question 3 

Efficacy of single nutrients and related pair

Vitamin E (alone) Selenium 

CVD Cancer Cataract Total mortality Cancer Cancer 

Quality and Consistency of Evidence:

Were study designs randomized trials (high quality), non-randomized controlled trials (medium quality), or observational studies (low quality)? 

High High High High High High 

Did the studies have serious (-1) or very serious (-2) limitations in quality? (Enter 0 if none) 

-1 -1 0 -1 0 0 

Did the studies have important inconsistency? (-1) 0 -1 0 0 0 -1 Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest? 

-1 -1 0 -1 -2 0 

Were data imprecise or sparse? (-1) 0 0 -1 0 -1 0 Did the studies have high probability of reporting bias? (-1) 0 0 0 0 0 0 Did the studies show strong evidence of association between intervention and recruitment outcome? (“strong” if significant relative risk or odds ratio > 2 based on consistent evidence from 2 or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > 5 based on direct evidence with no major threats to validity (+2)) 

0 0 0 0 2 0 

Did the studies have evidence of a dose-response gradient? (+1) 

0 0 0 0 0 0 

Did the studies have unmeasured plausible confounders that most likely reduced the magnitude of the observed association? (+1) 

0 0 0 0 0 0 

Overall grade of evidence (high, medium, low, very low) Low Very 

low 

Moderate Low Low Modera
112 

Table 6. Grading of the quality of evidence of the efficacy of single nutrients in the prevention of chronic disease (continued)

Key Question 3 

Efficacy of single nutrients and related pair

Calcium Vitamin D 

BMD Fracture BMD Fracture 

Quality and Consistency of Evidence:

Were study designs randomized trials (high quality), non-randomized controlled trials (medium quality), or observational studies (low quality)? 

4 4 4 4 

Did the studies have serious (-1) or very serious (-2) limitations in quality? (Enter 0 if none) 

-2 -1 -1 -1 

Did the studies have important inconsistency? (-1) -1 -1 -1 -1 Was there some (-1) or major (-2) uncertainty about the directness or extent to which the people, interventions and outcomes are similar to those of interest? 

0 0 0 0 

Were data imprecise or sparse? (-1) 0 -1 0 0 Did the studies have high probability of reporting bias? (-1) 0 0 0 0 Did the studies show strong evidence of association between intervention and recruitment outcome? (“strong” if significant relative risk or odds ratio > 2 based on consistent evidence from 2 or more studies with no plausible confounders (+1); “very strong” if significant relative risk or odds ratio > 5 based on direct evidence with no major threats to validity (+2)) 

+1 0 0 0 

Did the studies have evidence of a dose-response gradient? (+1) 

0 0 0 0 

Did the studies have unmeasured plausible confounders that most likely reduced the magnitude of the observed association? (+1) 

0 0 0 0 

Overall grade of evidence (high, medium, low, very low) 

Low Very Low Low Low 

CVD = Cardiovascular disease; BMD = bone mineral density 
113 

Table 7. Summary of randomized controlled trials on vitamin E and chronic disease Study name/ Design 

Study site/ Year 

Sample size 

Study population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period Self-selected supplement use

Statistically statistically findings (lis

WHS 872 by 2 by 2 factorial trial of βcarotene, 

vitamin E and aspirin 

USA 1992-2004 

39876 Mean age (SD): 

54.6 (7.0), 100% women 

α-tocopherol (natural source, 600 IU on alternate day) 

10.1 years Users of 

individual supplements of vitamin A, vitamin E, or β-carotene 

more than once per week were ineligible for trial enrollment 40% used multivitamin supplements outside the trial 

STATISTICACardiovascu(RR 0.76, 95STATISTICAMajor cardioof myocardiastroke, ischehemorrhagic cancer, breacolon cancemortality 

29133 99 Mean age: 57.7 

Age range: 50-69 100% men Smokers (5 or more cigarettes per day) 

6.1 years STATISTICA

None STATISTICAPancreatic cpancreatic c

ATBC 90,97,98,101-103,106,107,109,99,100,110 2 by 2 factorial trial of α-tocopherol and β-carotene 

Finland 1984-1993 

1344 90 Mean age: 58.8 

100% men Low serum pepsinogen; Smokers (5 or more cigarettes per day) 

α-tocopheryl acetate 50 mg per day 

5.1 years (median) Serum pepsinogen measured in 1989-91 and 1992-93 

Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible 

STATISTICANone STATISTICAGastric dyspcarcinoid 
114 

Table 7. Summary of randomized controlled trials on vitamin E and chronic disease (continued) Study name/ Design 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period Self-selected supplement use

Statistically statistically findings (lis

1828 109 Mean age: 

64.5-65.1 years 100% men Smokers (5 or more cigarettes per day) 

6.6-6.7 years Ophthalmology exam performed in Nov 1992-March 1993 

STATISTICANone STATISTICANuclear cataposterior subcataract sev

941 110 Age 65 or older 

100% men Smokers (5 or more cigarettes per day) 

Ophthalmology exam performed in Dec 1992-March 1993 

STATISTICANone STATISTICAAge-related 

ATBC (continued) 

Finland 1984-1993 

29133 98 Age range: 50-69, 

100% men; Smokers (5 or more cigarettes per day) Stratified by baseline data 

α-tocopheryl acetate 50 mg per day 

6.1 years 

Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible 

STATISTICANone STATISTICALung cancer Overall and by age, cigacigarette sminhalation, aintake of vitavitamin C, reand serum lecarotene, an
115 

Table 7. Summary of randomized controlled trials on vitamin E and chronic disease (continued) Study name 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period Self-selected supplement use

Statistically statistically findings (lis

22269 106 Median age: 56.9, 

100% men Smokers (5 or more cigarettes per day) With no history of angina 

4.7 years (median) 

STATISTICAAngina (RR 0.91, 95α-tocopheroSTATISTICAAngina ( RR 0.97 antocopherol gtocopherol+βrespectively, 

29133 97 Mean age: 57.2 

100% men Smokers (5 or more cigarettes per day) 

6.1 years (median) 

STATISTICANone STATISTICALung cancertotal mortalit

ATBC (continued) 

Finland 1984-1993 

28519 107 Mean age: 57.7 

100% men Smokers (5 or more cigarettes per day) With no history of stroke

α-tocopheryl acetate 50 mg per day 

6 years (median)

Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible 

STATISTICAFatal subarastroke (RR 2.81, 95Cerebral infa(RR 0.86, 95STATISTICAIncidence of sub-arachno(RR 1.50, 95intracerebramortality of istroke, cereb
116 

Table 7. Summary of randomized controlled trials on vitamin E and chronic disease (continued)Study name 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special characteristics) 

Active Supplements 

Supplementation Period Self-selected supplement use

Statistically statistically findings (lis

29133102 STATISTICA

None STATISTICAColorectal ca0.55-1.09) 

29133101

Mean age: 57.1 100% men Smokers (5 or more cigarettes per day) 

6 years (mean) 

STATISTICAProstate can(RR 0.68, 95Prostate can(RR 0.59, 95STATISTICANone 

15538 100 Mean age: 57.0 

100% men Smokers (5 or more cigarettes per day) No colorectal cancer diagnosis (15 cases had a history of polyps) 

α-tocopheryl acetate 50 mg per day 

6.3 years (mean) 

STATISTICAColorectal ad(RR 1.66, 95STATISTICANone 

ATBC (continued) 

Finland 1984-1993 

Post-trial follow up 29133103 

Age range: 50-69 100% men Smokers (5 or more cigarettes per day) 

No study supplement use during post-trial follow up 

6 years for cancer incidence and cause-specific mortality 8 years for total mortality 

Users of vitamin A, vitamin E, or β-carotene in excess of predefined doses (20,000IU, 20 mg, or 6 mg, respectively) were ineligible 

STATISTICAHemorrhagic (RR 1.40, 95STATISTICALung cancercolorectalc curothelial cacancer, panccancers, cormortality, nomortality, tota
117 

Table 7. Summary of randomized controlled trials on vitamin E and chronic disease. (continued)Study name/ Design 

Study Site/ year 

Sample Size 

Study Population (Age, sex, special character-istics) 

Active Supplements 

Supplementation Period 

Selfselected supplement use 

Statistically statistically findings (lis

1031182 Mean age (SD): 

64.2 (7.6) 42% women Stratified by type 2 diabetes among those with at least one risk factor of cardiovascular disease at baseline 

all-rac α -

tocopherol 300 IU per day 

3.4 years (median) 

Prior long-term use of vitamin E was an exclusion criterion 

STATISTICAPeripheral a(RR 0.37, 95persons with baseline STATISTICACombined Cand stroke, tdeaths, non stroke , angiischemic attaprocedure, aor without didisease in pe

PPP112,181

2 by 2 factorial trial of all-rac αtocopheryl 

acetate and aspirin Premature termination of the trial 

Italy, 1994-1998 

4495112 Mean age (SD): 

64.4 (7.6) 57% women With at least one risk factor for cardiovascular disease; 23% disbetics 

all-rac α -

tocopherol 300 IU per day 

3.7 years (median) 

Prior long-term use of vitamin E was an exclusion criterion 

STATISTICAPeripheral a(RR =0.54, CSTATISTICAMain combinevents or disCV deaths, astroke, non-fischemic attadisease, revprocedures, deaths 

VECAT 113 Melbourne, 

Australia, 1995-2000 

1193 Mean age: 65.7 

56% women 

RRR-αtocopherol 

500 IU per day 

4 years planned 24% STATISTICA

None STATISTICACortical cataposterior subcataract 

WHS (Women's Health Study); VECAT (Vitamin E, Cataract and Age-Related Maculopathy Trial); ATBC (Alpha-Tocopherol, Beta Carotene Cancer P(Beta Carotene and Retinol Efficacy Trial); PPP (Primary Prevention Project); SD (Standard Dilatation). 
118 
FIGURES 

81 

Figure 1. Conceptual framework for the prevention of chronic diseases and conditions with 

vitamin/mineral supplements (circled numbers represent the key questions addressed in this 

systematic review) 

General 

Population

Age,

Sex,

Race/ethnicity

Genetic 

susceptibility

Geographic

location

Smoking,

Intake of fruits/ 

vegetables,

Intake of 

energy/fat/ 

carbohydrate,

Sunlight

exposure,

Physical activity, 

Obesity

Self-selected

supplement use

Anti-oxidant effects,

Anti-inflammatory effects,

Anti-proliferation/Apoptosis,

Regulate one-carbon metabolism,

Regulate bone mineral density/

content and bone quality,

Regulate electrolyte homeostasis, 

Regulate cellular and enzymatic 

functions and immune responses

Supplementation with multivitamins/

minerals (chemical form, dose, 

timing, frequency, duration)

Supplementation with single nutrients

(chemical form, dose, timing, 

frequency, duration)

Adverse effect of multivitamin/

mineral supplement use

3

2

nutrient-nutrient interaction

4

Primary Prevention of 

a) breast cancer, 

colorectal cancer, lung 

cancer, prostate cancer, 

gastric cancer, or any 

other malignancy

b) myocardial infarction, 

stroke

c) type 2 diabetes 

mellitus

d) Parkinson’s disease, 

cognitive decline, 

memory loss, dementia 

e) cataracts, macular 

degeneration, hearing 

loss

f) osteoporosis, 

osteopenia, rheumatoid 

arthritis, osteoarthritis

g) non-alcoholic 

steatorrheic hepatitis,

non-alcoholic fatty-liver 

disease

h) chronic renal 

insufficiency, chronic 

nephrolithiasis

i) HIV infection, hepatitis 

C, tuberculosis

Adverse effect of single 

vitamin or mineral 

supplement use

1
Figure 2. Summary of literature search and review process (number of articles ) 

Electronic Databases 

MEDLINE® (7880) 

Cochran: Reviews and 

CENTRAL (15) 

EMBASE® (3350)

Retrieved 

11324

Title Review 

10475

Abstract Review 

3612 

Article Inclusion/

exclusion 

449

Included Studies 

63 

KQ 1 = 11 

KQ 2 = 8 

KQ3 = 44 

KQ4 = 24 

(articles can apply to more than 

one Key Question) 

Hand Searching 

79 

Duplicates 

849 

Excluded 

6863 

Excluded 

3163 

Excluded 

386 

KQ = Key Question; RCT = randomized controlled trial. 

*

 Total is greater than 3062, reviewers were allowed to choose more than one reason for exclusion at this level. 

†

 Total is greater than 296, reviewers were allowed to choose more than one reason for exclusion at this level. 

82 

Reasons for Exclusion 

at the Abstract Review Level*

Not English language: 0 

No human data: 18 

Includes ONLY pregnant women: 69 

Includes ONLY patients with a chronic disease or condition: 

878 

Includes ONLY patients receiving treatment for dialysis, transplant, chemotherapy, HIV infection, tuberculosis, end-stage 

renal disease, or patients in long-term care facilities: 170 

ONLY covers clinical nutritional deficiency: 66 

Does not apply to the KEY QUESTIONS: 1296 

Does not address the use of supplements: 735 

Does not report the use of supplements separately from dietary 

intake: 165 

Does NOT cover the defined major disease endpoints or adverse effects of vitamins/minerals: 1489 

Editorial/Commentary/Letter: 300 

Other: 741 

Reasons for Exclusion 

at the Article Inclusion/Exclusion Level†

 

Not English language: 0 

No human data: 2 

Includes ONLY pregnant women: 2 

Includes ONLY patients with a chronic disease or condition: 32 

Includes ONLY patients receiving treatment for dialysis, transplant, chemotherapy, HIV infection, tuberculosis, end-stage 

renal disease, or patients in long-term care facilities: 11 

ONLY covers nutritional deficiency: 3 

Does not apply to the KEY QUESTIONS: 123 

Does not address the use of supplements: 51 

Does not report the use of supplements separately from dietary 

intake: 3 

Does NOT cover the defined major disease endpoints or adverse effects of vitamins/minerals: 64 

Editorial/Commentary/Letter: 35 

Other: 133 

Narrative review, contains studies of interest OR not an RCT, 

systematic review, or meta-analysis: 87 

Includes ONLY infants: 6 

Includes ONLY subjects less than 19 years of age (exclusion 

for KQs 1 an 2 only): 1 
83 

Figure 3. Relative risk (RR) of total cancer, gastric cancer and esophageal cancer incidence in relation to 

multivitamin/mineral supplement use 

RR

.25 .5 1 1.5 2.5 5

*For beta carotene, vitamin E and selenium users vs. non-users

SUVIMAX all cancer incidence, male; RR=0.69 

(0.53-0.91); Antioxidants vs. placebo 

SUVIMAX all cancer incidence, female; RR=1.04 

(0.85-1.29); Antioxidants vs. placebo 

SUVIMAX prostate cancer incidence; RR=0.88 

(0.60-1.29); Antioxidants vs. placebo 

Linxian gastric cancer incidence RR=0.84 

(0.71-1.00)* 

Linxian esophageal cancer incidence 

RR=1.02 (0.87-1.19)* 
84 

Figure 4. Relative risk (RR) of total cancer, gastric cancer and esophageal cancer mortality in relation to 

multivitamin/mineral supplement use 

 RR

.25 .5 1 1.5 2.5 5

*For beta carotene, vitamin E and selenium users vs. non-users

Linxian gastric cancer mortality 

RR=0.79 (0.64-0.99)* 

Linxian esophageal cancer mortality 

RR=0.96 (0.78-1.18)* 

Linxian all cancer mortality 

RR=0.87 (0.75-1.00)* 
85 

Figure 5. Relative risk (RR) of cardiovascular disease incidence in relation to multivitamin/mineral 

supplement use 

 RR

.25 .5 1 1.5 2.5 5

*For beta carotene, vitamin E and selenium users vs. non-users

SUVIMAX IHD incidence, male RR=0.82 

(0.71-1.20); Antioxidants vs. placebo 

SUVIMAX IHD incidence, female RR=1.17 

(0.67-2.05); Antioxidants vs. placebo 

Linxian cerebrovascular mortality RR=0.90 

(0.76-1.07)* 
86 

Figure 6. Relative risk (RR) of all cause mortality in relation to multivitamin/ mineral supplement use 

 RR

.25 .5 1 1.5 2.5 5

*For beta carotene, vitamin E and selenium users vs. non-users

SUVIMAX all cause mortality, male RR=0.63 (0.42-

0.93) Antioxidants vs. placebo 

SUVIMAX all cause mortality, female RR=1.03 

(0.64-1.63) Antioxidants vs. placebo

Linxian all cause mortality 

RR=0.91 (0.84-0.99)* 

AREDs all cause mortality 

RR=1.06 (0.84-1.33) 

Antioxidants vs. no antioxidants 
APPENDIXES 
Appendix A: Technical Experts and Peer Reviewers 

A 1 

Technical Experts and Peer Reviewers 

Lindsay Allen, RD, PhD 

USDA – Agricultural Research Center 

Western Human Nutrition Research Center 

and Program in International Nutrition 

1 Shields Avenue, SurgeE IV 

Davis, CA 

Bruce Ames, PhD 

Children's Hospital Oakland Research 

Institute (CHORI) 

5700 Martin Luther King Jr. Way 

Oakland, CA 

John Beard, PhD 

Department of Nutritional Sciences, 

Penn State University 

S-128A Henderson South Bldg. 

University Park, PA 

John W. Erdman, Jr. 

Professor 

University of Illinois 

Division of Nutritional Sciences 

Urbana, IL 

Gary Goodman, MD, MS 

Fred Hutchinson Cancer Research Center 

Seattle, WA 

Alice Lichtenstein, DSc 

Senior Scientist 

Director of the Cardiovascular Nutrition 

Laboratory, Jean Mayer USDA Human 

Nutrition Research Center on Aging 

Professor of Family Medicine and 

Community Health 

Tufts University School of Medicine 

Boston, MA 

Joel A. Simon, MD, MPH 

General Internal Medicine Section (111A1) 

San Francisco Veterans Affairs Medical 

Center and University of California 

4150 Clement Street 

San Francisco, CA 

Emily White, PhD 

Cancer Prevention Research Program 

Fred Hutchinson Cancer Research Center 

Seattle, WA
Appendix A: Technical Experts and Peer Reviewers 

A 2 

Internal Technical Experts 

Leon Gordis, MD, DPH 

Professor 

Bloomberg School of Public Health 

Department of Epidemiology 

Baltimore, MD 

Alfred Sommer, MD 

Bloomberg School of Public Health 

Dean- Finance & Admin 

Baltimore, MD 
Appendix B: Hand Searched Journals 

B 1 

All Journals Hand Searched 

January 2005 through February 2006 

Annals of Epidemiology 

Annals of Internal Medicine 

Annals of the New York Academy of Science 

Archives of Ophthalmology 

Cancer Causes and Control 

Cancer Research 

Cancer Research 

Controlled Clinical Trials 

International Journal for Vitamin and Nutrition Research 

Journal of Bone and Mineral Metabolism 

Journal of the American Medical Association 

Journal of the National Cancer Institute 

Lancet 

Osteoporosis International 

The Journal of Nutrition 
Appendix C: Detailed Electronic Database Search Strategies

C 1 

MEDLINE Strategy 

((((“Calcium, dietary”[mh] OR “dietary Calcium”[tiab] OR “Calcium supplement*”[tiab] OR “folic 

acid”[tiab] OR “folic acid”[mh] OR folate[tiab] OR “folate supplement*”[tiab] OR “Vitamin B 6”[tiab] OR 

“Vitamin B6”[tiab] OR Pyridoxine[tiab] OR “Vitamin B 6”[mh] OR “Vitamin B 12”[tiab] OR “Vitamin 

B12”[tiab] OR “Vitamin B 12”[mh] OR “Vitamin D”[tiab] OR Cholecalciferol[tiab] OR “Vitamin D”[mh] 

OR “Vitamin E”[tiab] OR Tocopherol[tiab] OR “Vitamin E”[mh] OR “Vitamin C”[tiab] OR “Ascorbic 

acid”[tiab] OR ascorbate[tiab] OR “Ascorbic acid”[mh] OR “Vitamin A”[tiab] OR “Vitamin A”[mh] OR 

“beta carotene”[tiab] OR “beta carotene”[mh] OR (iron[tiab] AND (“dietary supplement*”[tiab] OR 

supplement*[tiab])) OR “iron, dietary”[mh] OR (zinc[tiab] AND (“dietary supplement*”[tiab] OR 

supplement*[tiab])) OR (Magnesium[tiab] AND (“dietary supplement*”[tiab] OR supplement*[tiab])) OR 

“Vitamin B 1”[tiab] OR “Vitamin B1”[tiab] OR Thiamin[tiab] OR Thiamine[tiab] OR Thiamine[mh] OR 

“Vitamin B 2”[tiab] OR “Vitamin B2”[tiab] OR Riboflavin[tiab] OR Riboflavin[mh] OR Niacin[tiab] OR 

“Nicotinic acids”[tiab] OR “nicotinic acid”[tiab] OR “Nicotinic acids”[mh] OR Selenium[tiab] OR 

Selenium [mh] OR Multivitamin*[tiab] OR Vitamin*[tiab] OR Vitamins[mh] OR Mineral*[tiab] OR 

Minerals[mh] OR “Vitamin Supplement*”[tiab] OR “Mineral Supplement*”[tiab] OR “multivitamin 

supplement*”[tiab] OR “multimineral supplement*”[tiab]) AND (Neoplasms[mh] OR neoplasm*[tiab] 

OR “Cardiovascular diseases”[mh] OR ”cardiovascular disease*”[tiab] OR “Endocrine system 

diseases”[mh] OR “Endocrine system diseases”[tiab] OR “Nervous system diseases”[mh] OR 

“Nervous system disease*”[tiab] OR “eye diseases”[mh] OR “eye disease*”[tiab] OR “hearing 

loss”[mh] OR “hearing loss”[tiab] OR “Musculoskeletal diseases”[mh] OR “Musculoskeletal 

disease*”[tiab] OR “digestive system diseases”[mh] OR “digestive system disease*”[tiab] OR “Kidney 

diseases”[mh] OR “Kidney disease*”[tiab] OR “Communicable diseases”[mh] OR “Communicable 

diseases”[tiab] OR “infectious disease”[tiab] OR “Lung diseases”[mh] OR “Lung disease*”[tiab] OR 

“Lung neoplasms”[tiab] OR “breast cancer”[tiab] OR “Breast neoplasms”[tiab] OR “colorectal 

cancer”[tiab] OR “Colorectal neoplasms”[tiab] OR “lung cancer”[tiab] OR “prostate cancer”[tiab] OR 

“Prostatic neoplasms”[tiab] OR “gastric cancer”[tiab] OR “stomach cancer”[tiab] OR “Stomach 

neoplasms”[tiab] OR “Abdominal neoplasms”[tiab] OR “colorectal polyps”[tiab] OR “Colon 

polyps”[tiab] OR adenomas[tiab] OR Polyps[tiab] OR “myocardial infarction”[tiab] OR “Heart 

arrest”[tiab] OR “myocardial ischemia”[tiab] OR “Coronary artery disease”[tiab] OR “heart attack”[tiab] 

OR “Ischemic heart disease”[tiab] OR stroke[tiab] OR “cerebrovascular accident”[tiab] OR 

“Cerebrovascular disease”[tiab] OR “type 2 diabetes”[tiab] OR “Diabetes mellitus”[tiab] OR “adult 

onset diabetes”[tiab] OR “Alzheimer’s disease”[tiab] OR “Parkinson disease”[tiab] OR dementia[tiab] 

OR “Alzheimer’s disease”[tiab] OR “Alzheimer disease”[tiab] OR cataract[tiab] OR cataracts[tiab] OR 

“macular degeneration”[tiab] OR deafness[tiab] OR osteoporosis[tiab] OR Fractures[tiab] OR 

“rheumatoid arthritis”[tiab] OR osteoarthritis[tiab] OR “Degenerative joint disease”[tiab] OR 

osteopenia[tiab] OR “Metabolic bone diseases”[tiab] OR “steatohepatitis”[tiab] OR NASH[tiab] OR 

“fatty-liver disease“[tiab] OR NAFLD[tiab] OR “renal insufficiency”[tiab] OR “Chronic kidney 

failure”[tiab] OR “nephrolithiasis”[tiab] OR Nephropathy[tiab] OR “HIV infection”[tiab] OR AIDS[tiab] 

OR "acquired immunodeficiency syndrome"[tiab] OR “hepatitis C”[tiab] OR tuberculosis[tiab] OR 

“chronic obstructive pulmonary disease”[tiab] OR Emphysema[tiab] OR “Chronic bronchitis”[tiab])) 

AND (“Randomized controlled trial”[pt] OR “controlled clinical trial”[pt] OR “Randomized controlled 

trials”[mh] OR “Random allocation”[mh] OR “double-blind method”[mh] OR “single-blind 

method”[mh])) OR ((“Calcium, dietary”[mh] OR “dietary Calcium”[tiab] OR “Calcium supplement*”[tiab] 

OR “folic acid”[tiab] OR “folic acid”[mh] OR folate[tiab] OR “folate supplement*”[tiab] OR “Vitamin B 

6”[tiab] OR “Vitamin B6”[tiab] OR Pyridoxine[tiab] OR “Vitamin B 6”[mh] OR “Vitamin B 12”[tiab] OR 

“Vitamin B12”[tiab] OR “Vitamin B 12”[mh] OR “Vitamin D”[tiab] OR Cholecalciferol[tiab] OR “Vitamin 

D”[mh] OR “Vitamin E”[tiab] OR Tocopherol[tiab] OR “Vitamin E”[mh] OR “Vitamin C”[tiab] OR 

“Ascorbic acid”[tiab] OR “Ascorbic acid”[mh] OR “Vitamin A”[tiab] OR “Vitamin A”[mh] OR “beta 

carotene”[tiab] OR “beta carotene”[mh] OR “dietary iron”[tiab] OR “iron supplement*”[tiab] OR “iron, 

dietary”[mh] OR “dietary zinc”[tiab] OR “zinc supplement*”[tiab] OR “dietary Magnesium”[tiab] OR 

“Magnesium supplement*”[tiab] OR “Vitamin B 1”[tiab] OR “Vitamin B1”[tiab] OR Thiamin[tiab] OR 

Thiamine[tiab] OR Thiamine[mh] OR “Vitamin B 2”[tiab] OR “Vitamin B2”[tiab] OR Riboflavin[tiab] OR 

Riboflavin[mh] OR Niacin[tiab] OR “Nicotinic acids”[tiab] OR “nicotinic acid”[tiab] OR “Nicotinic 

acids”[mh] OR Multivitamin*[tiab] OR Vitamin*[tiab] OR Vitamins[mh] OR Mineral*[tiab] OR 

Minerals[mh] OR “Vitamin Supplement*”[tiab] OR “Mineral Supplement*”[tiab] OR “multivitamin 

supplement*”[tiab] OR “multimineral supplement*”[tiab] OR Selenium[tiab] OR “dietary selenium”[tiab] 

OR Selenium[mh]) AND (safety[mh] OR safety[tiab] OR “adverse event*”[tiab] OR 

“pharmacology”[mh] OR “adverse effects”[subheading] OR “adverse effect*”[tiab] OR “side 

effect*”[tiab] OR “product surveillance, postmarketing”[mh] “Adverse reaction*”[tiab] OR “drug 

toxicity”[mh] OR “drug toxicity”[tiab]))) AND (English[lang] NOT (animal[mh] NOT human[mh])) 

7880 
Appendix C: Detailed Electronic Database Search Strategies

C 2 

Cochrane Library (Reviews and CENTRAL) Strategy 

(((TX dietary AND (TX Calcium OR TX “folic acid” OR TX folate OR TX “vitamin B6” OR TX vitamin B 

6” TX OR pyridoxine OR TX “vitamin B12” OR TX “vitamin B 12” OR TX “Vitamin D” OR TX 

cholecalciferol OR TX “Vitamin E” OR TX tocopherol OR TX “Vitamin E” OR TX “Vitamin C” OR TX 

“Ascorbic Acid” OR TX ascorbate OR TX “Vitamin A” OR TX “beta carotene” OR TX Iron OR TX zinc 

OR TX magnesium OR TX “Vitamin B1” OR TX “Vitamin B 1” OR TX “Vitamin B1” OR TX “Vitamin B 

2” Or TX Thiamine OR TX Thiamin OR TX Riboflavin OR TX Niacin OR TX “nicotinic acid” OR TX 

multivitamin OR TX Multimineral OR TX selenium)) OR ((TX Calcium OR TX “folic acid” OR TX folate 

OR TX “vitamin B6” OR TX vitamin B 6” TX OR pyridoxine OR TX “vitamin B12” OR TX “vitamin B 12” 

OR TX “Vitamin D” OR TX cholecalciferol OR TX “Vitamin E” OR TX tocopherol OR TX “Vitamin E” 

OR TX “Vitamin C” OR TX “Ascorbic Acid” OR TX ascorbate OR TX “Vitamin A” OR TX “beta 

carotene” OR TX Iron OR TX zinc OR TX magnesium OR TX “Vitamin B1” OR TX “Vitamin B 1” OR 

TX “Vitamin B1” OR TX “Vitamin B 2” Or TX Thiamine OR TX Thiamin OR TX Riboflavin OR TX Niacin 

OR TX “nicotinic acid” OR TX multivitamin OR TX Multimineral OR TX selenium) AND TX 

supplement)) AND ((TX Neoplasm OR TX “Cardiovascular disease” OR TX “Endocrine system 

disease” OR TX “Nervous system disease” OR TX “eye disease” OR TX “hearing loss” OR TX 

“Musculoskeletal disease” OR TX “digestive system disease” OR TX “Kidney disease” OR TX 

“Communicable disease” OR TX “infectious disease” OR TX “Lung diseases” OR TX “Lung 

neoplasms” OR TX “breast cancer” OR TX “Breast neoplasms” OR TX “colorectal cancer” OR TX 

“Colorectal neoplasms” OR TX “lung cancer” OR TX “prostate cancer” OR TX “Prostatic neoplasms” 

OR TX “gastric cancer” OR TX “stomach cancer” OR TX “Stomach neoplasms” OR TX “Abdominal 

neoplasms” OR TX “colorectal polyps” OR TX “Colon polyps” OR TX adenomas OR TX Polyps OR 

TX “myocardial infarction” OR TX “Heart arrest” OR TX “myocardial ischemia”) OR (TX “Coronary 

artery disease” OR TX “heart attack” OR TX “Ischemic heart disease” OR TX stroke OR TX 

“cerebrovascular accident” OR TX “Cerebrovascular disease” OR TX “type 2 diabetes” OR TX 

“Diabetes mellitus” OR TX “adult onset diabetes” OR TX “Alzheimer’s disease” OR TX “Parkinson 

disease” OR TX dementia OR TX cataract OR TX “macular degeneration” OR TX deafness OR TX 

osteoporosis OR TX Fractures OR TX “rheumatoid arthritis” OR TX osteoarthritis OR TX 

“Degenerative joint disease” OR TX osteopenia OR TX “Metabolic bone diseases” OR TX 

“steatohepatitis” OR TX “fatty-liver disease“ OR TX “renal insufficiency” OR TX “Chronic kidney 

failure” OR TX “nephrolithiasis” OR TX Nephropathy OR TX “HIV infection” OR TX AIDS OR TX 

“acquired immunodeficiency syndrome” OR TX “hepatitis C” OR TX tuberculosis OR TX “chronic 

obstructive pulmonary disease” OR TX Emphysema OR TX “Chronic bronchitis”)) OR (((TX dietary 

AND (TX Calcium OR TX “folic acid” OR TX folate OR TX “vitamin B6” OR TX vitamin B 6” TX OR 

pyridoxine OR TX “vitamin B12” OR TX “vitamin B 12” OR TX “Vitamin D” OR TX cholecalciferol OR 

TX “Vitamin E” OR TX tocopherol OR TX “Vitamin E” OR TX “Vitamin C” OR TX “Ascorbic Acid” OR 

TX ascorbate OR TX “Vitamin A” OR TX “beta carotene” OR TX Iron OR TX zinc OR TX magnesium 

OR TX “Vitamin B1” OR TX “Vitamin B 1” OR TX “Vitamin B1” OR TX “Vitamin B 2” Or TX Thiamine 

OR TX Thiamin OR TX Riboflavin OR TX Niacin OR TX “nicotinic acid” OR TX multivitamin OR TX 

Multimineral OR TX selenium)) OR ((TX Calcium OR TX “folic acid” OR TX folate OR TX “vitamin B6” 

OR TX vitamin B 6” TX OR pyridoxine OR TX “vitamin B12” OR TX “vitamin B 12” OR TX “Vitamin D” 

OR TX cholecalciferol OR TX “Vitamin E” OR TX tocopherol OR TX “Vitamin E” OR TX “Vitamin C” 

OR TX “Ascorbic Acid” OR TX ascorbate OR TX “Vitamin A” OR TX “beta carotene” OR TX Iron OR 

TX zinc OR TX magnesium OR TX “Vitamin B1” OR TX “Vitamin B 1” OR TX “Vitamin B1” OR TX 

“Vitamin B 2” Or TX Thiamine OR TX Thiamin OR TX Riboflavin OR TX Niacin OR TX “nicotinic acid” 

OR TX multivitamin OR TX Multimineral OR TX selenium) AND TX supplement)) AND (TX safety OR 

TX “adverse event” OR TX “pharmacology” OR TX “adverse effects” OR TX “adverse effect” OR TX 

“side effect” OR (TX postmarketing W1 “product surveillance”) OR TX “Adverse reaction” OR TX 

“drug toxicity” OR TX “drug toxicity”))) 

15
Appendix C: Detailed Electronic Database Search Strategies

C 3 

EMBASE Strategy 

(((((('calcium'/exp/mj OR 'calcium') OR ('folic acid'/exp/mj OR 'folic acid') OR ('folate'/exp/mj OR 'folate') 

OR ('vitamin b6'/exp/mj OR 'vitamin b6') OR ('vitamin b 6'/exp/mj OR 'vitamin b 6') OR 

('pyridoxine'/exp/mj OR 'pyridoxine') OR ('vitamin b12'/exp/mj OR 'vitamin b12') OR ('vitamin b 

12'/exp/mj OR 'vitamin b 12') OR ('vitamin d'/exp/mj OR 'vitamin d') OR ('cholecalciferol'/exp/mj OR 

'cholecalciferol') OR ('vitamin e'/exp/mj OR 'vitamin e') OR ('tocopherol'/exp/mj OR 'tocopherol') OR 

('vitamin c'/exp/mj OR 'vitamin c') OR acorbate OR ('ascorbic acid'/exp/mj OR 'ascorbic acid') OR 

('vitamin a'/exp/mj OR 'vitamin a') OR ('beta carotene'/exp/mj OR 'beta carotene') OR ('vitamin 

b1'/exp/mj OR 'vitamin b1') OR ('vitamin b 1'/exp/mj OR 'vitamin b 1') OR ('thiamin'/exp/mj OR 

'thiamin') OR ('thiamine'/exp/mj OR 'thiamine') OR ('vitamin b2'/exp/mj OR 'vitamin b2') OR ('vitamin b 

2'/exp/mj OR 'vitamin b 2') OR ('riboflavin'/exp/mj OR 'riboflavin') OR ('niacin'/exp/mj OR 'niacin') OR 

('nicotinic acid'/exp/mj OR 'nicotinic acid') OR ('multivitamin'/exp/mj OR 'multivitamin') OR 

('vitamin'/exp/mj OR 'vitamin') OR vitmins OR ('mineral'/exp/mj OR 'mineral') OR minerals OR 

multiminerals AND [english]/lim AND [humans]/lim) OR ((('iron'/exp/mj OR 'iron') OR ('zinc'/exp/mj OR 

'zinc') OR ('magnesium'/exp/mj OR 'magnesium')) AND (supplement OR ('dietary supplement'/exp/mj 

OR 'dietary supplement')) AND [english]/lim AND [humans]/lim)) AND ((neoplasm or 'hearing loss' or 

'colorectal polyps' or 'colon polyps' or adenoma or polyp or 'myocardial infarction' or 'heart arrest' or 

'myocardial ischemia' or 'heart attack' or stroke or 'cerebrovacular accident' or 't ype 2 diabetes' or 

'diabetes mellitus' or 'adult onset diabetes' or dementia or cataract or cataracts or 'macular 

degeneration' or deafness or osteoporosis or osteoarthritis or osteopenia or fracture or 'rheumatoid 

arthritis' or 'rheumatiod arthritis' or steatohepatits or nash or nafld or 'renal insufficiency' or 'chronic 

kidney failure' or nephrolithiasis or nephropathy or 'hiv infection' or aids or 'acquired immunodeficiency 

syndrome' or 'hepatitis c' or tuberculosis or 'chronic obstructive pulmonary disease' or emphysema or 

'chronic bronchitis')or AND ((cardiovascular OR 'endocrin system' OR ('nervous system'/exp/mj OR 

'nervous system') OR ('eye'/exp/mj OR 'eye') OR musculoskeletal OR ('digestive system'/exp/mj OR 

'digestive system') OR ('kidney'/exp/mj OR 'kidney') OR communicable OR infectious OR ('lung'/exp/mj 

OR 'lung') OR ('coronary artery'/exp/mj OR 'coronary artery') OR ('ischemic heart'/exp/mj OR 'ischemic 

heart') OR cerebrovascular OR alzheimer's or parkinson's OR 'degenerative joint' OR 'metabolic bone' 

OR ('fatty liver'/exp/mj OR 'fatty liver')) AND ('disease'/exp/mj OR 'disease')) OR ((('lung'/exp/mj OR 

'lung') OR ('breast'/exp/mj OR 'breast') OR ('colon'/exp/mj OR 'colon') OR colorectal OR 

('prostate'/exp/mj OR 'prostate') OR gastric OR ('stomach'/exp/mj OR 'stomach') OR abdominal) AND 

(('cancer'/exp/mj OR 'cancer') OR ('neoplasm'/exp/mj OR 'neoplasm'))) AND [english]/lim AND 

[humans]/lim)) AND ('randomized controlled trial':it OR 'controlled clinical trial':it AND [english]/lim AND 

[humans]/lim)) OR ((((('calcium'/exp/mj OR 'calcium') OR ('folic acid'/exp/mj OR 'folic acid') OR 

('folate'/exp/mj OR 'folate') OR ('vitamin b6'/exp/mj OR 'vitamin b6') OR ('vitamin b 6'/exp/mj OR 

'vitamin b 6') OR ('pyridoxine'/exp/mj OR 'pyridoxine') OR ('vitamin b12'/exp/mj OR 'vitamin b12') OR 

('vitamin b 12'/exp/mj OR 'vitamin b 12') OR ('vitamin d'/exp/mj OR 'vitamin d') OR 

('cholecalciferol'/exp/mj OR 'cholecalciferol') OR ('vitamin e'/exp/mj OR 'vitamin e') OR 

('tocopherol'/exp/mj OR 'tocopherol') OR ('vitamin c'/exp/mj OR 'vitamin c') OR acorbate OR ('ascorbic 

acid'/exp/mj OR 'ascorbic acid') OR ('vitamin a'/exp/mj OR 'vitamin a') OR ('beta carotene'/exp/mj OR 

'beta carotene') OR ('vitamin b1'/exp/mj OR 'vitamin b1') OR ('vitamin b 1'/exp/mj OR 'vitamin b 1') OR 

('thiamin'/exp/mj OR 'thiamin') OR ('thiamine'/exp/mj OR 'thiamine') OR ('vitamin b2'/exp/mj OR 

'vitamin b2') OR ('vitamin b 2'/exp/mj OR 'vitamin b 2') OR ('riboflavin'/exp/mj OR 'riboflavin') OR 

('niacin'/exp/mj OR 'niacin') OR ('nicotinic acid'/exp/mj OR 'nicotinic acid') OR ('multivitamin'/exp/mj OR 

'multivitamin') OR ('vitamin'/exp/mj OR 'vitamin') OR vitmins OR ('mineral'/exp/mj OR 'mineral') OR 

minerals OR multiminerals) OR (('iron'/exp/mj OR 'iron') OR ('zinc'/exp/mj OR 'zinc') OR 

('magnesium'/exp/mj OR 'magnesium') OR ('selenium'/exp/mj OR 'selenium')) AND (supplement OR 

('dietary supplement'/exp/mj OR 'dietary supplement'))) AND [english]/lim AND [humans]/lim) AND 

(('safety'/exp/mj OR 'safety') OR 'adverse event' OR ('pharmacology'/exp/mj OR 'pharmacology') OR 

'adverse effects' OR ('adverse effect'/exp/mj OR 'adverse effect') OR ('side effect'/exp/mj OR 'side 

effect') OR 'product surveillance' OR ('adverse reaction'/exp/mj OR 'adverse reaction') OR ('drug 

toxicity'/exp/mj OR 'drug toxicity') AND [english]/lim AND [humans]/lim))) 

3350 
Appendix D: Excluded Articles 

D 1 

Excluded Articles 

Albanes D. Beta-carotene and lung cancer: a case 

study. Am J Clin Nutr 99;69(6):1345S-1350S. 

Narrative review 

Allender PS, Cutler JA, Follmann D et al. Dietary 

calcium and blood pressure: a meta-analysis of 

randomized clinical trials. Ann Intern Med 

96;124(9):825-31. Does not cover the defined 

disease endpoints 

Arab L, Steck-Scott S, Bowen P. Participation of 

lycopene and beta-carotene in carcinogenesis: 

defenders, aggressors, or passive bystanders?. 

Epidemiol Rev 2001;23(2):211-30. Narrative 

review 

Arthur R S, Piraino B, Candib D et al. Effect of lowdose calcitriol and calcium therapy on bone 

histomorphometry and urinary calcium excretion 

in osteopenic women. Miner Electrolyte Metab 

90;16(6):385-90. Includes ONLY patients with 

a particular chronic disease

Audicana M, Schmidt R, Fernandez de et al. Allergic 

contact dermatitis from nicotinic acid esters. 

Contact Dermatitis 90;22(1):60-1. Does not 

address the use of supplements

Balato N, Patruno C, Lembo G et al. Allergic contact 

dermatitis from retinoic acid. Contact Dermatitis 

95;32(1):51. Does not apply to the key 

questions, does not address the use of 

supplements

Baqui AH, de Francisco A, Arifeen SE et al. Bulging 

fontanelle after supplementation with 25,000 IU 

of vitamin A in infancy using immunization 

contacts. Acta Paediatr 95;84(8):863-6. Does not 

apply to the key questions, does not cover the 

defined disease endpoints, includes only 

infiants

Baris B. Lung cancer chemoprevention with 

antioxidant vitamins. Turk J Med Sci 

94;22(1):63-64. Editorial 

Bartels CL, Miller SJ. Dietary supplements marketed 

for weight loss. Nutr Clin Prac 2003;18(2):156-

169. Does not apply to the key questions, does 

not address the use of supplements

Bigby M, Stern RS. Adverse reactions to isotretinoin. 

A report from the Adverse Drug Reaction 

Reporting System. J Am Acad Dermatol 

88;18(3):543-52. Does not apply to the key 

questions, does not address the use of 

supplements

Blondeel A. Contact allergy to vitamin A. Contact 

Dermatitis 84;11(3):191-2. Does not apply to 

the key questions, does not address the use of 

supplements

Blot WJ. Vitamin/mineral supplementation and cancer 

risk: international chemoprevention trials. Proc 

Soc Exp Biol Med 97;216(2):291-6. Narrative 

review 

Bostick RM, Potter JD, Fosdick L et al. Calcium and 

colorectal epithelial cell proliferation: a 

preliminary randomized, double-blinded, 

placebo-controlled clinical trial. J Natl Cancer 

Inst 93;85(2):132-41. Does not cover the 

defined disease endpoints 

Boyd EM. Food and drug toxicity. A summary of 

recent studies. J Clin Pharmacol J New Drugs 

68;8(5):281-4. Narrative review 

Brawley OW, Thompson IM. The chemoprevention of 

prostate cancer and the Prostate Cancer 

Prevention Trial. Cancer Treat Res 96;88189-

200. Narrative review 

Bridge EV. Chemoprophylaxis: a major adjunct in the 

prevention of tuberculosis. Mich Med 

67;66(24):1553-5. Does not apply to the key 

questions, does not address the use of 

supplements, does not cover the defined 

disease endpoints

Brown BG, Zhao XQ, Chait A et al. Simvastatin and 

niacin, antioxidant vitamins, or the combination 

for the prevention of coronary disease. N Engl J 

Med 2001;345(22):1583-92. Includes ONLY 

patients with a particular chronic disease, does 

not apply to the key questions

Brown S. Aspirin and vitamin E of little effect in the 

prevention of cardiovascular disease or cancers in 

older women. J Br Menopause Soc 

2005;11(3):80-81. Editorial 

Browne R, Boag F. What is your patient taking? 

Dietary supplements in an HIV-positive patient. 

Int J STD Aids 2005;16(9):639-641. Includes 

ONLY patients with a particular chronic 

disease

Bruppacher R. Epidemiological criteria for evidence 

of beneficial or adverse effects of elevated 

dosages of vitamins.. Int J Vitam Nutr Res Suppl 

89;30(-):21-24. Editorial 

Bucher HC, Cook RJ, Guyatt GH et al. Effects of 

dietary calcium supplementation on blood 

pressure. A meta-analysis of randomized 

controlled trials. JAMA 96;275(13):1016-22. 

Does not cover the defined disease endpoints 

Buiatti E. Prevention trials on oesophageal and 

stomach cancer. Eur J Cancer Prev 94;3(4):379-

82. Narrative review 
Appendix D: Excluded Articles 

D 2 

Buring JE, Hennekens C H. beta-carotene and cancer 

chemoprevention. J Cell Biochem Suppl 

95;22226-30. Narrative review 

Bussey HJ, DeCosse JJ, Deschner EE et al. A 

randomized trial of ascorbic acid in polyposis 

coli. Cancer 82;50(7):1434-9. Includes ONLY 

patients with a particular chronic disease

Anonymous. Calcium supplements. Med Lett Drugs 

Ther 96;38(989):108-109. Narrative review 

Anonymous. Calcium-D-glucarate. Altern Med Rev 

2002;7(4):336-339. Does not address the use of 

supplements

Siegel BV, Leibovitz B. The multifactorial role of 

vitamin C in health and disease.. Int J Vitam Nutr 

Res Suppl 82;23:9-22. No human data 

Camarasa JG, Serra-Baldrich E, Lluch M. Contact 

allergy to vitamin B6. Contact Dermatitis 

90;23(2):115. Does not apply to the key 

questions, Does not address the use of 

supplements

Camarasa JG, Serra-Baldrich E, Lluch M. Contact 

allergy to vitamin B6. Contact Dermatitis 

90;23(2):115. 

Canner PL, Berge KG, Wenger N K et al. Fifteen year 

mortality in Coronary Drug Project patients: 

long-term benefit with niacin. J Am Coll Cardiol 

86;8(6):1245-55. Includes ONLY patients with 

a particular chronic disease

Canter PH, Ernst E. Herbal supplement use by persons 

aged over 50 years in Britain: Frequently used 

herbs, concomitant use of herbs, nutritional 

supplements and prescription drugs, rate of 

informing doctors and potential for negative 

interactions. Drugs Aging 2004;21(9):597-605. 

Does not apply to the key questions, Does not 

address the use of supplements

Cats A, Kleibeuker JH, Van der et al. Randomized, 

double-blinded, placebo-controlled intervention 

study with supplemental calcium in families with 

hereditary nonpolyposis colorectal cancer. J Natl 

Cancer Inst 95;87(8):598-603. Includes ONLY 

patients with a particular chronic disease,

Does not cover the defined disease endpoints

Chan JM, Pietinen P, Virtanen M et al. Diet and 

prostate cancer risk in a cohort of smokers, with a 

specific focus on calcium and phosphorus 

(Finland). Cancer Causes Control 

2000;11(9):859-67. Does not address the use of 

supplements

Chan P, Huang TY, Chen YJ et al. Randomized, 

double-blind, placebo-controlled study of the 

safety and efficacy of vitamin B complex in the 

treatment of nocturnal leg cramps in elderly 

patients with hypertension. J Clin Pharmacol 

98;38(12):1151-4. Does not apply to the key 

questions

Chapuy MC, Arlot ME, Duboeuf F et al. Vitamin D3 

and calcium to prevent hip fractures in the elderly 

women. N Engl J Med 92;327(23):1637-42. 

Includes ONLY patients receiving specified 

treatments

Chen M, Chow SN. Additive effect of alfacalcidol on 

bone mineral density of the lumbar spine in 

Taiwanese postmenopausal women treated with 

hormone replacement therapy and calcium 

supplementation: a randomized 2-year study. Clin 

Endocrinol (Oxf) 2001;55(2):253-8. Does not 

apply to the key questions

Chesnut CH, 3rd. Osteoporosis and its treatment. N 

Engl J Med 92;326(6):406-8. Editorial 

Childers JM, Chu J, Voigt L F et al. Chemoprevention 

of cervical cancer with folic acid: a phase III 

Southwest Oncology Group Intergroup study. 

Cancer Epidemiol Biomarkers Prev 95;4(2):155-

9. Does not cover the defined disease endpoints 

Christen WG, Gaziano JM, Hennekens CH. Design of 

Physicians' Health Study II--a randomized trial of 

beta-carotene, vitamins E and C, and 

multivitamins, in prevention of cancer, 

cardiovascular disease, and eye disease, and 

review of results of completed trials. Ann 

Epidemiol 2000;10(2):125-34. Narrative review 

Christiansen C, Christensen MS, McNair P et al. 

Prevention of early postmenopausal bone loss: 

controlled 2-year study in 315 normal females. 

Eur J Clin Invest 80;10(4):273-9. Does not apply 

to the key questions

Christiansen C, Rodbro P, Lund M. Effect of vitamin 

D on bone mineral mass in normal subjects and 

in epileptic patients on anticonvulsants: a 

controlled therapeutic trial. Br Med J 

73;2(5860):208-9. Does not cover the defined 

disease endpoints 

Clarke R, Armitage J. Antioxidant vitamins and risk of 

cardiovascular disease. Review of large-scale 

randomised trials. Cardiovasc Drugs Ther 

2002;16(5):411-5. Narrative review 

Clayton AH. Complementary and alternative 

medicine. Prim Psychiatry 2005;12(8):20-21. 

Editorial 

Chemoprevention Branch and Agent Development 

Committee. Clinical development plan: folic 

acid.. J Cell Biochem Suppl 96;26(-):100-113. 

Narrative review 
Appendix D: Excluded Articles 

D 3 

Anonymous. Update on isotretinoin (Accutane) for 

acne. Med Lett Drugs Ther 83;25(649):105-6. 

Includes ONLY patients with a particular 

chronic disease

Anonymous. Clofibrate and niacin in coronary heart 

disease. JAMA 75;231(4):360-81. Does not 

apply to the key questions

Coburn JW. An update on vitamin D as related to 

nephrology practice: 2003. Kidney Int Suppl 

2003;64(87):S125-S130. Includes ONLY 

patients receiving specified treatments, Does 

not apply to the key questions

Combs GF, Clark L C, Turnbull BW. Reduction of 

cancer mortality and incidence by selenium 

supplementation. Med Klin (Munich) 97;92 

Suppl 342-5. Includes ONLY patients receiving 

specified treatments, Includes ONLY patients 

receiving specified treatments

Collins R, Peto R, Armitage J. The MRC/BHF Heart 

Protection Study: preliminary results. Int J Clin 

Pract 2002;56(1):53-6. Does not apply to the 

key questions

Combs GF, Combs SB. Selenium effects on drug and 

foreign compound toxicity. Pharmacol Ther 

87;33(2-3):303-15. Does not apply to the key 

questions, Does not address the use of 

supplements

Complementary medicine - General. Focus Altern 

Complement Ther 2005;10(3):233-235. Editorial 

Compston JE. Pharmacological interventions for postmenopausal osteoporosis: An evidence-based 

approach. Rheumatology (UK) 

2000;39(12):1309-1312. Editorial 

Cook NR, Stampfer MJ, Ma J et al. (beta)-carotene 

supplementation for patients with low baseline 

levels and decreased risks of total and prostate 

carcinoma. Cancer 99;86(9):1783-1792. Does not 

apply to the key questions, Does not address 

the use of supplements

Cronin JR. Special report: Dietary supplements. 

Safety, certification, labeling, and efficacy. 

Altern Complement Ther 2002;8(3):141-148. 

Does not apply to the key questions

de Groot AC. Contact allergy to calcipotriol. Contact 

Dermatitis 94;30(4):242-3. Does not apply to 

the key questions

Cronin JR. Special report: Dietary supplements. 

Safety, certification, labeling, and efficacy. 

Altern Complement Ther 2002;8(3):141-148 

Anonymous. Cutaneous drug reaction case reports: 

from the world literature. Am J Clin Dermatol 

2003;4(5):365-70. Does not apply to the key 

questions, Does not address the use of 

supplements, Does not cover the defined 

disease endpoints

Czeizel AE, Dudas I, Fritz G et al. The effect of 

periconceptional multivitamin-mineral 

supplementation on vertigo, nausea and vomiting 

in the first trimester of pregnancy. Arch Gynecol 

Obstet 92;251(4):181-5. Includes ONLY 

pregnant women

Czeizel AE. Reduction of urinary tract and 

cardiovascular defects by periconceptional 

multivitamin supplementation. Am J Med Genet 

96;62(2):179-83. Does not cover the defined 

disease endpoints 

Dangour AD, Sibson VL, Fletcher AE. Micronutrient 

supplementation in later life: limited evidence for 

benefit. J Gerontol A Biol Sci Med Sci 

2004;59(7):659-73. Narrative review 

Dawsey SM, Wang GQ, Taylor PR et al. Effects of 

vitamin/mineral supplementation on the 

prevalence of histological dysplasia and early 

cancer of the esophagus and stomach: results 

from the Dysplasia Trial in Linxian, China. 

Cancer Epidemiol Biomarkers Prev 94;3(2):167-

72. Includes ONLY patients with a particular 

chronic disease

Dawson MI. The importance of vitamin A in nutrition. 

Curr Pharm Des 2000;6(3):311-325. Narrative 

review 

Dawson-Hughes B. Vitamin D and calcium: 

recommended intake for bone health. Osteoporos 

Int 98;8 Suppl 2S30-4. Narrative review 

de Groot A C. Contact allergy to calcipotriol. Contact 

Dermatitis 94;30(4):242-3. Does not address the 

use of supplements

de Klerk NH, Musk AW, Ambrosini G L et al. 

Vitamin A and cancer prevention II: comparison 

of the effects of retinol and beta-carotene. Int J 

Cancer 98;75(3):362-7. Includes ONLY 

patients with a particular chronic disease, 

Does not apply to the key questions

Dean BS, Krenzelok EP. Multiple vitamins and 

vitamins with iron: Accidental poisoning in 

children. Vet Hum Toxicol 88;30(1):23-25. 

Narrative review 

DeAngelis CD, Fontanarosa PB. Drugs Alias Dietary 

Supplements. JAMA 2003;290(11):1519-1520. 

Editorial 
Appendix D: Excluded Articles 

D 4 

Debourdeau PM, Djezzar S, Estival J L et al. Lifethreatening eosinophilic pleuropericardial 

effusion related to vitamins B5 and H. Ann 

Pharmacother 2001;35(4):424-6. Does not apply 

to the key questions, Does not address the use 

of supplements

DeCosse JJ, Miller HH, Lesser ML. Effect of wheat 

fiber and vitamins C and E on rectal polyps in 

patients with familial adenomatous polyposis. J 

Natl Cancer Inst 89;81(17):1290-7. Includes 

ONLY patients with a particular chronic 

disease

Dembinska-Kiec A. Carotenoids: Risk or benefit for 

health. Biochim Biophys Acta 2005;1740(2):93-

94. Editorial 

Dennehy CE, Tsourounis C, Horn AJ. Dietary 

supplement-related adverse events reported to the 

California Poison Control System. Am J HealthSyst Pharm 2005;62(14):1476-1482. Narrative 

review 

Dimery IW, Hong WK, Lee J J et al. Phase I trial of 

alpha-tocopherol effects on 13-cis-retinoic acid 

toxicity. Ann Oncol 97;8(1):85-9. Includes 

ONLY patients with a particular chronic 

disease, Includes ONLY patients receiving 

specified treatment, Does not apply to the key 

questions, Does not cover the defined disease 

endpoints 

Domrongkitchaiporn S, Ongphiphadhanakul B, 

Stitchantrakul W et al. Risk of calcium oxalate 

nephrolithiasis in postmenopausal women 

supplemented with calcium or combined calcium 

and estrogen. Maturitas 2002;41(2):149-56. Does 

not apply to the key questions, Does not cover 

the defined disease endpoints

Domrongkitchaiporn S, Sopassathit W, Stitchantrakul 

W et al. Schedule of taking calcium supplement 

and the risk of nephrolithiasis. Kidney Int 

2004;65(5):1835-41. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints

Dursun N, Dursun E, Yalcin S. Comparison of 

alendronate, calcitonin and calcium treatments in 

postmenopausal osteoporosis. Int J Clin Pract 

2001;55(8):505-9. Does not apply to the key 

questions

Duthie GG, Arthur JR, Beattie JA et al. Cigarette 

smoking, antioxidants, lipid peroxidation, and 

coronary heart disease. NY Acad 93;686120-9. 

Does not address the use of supplements, Does 

not cover the defined disease endpoints

El-Kadiki A, Sutton AJ. Role of multivitamins and 

mineral supplements in preventing infections in 

elderly people: Systematic review and metaanalysis of randomised controlled trials. BMJ 

2005;330(7496):871-874. Does not cover the 

defined disease endpoints 

Elliott RB, Pilcher CC, Fergusson DM et al. A 

population based strategy to prevent insulindependent diabetes using nicotinamide. J Pediatr 

Endocrinol Metab 96;9(5):501-9. Efficacy study 

of subjects less than 19 years old only 

Engelen W, Keenoy BM, Vertommen J et al. Effects 

of long-term supplementation with moderate 

pharmacologic doses of vitamin E are saturable 

and reversible in patients with type 1 diabetes. 

Am J Clin Nutr 2000;72(5):1142-9. Includes 

ONLY patients with a particular chronic 

disease, Does not cover the defined disease 

endpoints

Evans CDH, Lacey JH. Toxicity of vitamins: 

Complications of a health movement. BMJ 

86;292(6519):509-510. Narrative review 

Anonymous . Evidence of harm from antioxidant 

supplements. Pharm J 2004;273(7320):506. 

Editorial 

Exner JH, Dahod S, Pochi PE. Pyogenic granulomalike acne lesions during isotretinoin therapy. 

Arch Dermatol 83;119(10):808-11. Does not 

apply to the key questions, Does not address 

the use of supplements, Does not cover the 

defined disease endpoints

Fabricius P, Lange P. Diet and lung cancer. Monaldi 

Arch Chest Dis Pulm Ser 2003;59(3):207-211. 

Does not apply to the key questions

Fabricius P, Lange P. Diet and lung cancer. Monaldi 

Arch Chest Dis Pulm Ser 2003;59(3):207-211. 

Narrative review 

Faivre J, Boutron MC, Doyon F et al. The ECP 

calcium fibre polyp prevention study preliminary 

report. ECP Colon Group. Eur J Cancer Prev 93;2 

Suppl 2(-):99-106. Includes ONLY patients 

with a particular chronic disease, Does not 

apply to the key questions, Does not cover the 

defined disease endpoints

Faivre J, Couillault C, Belghiti C. Intervention trials 

on colorectal cancer prevention. IARC Sci Publ 

96;(139):115-24. Narrative review 

Faivre J, Doyon F, Boutron MC. The ECP calcium 

fibre polyp prevention study. The ECP Colon 

Group. Eur J Cancer Prev 91;1 Suppl 283-9. 

Does not cover the defined disease endpoints 
Appendix D: Excluded Articles 

D 5 

Farvid MS, Jalali M, Siassi F et al. The impact of 

vitamins and/or mineral supplementation on 

blood pressure in type 2 diabetes. J Am Coll Nutr 

2004;23(3):272-9. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints

Finer NN, Schindler RF, Peters KL et al. Vitamin E 

and retrolental fibroplasia. Improved visual 

outcome with early vitamin E. Ophthalmology 

83;90(5):428-35. Includes only infiants

Fisher AA. Three faces of vitamin E topical allergy. 

Cutis 91;48(4):272-4. Does not address the use 

of supplements

Fisher AA. Unusual acute, nonallergic eruptions of the 

scalp from combined use of minoxidil and 

retinoic acid. Cutis 93;51(1):17-8. Does not 

apply to the key questions

Floren LC, Zangwill AC, Schroeder DJ. Antioxidants 

may retard cataract formation. Ann Pharmacother 

94;28(9):1040-2. Editorial 

Florentino RF, Tanchoco CC, Ramos AC et al. 

Tolerance of preschoolers to two dosage 

strengths of vitamin A preparation. Am J Clin 

Nutr 90;52(4):694-700. Only covers nutritional 

deficiency

Flynn CA. Calcium supplementation in 

postmenopausal women. Am Fam Phys 

2004;69(12):2822-2823. Narrative review 

Fox W, Robinson DK, Tall R et al. A study of acute 

intolerance to ethionamide, including a 

comparison with prothionamide, and of the 

influence of a vitamin B-complex additive in 

prophylaxis. Tubercle 69;50(2):125-43. Includes 

ONLY patients with a particular chronic 

disease, Includes ONLY patients receiving 

specified treatments, Does not apply to the key 

questions

Fraga CG. Relevance, essentiality and toxicity of trace 

elements in human health. Mol Asp Med 

2005;26(4-5 SPEC. ISS.):235-244. Narrative 

review 

Frank DH, Roe DJ, Chow HH et al. Effects of a highselenium yeast supplement on celecoxib plasma 

levels: a randomized phase II trial. Cancer 

Epidemiol Biomarkers Prev 2004;13(2):299-303. 

Does not apply to the key questions, Does not 

cover the defined disease endpoints

Fraunfelder FW. The science and marketing of dietary 

supplements. Am J Ophthalmol 2005;140(2):302-

304. Does not apply to the key questions

Fraunfelder FW. The science and marketing of dietary 

supplements. Am J Ophthalmol 2005;140(2):302-

304. Editorial 

Fuller CJ, Chandalia M, Garg A et al. RRR-alphatocopheryl acetate supplementation at 

pharmacologic doses decreases low-densitylipoprotein oxidative susceptibility but not 

protein glycation in patients with diabetes 

mellitus. Am J Clin Nutr 96;63(5):753-9. 

Includes ONLY patients with a particular 

chronic disease, Does not cover the defined 

disease endpoints

Fuller CJ, Grundy SM, Norkus EP et al. Effect of 

ascorbate supplementation on low density 

lipoprotein oxidation in smokers. Atherosclerosis 

96;119(2):139-50. Does not cover the defined 

disease endpoints 

Gardiner P. Dietary supplement use in children: 

Concerns of efficacy and safety. Am Fam Phys 

2005;71(6):1068-1071. Narrative review 

Garland C, Shekelle RB, Barrett-Connor E et al. 

Dietary vitamin D and calcium and risk of 

colorectal cancer: a 19-year prospective study in 

men. Lancet 85;1(8424):307-9. Does not address 

the use of supplements

Gaulin C. Food poisoning involving a chemical 

product--Quebec. Can Commun Dis Rep 

93;19(11):80-3. Does not apply to the key 

questions, Does not address the use of 

supplements

Gaziano JM, Hennekens CH. The role of betacarotene in the prevention of cardiovascular 

disease. NY Acad 93;691148-55. Narrative 

review 

Geleijnse JM, Grobbee DE. Calcium intake and blood 

pressure: an update. J Cardiovasc Risk 

2000;7(1):23-9. Narrative review 

Goldberg SH, Von Feldt JM, Lonner JH. 

Pharmacologic therapy for osteoarthritis. Am J 

Orthop 2002;31(12):673-80. Narrative review 

Goodman GE, Valanis B, Meyskens F L et al. 

Strategies for recruitment to a population-based 

lung cancer prevention trial: the CARET 

experience with heavy smokers. Beta-Carotene 

and Retinol Efficacy Trial. Cancer Epidemiol 

Biomarkers Prev 98;7(5):405-12 

Goorin AM, Abelson HT, Frei E et al. Osteosarcoma: 

fifteen years later. N Engl J Med 

85;313(26):1637-43. Narrative review 

Greenberg ER, Baron JA, Stevens MM et al. The Skin 

Cancer Prevention Study: design of a clinical trial 

of beta-carotene among persons at high risk for 

nonmelanoma skin cancer. Control Clin Trials 

89;10(2):153-66. Other
Appendix D: Excluded Articles 

D 6 

Greenberg ER, Baron JA, Tosteson TD et al. A 

clinical trial of antioxidant vitamins to prevent 

colorectal adenoma. New Engl J Med 

94;331(3):141-147. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints

Griffiths LL. Myoedema and vitamins. BMJ 

69;3(665):299. Editorial 

Gurlek A, Bayraktar M, Gedik O. Comparison of 

calcitriol treatment with etidronate-calcitriol and 

calcitonin-calcitriol combinations in Turkish 

women with postmenopausal osteoporosis: a 

prospective study. Calcif Tissue Int 97;61(1):39-

43. Includes ONLY patients with a particular 

chronic disease, Does not address the use of 

supplements

Hall WD, Davis BR, Frost P et al. Systolic 

Hypertension in the Elderly Program (SHEP). 

Part 7: Baseline laboratory characteristics. 

Hypertension 91;17(3 Suppl):II102-22. Does not 

apply to the key questions

Hanck A, Altman RF, Fidanza A et al. Workshop on 

the role of vitamin C in lipid metabolism.. Int J 

Vitam Nutr Res Suppl 82;23(-):197-207. 

Editorial 

Hathcock JN. Vitamins and minerals: Efficacy and 

safety. Am J Clin Nutr 97;66(2):427-437. Does 

not apply to the key questions

Hayasaka E. Randomized trial of aspirin, vitamin E 

raises questions for future chemoprevention 

studies.. J Natl Cancer Inst 2005;97(17):1242-

1243. Editorial 

Head A. Treatment of intermittent claudication with 

inositol nicotinate. Practitioner 86;230(1411):49-

54. Includes ONLY patients with a particular 

chronic disease, Does not cover the defined 

disease endpoints

Helfman RJ, Brickman M, Fahey J. Isotretinoin 

dermatitis simulating acute pityriasis rosea. Cutis 

84;33(3):297-300. Does not address the use of 

supplements, Does not cover the defined 

disease endpoints

Hennekens CH, Eberlein K. A randomized trial of 

aspirin and beta-carotene among U.S. physicians. 

Prev Med 85;14(2):165-8. Narrative review 

Hennekens CH. Vitamin A analogues in cancer 

chemoprevention. Important Adv Oncol 86;23-

35. Narrative review 

Hercberg S, Galan P, Preziosi P et al. Background and 

rationale behind the SU.VI.MAX Study, a 

prevention trial using nutritional doses of a 

combination of antioxidant vitamins and minerals 

to reduce cardiovascular diseases and cancers. 

Supplementation en Vitamines et Mineraux 

AntioXydants Study. Int J Vitam Nutr Res 

98;68(1):3-20. Narrative review 

Hercberg S, Galan P, Preziosi P et al. The 

SU.VI.MAX trial on antioxidants. IARC Sci Publ 

.2002;156451-5. Does not apply to the key 

questions

Hercberg S, Preziosi P, Briancon S et al. A primary 

prevention trial using nutritional doses of 

antioxidant vitamins and minerals in 

cardiovascular diseases and cancers in a general 

population: the SU.VI.MAX study--design, 

methods, and participant characteristics. 

Supplementation en Vitamines et Mineraux 

AntioXydants. Control Clin Trials 98;19(4):336-

51. Other

Hercberg S, Preziosi P, Galan P et al. "The 

SU.VI.MAX Study": a primary prevention trial 

using nutritional doses of antioxidant vitamins 

and minerals in cardiovascular diseases and 

cancers. Supplementation on Vitamines et 

Mineraux AntioXydants. Food Chem Toxicol 

99;37(9-10):925-30. Other

Hofstad B, Almendingen K, Vatn M et al. Growth and 

recurrence of colorectal polyps: a double-blind 3-

year intervention with calcium and antioxidants. 

Digestion 98;59(2):148-56. Includes ONLY 

patients receiving specified treatments

Hoogwerf BJ, Young JB. The HOPE study. Ramipril 

lowered cardiovascular risk, but vitamin E did 

not. Cleve Clin J Med 2000;67(4):287-93. 

Narrative review 

Horsman A, Gallagher JC, Simpson M et al. 

Prospective trial of oestrogen and calcium in 

postmenopausal women. Br Med J 

77;2(6090):789-92. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints

Hsu CH, Patel SR. Uremic toxins and vitamin D 

metabolism. Kidney Int Suppl 97;51(62):S65-

S68. Does not apply to the key questions, Does 

not address the use of supplements

Kingston TP, Lowe NJ, Winston J et al. Visual and 

cutaneous toxicity which occurs during N-(4-

hydroxyphenyl) retinamide therapy for psoriasis. 

Clin Exp Dermatol 86;11(6):624-7. Does not 

address the use of supplements
Appendix D: Excluded Articles 

D 7 

Huttunen JK. Health effects of supplemental use of 

antioxidant vitamins. Experiences from the alphatocopherol beta-carotene (ATBC) cancer 

prevention study. Scand J Nutr 95;39(3):103-104. 

Does not apply to the key questions

Hyman J, Baron J A, Dain BJ et al. Dietary and 

supplemental calcium and the recurrence of 

colorectal adenomas. Cancer Epidemiol 

Biomarkers Prev 98;7(4):291-5. Narrative 

review 

Inkeles SB, Connor WE, Illingworth DR. Hepatic and 

dermatologic manifestations of chronic 

hypervitaminosis A in adults. Report of two 

cases. Am J Med 86;80(3):491-6 

Jain S K, McVie R, Jaramillo J J et al. The effect of 

modest vitamin E supplementation on lipid 

peroxidation products and other cardiovascular 

risk factors in diabetic patients. Lipids 96;31 

SupplS87-90. Includes ONLY patients with a 

particular chronic disease, Does not cover the 

defined disease endpoints

Jansen T, Romiti R, Kreuter A et al. Rosacea 

fulminans triggered by high-dose vitamins B6 

and B12. J Eur Acad Dermatol Venereol 

2001;15(5):484-5. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints

Javed MS, Taylor I. A review of recent randomized 

trials in colorectal disease. Colorectal Dis 

2002;4(2):90-96. Narrative review 

Jeppsen RB. Toxicology and safety of Ferrochel and 

other iron amino acid chelates.. Arch Latinoam 

Nutr 2001;51(1 Suppl 1):26-34. Narrative 

review 

Jha P, Flather M, Lonn E et al. The antioxidant 

vitamins and cardiovascular disease. A critical 

review of epidemiologic and clinical trial data. 

Ann Intern Med 95;123(11):860-72. Narrative 

review 

Johnston CS. Biomarkers for establishing a tolerable 

upper intake level for vitamin C. Nutr Rev 

99;57(3):71-77. Does not apply to the key 

questions

Kaikkonen J, Porkkala-Sarataho E, Morrow J D et al. 

Supplementation with vitamin E but not with 

vitamin C lowers lipid peroxidation in vivo in 

mildly hypercholesterolemic men. Free Radic 

Res 2001;35(6):967-78. Does not apply to the 

key questions, Does not cover the defined 

disease endpoints

Kaplan G, Haettich B. Rheumatological symptoms 

due to retinoids. Baillieres Clin Rheumatol. 

91;5(1):77-97. Narrative review 

Kaplan G, Haettich B. Rheumatological symptoms 

due to retinoids. Baillieres Clin Rheumatol 

91;5(1):77-97. Other

Kato T, Chen JT, Katase K et al. Effect of 1 alphahydroxyvitamin D3 on loss of bone mineral 

density immediately after artificial menopause. 

Endocr J 97;44(2):299-304. Includes ONLY 

patients with a particular chronic disease

Kelloff GJ, Crowell JA, Boone CW et al. Clinical 

development plan: vitamin E.. J Cell Biochem 

Suppl 94;20(-):282-299. Other

Kelloff GJ, Crowell JA, Boone CW et al. Clinical 

development plan: beta-carotene and other 

carotenoids.. J Cell Biochem Suppl 94;20(-):110-

140. Other

Kelly JP, Kaufman DW, Kelley K et al. Trends in 

dietary and herbal supplement use in the United 

States. J Clin Outcomes Manage 2005;12(4):184-

185. Editorial 

Kent S. Vitamin C therapy: colds, cancer, and 

cardiovascular disease. Geriatrics 78;33(10):91-4, 

99. Narrative review 

Kiely M, Flynn A, Harrington KE et al. The efficacy 

and safety of nutritional supplement use in a 

representative sample of adults in the 

North/South Ireland Food Consumption Survey. 

Public Health Nutr 2001;4(5A):1089-1097. Does 

not apply to the key questions

Kiely M, Flynn A, Harrington KE et al. The efficacy 

and safety of nutritional supplement use in a 

representative sample of adults in the 

North/South Ireland Food Consumption Survey. 

Public Health Nutr 2001;4(5A):1089-1097. 

Other

Kim I, Williamson DF, Byers T et al. Vitamin and 

mineral supplement use and mortality in a US 

cohort. Am J Public Health 93;83(4):546-550. 

Does not apply to the key questions

Kingston TP, Lowe NJ, Winston J et al. Visual and 

cutaneous toxicity which occurs during N-(4-

hydroxyphenyl) retinamide therapy for psoriasis. 

Clin Exp Dermatol 86;11(6):624-7. Does not 

apply to the key questions, Does not cover the 

defined disease endpoints

Kingston TP, Lowe NJ, Winston J et al. Visual and 

cutaneous toxicity which occurs during N-(4-

hydroxyphenyl) retinamide therapy for psoriasis. 

Clin Exp Dermatol 86;11(6):624-7. Other

Kirkwood BR, Ross DA, Arthur P et al. Effect of 

vitamin A supplementation on the growth of 

young children in northern Ghana. Am J Clin 

Nutr 96;63(5):773-81. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints
Appendix D: Excluded Articles 

D 8 

Knodel LC, Talbert RL. Adverse effects of 

hypolipidaemic drugs. Med Toxicol 87;2(1):10-

32. Does not apply to the key questions, Does 

not cover the defined disease endpoints

Knopp RH. Evaluating niacin in its various forms. Am 

J Cardiol 2000;86(12A):51L-56L. Does not 

apply to the key questions

Kritharides L, Stocker R. The use of antioxidant 

supplements in coronary heart disease. 

Atherosclerosis 2002;164(2):211-9. Narrative 

review 

Krone CA, Harms LC, Leitzmann M F et al. Re: Zinc 

supplement use and risk of prostate cancer 

(multiple letters) [4]. J Natl Cancer Inst 

2003;95(20):1556-1557. Editorial 

Krueger KJ, McClain CJ, McClave SA et al. 

Nutritional supplements and alternative medicine. 

Curr Opin Gastroenterol 2004;20(2):130-138. 

Narrative review 

Kruesi MJ, Rapoport JL. Diet and human behavior: 

how much do they affect each other? Annu Rev 

Nutr 86;6113-30. Narrative review 

Kumar A, Aitas A T, Hunter AG et al. Sweeteners, 

dyes, and other excipients in vitamin and mineral 

preparations. Clin Pediatr (Phila) 96;35(9):443-

50. Does not apply to the key questions

Lau EM, Woo J, Leung PC et al. The effects of 

calcium supplementation and exercise on bone 

density in elderly Chinese women. Osteoporos 

Int 92;2(4):168-73. Includes ONLY patients 

receiving specified treatments

Leger CS, Teik Chye, Ooi. Ferrous fumarate-induced 

malabsorption of thyroxine. Endocrinologist 

99;9(6):493-495. Does not apply to the key 

questions 

Levine MN, Anderson DR. Side-effects of 

antithrombotic therapy. Baillieres Clin Haematol 

90;3(3):815-29. Does not apply to the key 

questions, Does not address the use of 

supplements

Li B, Taylor PR, Li JY et al. Linxian nutrition 

intervention trials. Design, methods, participant 

characteristics, and compliance. Ann Epidemiol 

93;3(6):577-85. Does not apply to the key 

questions

Liede K, Hietanen J, Saxen L et al. Long-term 

supplementation with alpha-tocopherol and betacarotene and prevalence of oral mucosal lesions 

in smokers. Oral Dis 98;4(2):78-83. Does not 

apply to the key questions, Does not cover the 

defined disease endpoints

Lim LS, Fink HA, Kuskowski MA et al. Diuretic use 

and bone mineral density in older USA men: The 

osteoporotic fractures in men (MrOS) study [4]. 

Age Ageing 2005;34(5):504-507. Does not apply 

to the key questions, Does not report 

supplement use separately

Lonn EM, Yusuf S. Is there a role for antioxidant 

vitamins in the prevention of cardiovascular 

diseases? An update on epidemiological and 

clinical trials data. Can J Cardiol 97;13(10):957-

65. Narrative review 

Macdougall IC. Strategies for iron supplementation: 

oral versus intravenous. Kidney Int Suppl 99;69(-

):S61-66. Includes ONLY patients receiving 

specified treatments

Machlin LJ. Use and safety of elevated dosages of 

vitamin E in adults. Int J Vitam Nutr Res Suppl 

89;30(-):56-68. Narrative review 

Maeda K, Okamoto N, Nishimoto M et al. A 

multicenter study of the effects of vitamin B12 on 

sleep-waking rhythm disorders: in Shizuoka 

Prefecture. Jpn J Psychiatry Neurol 92;46(1):229-

30. Does not apply to the key questions

Malten KE. Flare reaction due to vitamin B12 in a 

patient with psoriasis and contact eczema. 

Contact Dermatitis 75;1(5):325-6. Does not 

apply to the key questions

Manson JE, Buring JE, Satterfield S et al. Baseline 

characteristics of participants in the Physicians' 

Health Study: a randomized trial of aspirin and 

beta-carotene in U.S. physicians. Am J Prev Med 

91;7(3):150-4. Does not apply to the key 

questions

Mariani SM. Phytoestrogens and antioxidants - Bits of 

experimental evidence. Medgenmed Medscape 

Gen Med 2005;7(1):6p. Editorial 

Mark SD, Liu SF, Li JY et al. The effect of vitamin 

and mineral supplementation on esophageal 

cytology: results from the Linxian Dysplasia 

Trial. Int J Cancer 94;57(2):162-6. Includes 

ONLY patients with a particular chronic 

disease

Marks J. The safety of the vitamins: an overview. Int J 

Vitam Nutr Res Suppl 89;30(-):12-20. Narrative 

review 

Martin GJ. The myth of the magic bullet. Exp Med 

Surg 64;22(2):199-211. Narrative review 

Mason P. New advice on safety of high doses of 

vitamins and minerals clarifies muddle. Pharm J 

2003;270(7249):677-678. Editorial 
Appendix D: Excluded Articles 

D 9 

Maxwell S, Greig L. Anti-oxidants-- a protective role 

in cardiovascular disease? Expert Opin 

Pharmacother 2001;2(11):1737-50. Narrative 

review 

Mayne ST, Zheng T, Janerich DT et al. A populationbased trial of beta-carotene chemoprevention of 

head and neck cancer. Adv Exp Med Biol 

92;320119-27. Includes ONLY patients with a 

particular chronic disease, Includes ONLY 

patients receiving specified treatments

McCann MA. Dietary supplement labeling: Cognitive 

biases, market manipulation & consumer choice. 

Am J Law Med 2005;31(2-3):215-268. Editorial 

McClinton-Adams JL, Hart LL. Cancer prevention 

with beta carotene. Ann Pharmacother 

94;28(4):470-2. Narrative review 

McKeown-Eyssen G, Holloway C, Jazmaji V et al. A 

randomized trial of vitamins C and E in the 

prevention of recurrence of colorectal polyps. 

Cancer Res 88;48(16):4701-5. Does not apply to 

the key questions, Does not cover the defined 

disease endpoints

McLarty JW. An intervention trial in high-risk 

asbestos-exposed persons. Adv Exp Med Biol 

92;320141-9. Does not cover the defined 

disease endpoints 

McLean J. The placebo effect. Drug trial 

considerations. Nurs Times 90;86(17):31-3. 

Editorial 

Menna VJ. Index of suspicion. Case 2. Diagnosis: 

niacin overdose. Pediatr Rev 93;14(11):433-5. 

Does not apply to the key questions

Meunier PJ. Evidence-based medicine and 

osteoporosis: a comparison of fracture risk 

reduction data from osteoporosis randomised 

clinical trials. Int J Clin Pract 99;53(2):122-9.

Does not report all trial results 

Meyskens FL, Gilmartin E, Alberts DS et al. Activity 

of isotretinoin against squamous cell cancers and 

preneoplastic lesions. Cancer Treat Rep 

82;66(6):1315-9. Does not cover the defined 

disease endpoints 

Miettinen TA, Taskinen MR, Pelkonen R et al. 

Glucose tolerance and plasma insulin in man 

during acute and chronic administration of 

nicotinic acid. Acta Med Scand 69;186(4):247-

53. Does not apply to the key questions, Does 

not cover the defined disease endpoints 

Miller KL, Liebowitz RS, Newby LK. 

Complementary and alternative medicine in 

cardiovascular disease: A review of biologically 

based approaches. Am Heart J 2004;147(3):401-

411. Narrative review 

Mills E, Prousky J, Raskin G et al. The safety of overthe-counter niacin. A randomized placebocontrolled trial. BMC Clin Pharmacol 2003;34. 

Does not apply to the key questions

Mitchell JR, Corcoran GB, Smith CV et al. Alkylation 

and peroxidation injury from chemically reactive 

metabolites. Adv Exp Med Biol 81;136 Pt A199-

223. Does not apply to the key questions, Does 

not cover the defined disease endpoints

Montessori ML, Scheele WH, Netelenbos JC et al. 

The use of etidronate and calcium versus calcium 

alone in the treatment of postmenopausal 

osteopenia: results of three years of treatment. 

Osteoporos Int 97;7(1):52-8. Does not provide a 

placebo group

Moon JC. A brief history of vitamin D toxicity. J Appl 

Nutr 97;49(1-2):18-31. Narrative review 

MRC/BHF Heart Protection Study Collaborative 

Group. Heart Protection Study of cholesterollowering therapy and of antioxidant vitamin 

supplementation in a wide range of patients at 

increased risk of coronary heart disease death: 

early safety and efficacy experience. Eur Heart J 

99;20(10):725-41. Does not apply to the key 

questions

Munoz N, Hayashi M, Bang LJ et al. Effect of 

riboflavin, retinol, and zinc on micronuclei of 

buccal mucosa and of esophagus: a randomized 

double-blind intervention study in China. J Natl 

Cancer Inst 87;79(4):687-91. Does not cover the 

defined disease endpoints 

Nair KM. Alternate strategies for improving iron 

nutrition: Lessons from recent research. Br J Nutr 

2001;85(SUPPL. 2):S187-S191. Narrative 

review 

Nelson ME, Fisher EC, Dilmanian FA et al. A 1-y 

walking program and increased dietary calcium 

in postmenopausal women: effects on bone. Am J 

Clin Nutr 91;53(5):1304-11. Does not address 

the use of supplements

Newport A, Lockwood B. Use of nutraceuticals for 

eye health. Pharm J 2005;275(7364):261-264. 

Narrative review 

Noah BA. Foreword: Dietary supplement regulation in 

flux. Am J Law Med 2005;31(2-3):147-153. 

Editorial 

Nolan CR, DeGoes JJ, Alfrey AC. Aluminum and lead 

absorption from dietary sources in women 

ingesting calcium citrate. South Med J 

94;87(9):894-898. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints
Appendix D: Excluded Articles 

D 10 

Novick NL, Lawson W, Schwartz IS. Bilateral nasal 

bone osteophytosis associated with short-term 

oral isotretinoin therapy for cystic acne vulgaris. 

Am J Med 84;77(4):736-9. Does not apply to 

the key questions, Does not address the use of 

supplements

O'Brien KO. Combined calcium and vitamin D 

supplementation reduces bone loss and fracture 

incidence in older men and women. Nutr Rev 

98;56(5 Pt 1):148-50. Narrative review 

O'Brien MM, Kiely M, Harrington KE et al. The 

North/South Ireland Food Consumption Survey: 

Vitamin intakes in 18-64-year-old adults. Public 

Health Nutr 2001;4(5 A):1069-1079. Does not 

apply to the key questions, Does not address 

the use of supplements, Does not report 

supplement use separately

Oldreive S. Safe intakes of vitamins and minerals: 

Recommendations from the Expert Group on 

Vitamins and Minerals. Nutr Bull 

2003;28(2):199-202. Does not apply to the key 

questions

Omaye ST, Krinsky NI, Kagan VE et al. (beta)-

Carotene: Friend or Foe?. Fundam Appl Toxicol 

97;40(2):163-174. Narrative review 

Onel S. Dietary supplements: A definition that is 

black, white, and gray. Am J Law Med 

2005;31(2-3):341-348. Editorial 

Opara EC. Oxidative stress, micronutrients, diabetes 

mellitus and its complications. J R Soc Promot 

Health 2002;122(1):28-34. Narrative review 

Pak RW, Lanteri VJ, Scheuch JR et al. Review of 

vitamin E and selenium in the prevention of 

prostate cancer: implications of the selenium and 

vitamin E chemoprevention trial. Integr Cancer 

Ther 2002;1(4):338-44. Narrative review 

Palestine AG. Transient acute myopia resulting from 

isotretinoin (accutane) therapy. Ann Ophthalmol 

84;16(7):660, 662. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints

Pandey DK, Shekelle R, Selwyn BJ et al. Dietary 

vitamin C and beta-carotene and risk of death in 

middle-aged men. The Western Electric Study. 

Am J Epidemiol 95;142(12):1269-78. Does not 

address the use of supplements, Does not 

report supplement use separately

Papagaroufalis C, Megreli C, Hagjigeorgi C et al. A 

trial of vitamin A supplementation for the 

prevention of intraventricular hemorrhage in very 

low birth weight neonates. J Perinat Med 91;19 

Suppl 1382-7. Does not address the use of 

supplements, Includes only infiants

Parkman CA. NCCAM herbal supplement studies 

underway in the United States. Case Manager 

2005;16(3):41-43. Narrative review 

Patruta SI, Horl WH. Iron and infection. Kidney Int 

Suppl 99;55(69):S125-S130. Does not address 

the use of supplements

Pauling L, Anderson R, Banic S et al. Workshop on 

vitamin C in immunology and cancer.. Int J 

Vitam Nutr Res Suppl 82;23(-):209-219. 

Editorial 

Pelton R. Keeping a watch on vision. Am Drug 

99;216(5):50-51. Narrative review 

Peng CC, Glassman PA, Trilli LE et al. Incidence and 

Severity of Potential Drug-Dietary Supplement 

Interactions in Primary Care Patients: An 

Exploratory Study of 2 Outpatient Practices. 

Arch Intern Med 2004;164(6):630-636. 

Narrative review 

Peretz A, Neve J, Duchateau J et al. Adjuvant 

treatment of recent onset rheumatoid arthritis by 

selenium supplementation: preliminary 

observations. Br J Rheumatol 92;31(4):281-2. 

Includes ONLY patients with a particular 

chronic disease, Does not apply to the key 

questions

Perharic L, Shaw D, Colbridge M et al. Toxicological 

problems resulting from exposure to traditional 

remedies and food supplements. Drug Saf 

94;11(4):284-294. Narrative review 

Pettinger MB, Waclawiw MA, Davis KB et al. 

Compliance to multiple interventions in a high 

risk population. Ann Epidemiol 99;9(7):408-18. 

Includes ONLY patients with a particular 

chronic disease, Does not cover the defined 

disease endpoints 

Pociot F, Reimers JI, Andersen HU. Nicotinamide--

biological actions and therapeutic potential in 

diabetes prevention. IDIG Workshop, 

Copenhagen, Denmark, 4-5 December 1992. 

Diabetologia 93;36(6):574-6. Does not apply to 

the key questions

Pouilles JM, Tremollieres F, Ribot C. Prevention of 

post-menopausal bone loss with 1 alpha-hydroxy 

vitamin D3. A three-year prospective study. Clin 

Rheumatol 92;11(4):492-7. Does not apply to 

the key questions

Pozzilli P, Visalli N, Cavallo MG et al. Vitamin E and 

nicotinamide have similar effects in maintaining 

residual beta cell function in recent onset insulindependent diabetes (the IMDIAB IV study). Eur J 

Endocrinol 97;137(3):234-9. Includes ONLY 

patients with a particular chronic disease
Appendix D: Excluded Articles 

D 11 

Anonymous. Preventing wintertime bone loss: effects 

of vitamin D supplementation in healthy 

postmenopausal women. Nutr Rev 92;50(2):52-4. 

Editorial 

Prince RL, Smith M, Dick IM et al. Prevention of 

postmenopausal osteoporosis. A comparative 

study of exercise, calcium supplementation, and 

hormone-replacement therapy. N Engl J Med 

91;325(17):1189-95. Does not apply to the key 

questions

Puig L, Moreno A, Llistosella E et al. Granulation 

tissue proliferation during isotretinoin treatment. 

Int J Dermatol 86;25(3):191-3. Does not apply to 

the key questions, Does not address the use of 

supplements

Quinn GE, Johnson L, Otis C et al. Incidence, severity 

and time course of ROP in a randomized clinical 

trial of vitamin E prophylaxis. Doc Ophthalmol 

90;74(3):223-8. Includes only infants

Rahmathullah L. Effect of receiving a weekly dose of 

vitamin A equivalent to the recommended dietary 

allowances among pre school children on 

mortality in south India. Indian J Pediatr 

91;58(6):837-47. Only covers nutritional 

deficiency, Does not apply to the key questions

Reddy GK, Tyagi P, Jain VK et al. Highlights from: 

26th annual San Antonio breast cancer 

symposium. San Antonio, Texas December 2003. 

Clin Breast Cancer 2004;5(1):22-28. Includes 

ONLY patients with a particular chronic 

disease, Does not apply to the key questions, 

Does not address the use of supplements 

Redlich CA, Chung JS, Cullen MR et al. Effect of 

long-term beta-carotene and vitamin A on serum 

cholesterol and triglyceride levels among 

participants in the Carotene and Retinol Efficacy 

Trial (CARET). Atherosclerosis 99;145(2):425-

32. Does not cover the defined disease 

endpoints 

Redlich CA, Van Bennekum AM, Wirth JA et al. 

Vitamin A chemoprevention of lung cancer. A 

short-term biomarker study. Adv Exp Med Biol 

95;37517-29. Does not cover the defined 

disease endpoints 

Rexrode KM, Lee IM, Cook NR et al. Baseline 

characteristics of participants in the Women's 

Health Study. J Womens Health Gend Based 

Med 2000;9(1):19-27. Does not apply to the key 

questions

Reynolds LG, Klein M. Iron poisoning - a preventable 

hazard of childhood. S Afr Med J 85;67(17):680-

683. Does not apply to the key questions, Does 

not cover the defined disease endpoints

Richy F, Ethgen O, Bruyere O et al. Efficacy of 

alphacalcidol and calcitriol in primary and 

corticosteroid-induced osteoporosis: a metaanalysis of their effects on bone mineral density 

and fracture rate. Osteoporos Int 2004;15(4):301-

10. Does not apply to the key questions

Richy F, Ethgen O, Bruyere O et al. Efficacy of 

alphacalcidol and calcitriol in primary and 

corticosteroid-induced osteoporosis: a metaanalysis of their effects on bone mineral density 

and fracture rate. Osteoporos Int. 

2004;15(4):301-10. Does not address the use of 

supplements

Riley S J, Stouffer G A. Cardiology Grand Rounds 

from the University of North Carolina at Chapel 

Hill. The antioxidant vitamins and coronary heart 

disease: Part II. Randomized clinical trials. Am J 

Med Sci 2003;325(1):15-9. Narrative review 

Riley S J, Stouffer G A. The antioxidant vitamins and 

coronary heart disease: Part II. Randomized 

clinical trials. Am J Med Sci 2003;325(1):15-19. 

Narrative review 

Roberts HJ. Lead in calcium supplements. JAMA 

2000;284(24):3126-3127. Editorial 

Rock CL, Newman VA, Neuhouser ML et al. 

Antioxidant supplement use in cancer survivors 

and the general population. J Nutr 

2004;134(11):3194S-3195S. Does not cover the 

defined disease endpoints 

Roe DA. Health foods and supplements for the elderly 

- Who can say no? NY J Med 93;93(2):109-112. 

Narrative review 

Roumie CL. Effect of folic acid supplementation on 

inflammatory markers. J Clin Outcomes Manage 

2005;12(8):386-387. Editorial 

Rudzki E, Grzywa Z. Dermatitis from retinoic acid. 

Contact Dermatitis 78;4(5):305-6. Does not 

apply to the key questions, Does not address 

the use of supplements

Ryan-Harshman M, Aldoori W. Health benefits of 

selected vitamins. Can Fam Physician 2005;51(-

):965-968. Does not cover the defined disease 

endpoints 

Anonymous. Safety and tolerability of calcipotriol in 

psoriasis. Br J Clin Pract Suppl 96;8326-8. Does 

not apply to the key questions, Does not 

address the use of supplements

Saldanha RL, Cepeda EE, Poland R L. The effect of 

vitamin E prophylaxis on the incidence and 

severity of bronchopulmonary dysplasia. J 

Pediatr 82;101(1):89-93. Includes ONLY 

patients with a particular chronic disease, 

Includes only infiants
Appendix D: Excluded Articles 

D 12 

Salonen JT, Alfthan G, Huttunen JK et al. Association 

between serum selenium and the risk of cancer. 

Am J Epidemiol 84;120(3):342-9. Does not 

address the use of supplements

Salonen JT. Epidemiological studies on antioxidants, 

lipid peroxidation and atherosclerosis. Arch 

Toxicol Suppl 98;20249-67. Narrative review 

Samman S, Roberts DC. The effect of zinc 

supplements on plasma zinc and copper levels 

and the reported symptoms in healthy volunteers. 

Med J Aust 87;146(5):246-9. Does not apply to 

the key questions

Sasaki S, Tsubono Y, Okubo S et al. Effects of threemonth oral supplementation of beta-carotene and 

vitamin C on serum concentrations of carotenoids 

and vitamins in middle-aged subjects: a pilot 

study for a randomized controlled trial to prevent 

gastric cancer in high-risk Japanese population. 

Jpn J Cancer Res 2000;91(5):464-70. Other

Schorah CJ. Ascorbic acid metabolism and cancer in 

the human stomach. Acta Gastroenterol Belg 

97;60(3):217-9. Narrative review 

Schrauzer GN. Nutritional selenium supplements: 

Product types, quality, and safety. J Am Coll 

Nutr 2001;20(1):1-4. Narrative review 

Scragg R, Khaw KT, Murphy S. Effect of winter oral 

vitamin D3 supplementation on cardiovascular 

risk factors in elderly adults. Eur J Clin Nutr 

95;49(9):640-6. Does not cover the defined 

disease endpoints 

Seddon JM, Christen WG, Manson JE et al. The use of 

vitamin supplements and the risk of cataract 

among US male physicians. Am J Public Health 

94;84(5):788-92. Other 

Shannon M. Alternative medicines toxicology: a 

review of selected agents. J Toxicol Clin Toxicol 

99;37(6):709-13. Does not apply to the key 

questions

Shaw D, Leon C, Kolev S et al. Traditional remedies 

and food supplements. A 5-year toxicological 

study (1991-1995). Drug Saf. 97;17(5):342-356. 

Narrative review 

Sherertz EF. Acneiform eruption due to "megadose" 

vitamins B6 and B12. Cutis 91;48(2):119-20. 

Does not apply to the key questions

Siegel BV, Leibovitz B. The multifactorial role of 

vitamin C in health and disease. Int J Vitam Nutr 

Res Suppl 82;23(-):9-22. Narrative review 

Singh RB. Can dietary magnesium supplementation 

decrease coronary heart disease and sudden 

cardiac death? Schriftenr Ver Wasser Boden 

Lufthyg 93;88474-90. Does not address the use 

of supplements

Siqueira LM. Adolescents and nutritional 

supplements: Important behavioral issues. Int 

Pediatr 2005;20(1):9-10. Editorial 

Sleeper RB, Kennedy SM. Adverse reaction to a 

dietary supplement in an elderly patient. Ann 

Pharmacother 2003;37(1):83-6. Does not apply 

to the key questions

Smallwood J, Ah-Kye D, Taylor I. Vitamin B6 in the 

treatment of pre-menstrual mastalgia. Br J Clin 

Pract 86;40(12):532-3. Does not apply to the 

key questions, Does not cover the defined 

disease endpoints

Smeeding SJW. Nutrition, supplements, and aging. 

Geriatr Nurs 2001;22(4):219-224. Narrative 

review 

Spittle CR. Vitamin C and deep-vein thrombosis. 

Lancet 73;2(7822):199-201. Editorial 

Sposito AC, Caramelli B, Serrano CV et al. Effect of 

niacin and etofibrate association on subjects with 

coronary artery disease and serum high-density 

lipoprotein cholesterol <35 mg/dl. Am J Cardiol 

99;83(1):98-100, A8. Includes ONLY patients 

with a particular chronic disease, Does not 

apply to the key questions

Stephens NG, Parsons A, Schofield PM et al. 

Randomised controlled trial of vitamin E in 

patients with coronary disease: Cambridge Heart 

Antioxidant Study (CHAOS). Lancet 

96;347(9004):781-6. Includes ONLY patients 

with a particular chronic disease

Stals H, Vercammen C, Peeters C et al. Acanthosis 

nigricans caused by nicotinic acid: case report 

and review of the literature. Dermatology. 

94;189(2):203-6. Does not cover the defined 

disease endpoints 

Stanner SA, Hughes J, Kelly CNM et al. A review of 

the epidemiological evidence for the 'antioxidant 

hypothesis'. Public Health Nutr 2004;7(3):407-

422. Narrative review 

Steiner M. Vitamin E, a modifier of platelet function: 

rationale and use in cardiovascular and 

cerebrovascular disease. Nutr Rev 99;57(10):306-

9. Narrative review 

Steinkjer B. Contact dermatitis from calcipotriol. 

Contact Dermatitis 94;31(2):122. Does not apply 

to the key questions, Does not address the use 

of supplements

Stephensen CB, Franchi LM, Hernandez H et al. 

Adverse effects of high-dose vitamin A 

supplements in children hospitalized with 

pneumonia. Pediatrics 98;101(5):E3. Includes 

ONLY patients with a particular chronic 

disease
Appendix D: Excluded Articles 

D 13 

Stevens VL, McCullough ML, Diver WR et al. Use of 

multivitamins and prostate cancer mortality in a 

large cohort of US men. Cancer Causes Control 

2005;16(6):643-50. Other

Sutton NA. The safety of calcium fortification. Med 

Health RI 2000;83(11):364-366. Narrative 

review 

Takahashi K. A multicenter study on sleep-wake 

rhythm disorders in Japan: a preliminary results. 

Jpn J Psychiatry Neurol 92;46(1):231-2. Does 

not apply to the key questions

Tanaka M, Niizeki H, Shimizu S et al. Photoallergic 

drug eruption due to pyridoxine hydrochloride. J 

Dermatol 96;23(10):708-9. Does not apply to 

the key questions

Tanji JL, Lew EY, Wong GY et al. Dietary calcium 

supplementation as a treatment for mild 

hypertension. J Am Board Fam Pract 

91;4(3):145-50. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints

Teegarden D, Legowski P, Gunther CW et al. Dietary 

calcium intake protects women consuming oral 

contraceptives from spine and hip bone loss. J 

Clin Endocrinol Metab 2005;90(9):5127-33. 

Does not address the use of supplements

The ATBC Cancer Prevention Study Group. The 

alpha-tocopherol, beta-carotene lung cancer 

prevention study: design, methods, participant 

characteristics, and compliance. Ann Epidemiol 

94;4(1):1-10. Other

Touvier M, Boutron-Ruault MC, Volatier JL et al. 

Efficacy and safety of regular vitamin and 

mineral supplement use in France: Results from 

the ECCA study. Int. J Vitam Nutr Res. 

2005;75(3):201-209. Does not apply to the key 

questions

Update on isotretinoin (Accutane) for acne. Med Lett 

Drugs Ther 83;25(649):105-6. Does not address 

the use of supplements

Valentic JP, Barr RJ, Weinstein GD. Inflammatory 

neovascular nodules associated with oral 

isotretinoin treatment of severe acne. Arch 

Dermatol 83;119(10):871-2. Does not apply to 

the key questions, Does not address the use of 

supplements

Van D, Berg H. Responding to consumer needs: Riskbenefit analysis of fortification. Scand J Nutr 

Suppl 99;43(4):112S-116S. Narrative review 

van Zandwijk N, Hirsch FR. Chemoprevention of lung 

cancer: current status and future prospects. Lung 

Cancer 2003;42 Suppl 1S71-9. Narrative review 

Vieth R. Vitamin D supplementation, 25-

hydroxyvitamin D concentrations, and safety. 

Am. J. Clin. Nutr. 99;69(5):842-856. Narrative 

review 

Vitamins, minerals, supplements and dietary 

approaches. Focus Altern. Complement. Ther. 

2005;10(3):227-232. Narrative review 

Waine C. Vitamin and mineral supplements. Pharm J 

2001;267(7165):352-354. Narrative review 

Ward BJ. Retinol (Vitamin A) supplements in the 

elderly. Drugs Aging 96;9(1):48-59. Narrative 

review 

Weisgerber UM, Boeing H, Owen R W et al. Effect of 

longterm placebo controlled calcium 

supplementation on sigmoidal cell proliferation 

in patients with sporadic adenomatous polyps. 

Gut 96;38(3):396-402. Does not cover the 

defined disease endpoints 

West KP, LeClerq SC, Shrestha SR et al. Effects of 

vitamin A on growth of vitamin A-deficient 

children: field studies in Nepal. J Nutr 

97;127(10):1957-65. Only covers nutritional 

deficiency 

Whiting SJ, Wood R, Kim K. Calcium 

supplementation. J Am Acad Nurse Pract 

97;9(4):187-192. Narrative review 

Wijewardene K. Does vitamin E prevent retinopathy 

of prematurity in low birth weight babies? 

Ceylon Med J 90;35(2):37-9. Does not apply to 

the key questions, Includes only infiants

Willett WC, MacMahon B. Diet and cancer--an 

overview. N Engl J Med 84;310(10):633-8. 

Narrative review 

Woodson K, Tangrea JA, Barrett MJ et al. Serum 

alpha-tocopherol and subsequent risk of lung 

cancer among male smokers. J Natl Cancer Inst 

99;91(20):1738-43. Does not address the use of 

supplements

Wright HO. Vitamin A supplementation. J Appl Nutr 

95;47(1-2):32-33. Editorial 

Yamori Y, Mizushima S. A review of the link between 

dietary magnesium and cardiovascular risk. J 

Cardiovasc Risk 2000;7(1):31-5. Narrative 

review 

Yu SY, Li WG, Zhu YJ et al. Chemoprevention trial 

of human hepatitis with selenium 

supplementation in China. Biol Trace Elem Res 

89;20(1-2):15-22. Does not apply to the key 

questions, Does not address the use of 

supplements
Appendix D: Excluded Articles 

D 14 

Yu SY, Mao BL, Xiao P et al. Intervention trial with 

selenium for the prevention of lung cancer among 

tin miners in Yunnan, China. A pilot study. Biol 

Trace Elem Res 90;24(2):105-8. Does not 

address the use of supplements

Yu SY, Zhu YJ, Li WG et al. A preliminary report on 

the intervention trials of primary liver cancer in 

high-risk populations with nutritional 

supplementation of selenium in China. Biol Trace 

Elem Res 91;29(3):289-94. Does not apply to 

the key questions 

Yusuf S, Dagenais G, Pogue J et al. Vitamin E 

supplementation and cardiovascular events in 

high-risk patients. The Heart Outcomes 

Prevention Evaluation Study Investigators. N 

Engl J Med 2000;342(3):154-60. Does not apply 

to the key questions

Zhang YH, Kramer TR, Taylor PR et al. Possible 

immunologic involvement of antioxidants in 

cancer prevention. Am J Clin Nutr 95;62(6 

Suppl):1477S-1482S. Does not apply to the key 

questions, Does not cover the defined disease 

endpoints

Zhao XQ, Morse JS, Dowdy AA et al. Safety and 

tolerability of simvastatin plus niacin in patients 

with coronary artery disease and low high-density 

lipoprotein cholesterol (The HDL Atherosclerosis 

Treatment Study). Am J Cardiol 2004;93(3):307-

12. Includes ONLY patients with a particular 

chronic disease, Does not apply to the key 

questions, Does not address th use of 

supplements, Does not cover the defined 

disease endpoints
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Cosman, F., Nieves, J., Zion, M., Woelfert, L., Luckey, M., and Lindsay, R.. Daily and cyclic parathyroid hormone in women receiving alendronate. 

N Engl J Med 353 6, 566-75-2005; 

Ref ID: 1 

Abstract: BACKGROUND: We evaluated whether patients with osteoporosis treated with long-term alendronate have a response to parathyroid 

hormone treatment and whether short, three-month cycles of parathyroid hormone therapy could be as effective as daily administration. METHODS: 

We randomly assigned 126 women with osteoporosis who had been taking alendronate for at least 1 year to continued alendronate plus parathyroid 

hormone (1-34) subcutaneously daily, continued alendronate plus parathyroid hormone (1-34) subcutaneously daily for three 3-month cycles 

alternating with 3-month periods without parathyroid hormone, or alendronate alone for 15 months. RESULTS: In both parathyroid hormone groups, 

bone formation indexes rose swiftly. Among the women who were receiving cyclic parathyroid hormone, bone formation declined during cycles 

without parathyroid hormone and increased again during cycles with parathyroid hormone. Bone resorption increased in both parathyroid hormone 

groups but increased progressively more in the daily-treatment group than in the cyclic-therapy group. Spinal bone mineral density rose 6.1 percent 

in the daily-treatment group and 5.4 percent in the cyclic-therapy group (P<0.001 for each parathyroid hormone group as compared with the 

alendronate group and no significant difference between parathyroid hormone groups). One woman in the daily-treatment group, two in the cyclictherapy group, and four in the alendronate group had new or worsening vertebral deformities. CONCLUSIONS: This study suggests that a regimen 

of three-month cycles of parathyroid hormone alternating with three-month cycles without parathyroid hormone causes the early phase of action of 

parathyroid hormone (characterized by pure stimulation of bone formation) to be dissociated from the later phase (activation of bone remodeling). 

The early phase may be more important to the increase in spinal bone mineral density. In patients with persistent osteoporosis after prior 

alendronate treatment, both daily treatment and cyclic treatment with parathyroid hormone increase spinal bone mineral density.

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Refid: 1, Cosman, F., Nieves, J., Zion, M., Woelfert, L., Luckey, M., and Lindsay, R., Daily and cyclic parathyroid hormone in women 

receiving alendronate, N Engl J Med, 353(6), 2005, p.566-75 

State: Excluded, Level: 1

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Abstract:

BACKGROUND: We evaluated whether patients with 

osteoporosis treated with long-term alendronate have a 

response to parathyroid hormone treatment and whether 

short, three-month cycles of parathyroid hormone therapy 

could be as effective as daily administration. METHODS: We 

randomly assigned 126 women with osteoporosis who had 

been taking alendronate for at least 1 year to continued 

alendronate plus parathyroid hormone (1-34) subcutaneously 

daily, continued alendronate plus parathyroid hormone (1-34) 

subcutaneously daily for three 3-month cycles alternating with 

3-month periods without parathyroid hormone, or alendronate 

alone for 15 months. RESULTS: In both parathyroid hormone 

groups, bone formation indexes rose swiftly. Among the 

women who were receiving cyclic parathyroid hormone, bone 

formation declined during cycles without parathyroid hormone 

and increased again during cycles with parathyroid hormone. 

Bone resorption increased in both parathyroid hormone 

groups but increased progressively more in the dailytreatment group than in the cyclic-therapy group. Spinal bone 

mineral density rose 6.1 percent in the daily-treatment group 

and 5.4 percent in the cyclic-therapy group (P<0.001 for each 

parathyroid hormone group as compared with the alendronate 

group and no significant difference between parathyroid 

hormone groups). One woman in the daily-treatment group, 

two in the cyclic-therapy group, and four in the alendronate 

group had new or worsening vertebral deformities. 

CONCLUSIONS: This study suggests that a regimen of threemonth cycles of parathyroid hormone alternating with threemonth cycles without parathyroid hormone causes the early 

phase of action of parathyroid hormone (characterized by 

pure stimulation of bone formation) to be dissociated from the 

later phase (activation of bone remodeling). The early phase 

may be more important to the increase in spinal bone mineral 

density. In patients with persistent osteoporosis after prior 

alendronate treatment, both daily treatment and cyclic 

treatment with parathyroid hormone increase spinal bone 

mineral density. 

 

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No abstract (pull article)

No (exclude)

No (Pull article for future reference)--included in this category: 

narrative reviews, and articles containing base-line data but no 

outcomes of interest.

Yes (include)

 Yes (Pull article for reference)

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2. Reason for exclusion (check all that apply) 

Not English Language

No human data

Includes ONLY pregnant women

Includes ONLY patients with a 

particular chronic disease (cancer, 

CVD, HIV)

Includes ONLY patients receiving 

the following treatments or 

treatments for: dialysis, transplant, 

chemotherapy, HIV infection, 

tuberculosis, end-stage renal 

disease, patients in long-term care 

facilities.

ONLY covers clinical nutritional 

deficiency

Does not apply to the KEY 

QUESTIONS

Does not address use of 

supplements 

Does not report use of 

supplements separately from dietary 

intake

Does NOT cover the defined 

major disease endpoints or adverse 

effects of vitamins/minerals

Editorial/commentary/letter

Other

3. Is this article a randomized-controlled trial, systematic review, or a 

meta-analysis? 

Yes (article MAY be eligible for any of the key questions)

No (article is NOT ELIGIBLE for key questions 1 and 2, but may 

be eligible for key questions 3 and 4)

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4. This article potentially applies to the following key 

question(s) (choose all that apply).

Key Question 1: What is the efficacy determined in randomized 

controlled trials of supplementation with the single nutrients or 

functionally related nutrient pairs listed below, each at a dose less than 

the upper limit determined by the Food and Nutrition Board, in the 

general adult population for the primary or secondary prevention* of 

the following chronic diseases/conditions. (i.e., for those without 

clinically diagnosed disease, who could have risk factors or 

asymptomatic disease)?

Key Question 2: What is the efficacy determined in randomized 

controlled trials of multivitamin/mineral supplement use (defined as 3 

or more vitamins and/or minerals without herbs, hormones, or drugs), 

each at a dose less than the upper limit determined by the Food and 

Nutrition Board, in the general adult population for the primary or 

secondary prevention of the diseases/conditions listed below? 

Key Question 3: What is known about the safety of use of 

multivitamin/mineral supplements (as defined in question 2), in the 

general population of adults and children, based primarily on data from 

randomized controlled trials and well-designed observational studies? 

We may also consider case-reports and post-marketing surveillance 

data.

Key Question 4: What is known about the safety of use of the 

following single nutritional supplements, selenium, iron, â-carotene, 

and vitamin A, in the general population of adults and children, based 

primarily on data from randomized controlled trials and well-designed 

observational studies? We may also consider case-reports and postmarket surveillance data. (We will focus primarily on selenium, iron, 

beta carotene, and vitamin A. Vitamin E, calcium (with or without 

Vitamin D), vitamin D, and folate may also be considered.)

Does not apply to any of the KEY QUESTIONS

5. Select the nutrients included in this study. Answer ONLY if this article 

applies to KQ1 and/or KQ2 (check all that apply) 

Calcium

Folic acid

Vitamin B6

Vitamin B12

Vitamin D

Vitamin E

Vitamin C

Vitamin A

Iron

Zinc

Magnesium

Vitamin B1

Vitamin B2

Niacin

beta-carotene

Selenuim

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Multivitamin

6. Select the disease/conditions included in this study. Answer ONLY if 

this article applies to KQ1 or KQ2 (choose all that apply). 

Oncologic: breast cancer, colorectal cancer, lung cancer, prostate 

cancer, gastric, (colorectal polyps will be included in this category)

Cardiovascular: myocardial infarction, stroke

Endocrine: type II diabetes

Neurologic: Parkinson’s disease, dementia

Age-related sensory loss: cataracts, macular degeneration, 

hearing loss

Musculoskeletal: osteoporosis, rheumatoid arthritis, osteoarthritis, 

osteopenia

Gastroenterologic: non-alcoholic steatorrheic hepatitis, nonalcoholic fatty-liver disease

Renal: chronic renal insufficiency, chronic nephrolithiasis

Infectious: HIV infection, hepatitis C, tuberculosis

Pulmonary: chronic obstructive pulmonary disease

 

DEFINITIONS 

“Primary prevention denotes an action taken to prevent the 

development of a disease in a person who is well and does not have 

the disease in question.”

“Secondary prevention denotes the identification of people who have 

already developed a disease, at an early stage in the disease’s natural 

history, through screening and early intervention.”

 

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Refid: 1, Cosman, F., Nieves, J., Zion, M., Woelfert, L., Luckey, M., and Lindsay, R., Daily and cyclic parathyroid hormone in women 

receiving alendronate, N Engl J Med, 353(6), 2005, p.566-75 

State: Excluded, Level: 1

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1. After reviewing the ENTIRE article, should it be INCLUDED in the review (choose one)

Yes

No

Clear Selection

2. Reason for exclusion (choose all that apply).

Not English language

No human data

Includes ONLY pregnant women

Includes ONLY patients with a particular chronic disease (cancer, CVD, HIV)

Includes ONLY patients receiving the following treatments or treatments for: dialysis, transplant, 

chemotherapy, HIV infection, tuberculosis, end-stage renal disease, patients in long-term care facilities)

ONLY covers nutritional deficiency

Does not apply to the KEY QUESTIONS

Does not address use of supplements 

Does not report supplement use separately from dietary intake

Does NOT cover the defined major endpoints or advers effects of vitamins/minerals

Editorial/commentary/letter

Other

Narrative review--contains studies of interest OR Not an RCT, Systematic Review, or Meta-analysis 

[NOTE: Narrative Review articles ARE NOT applicable to Key Questions 1 or 2 but MAY BE 

APPLICABLE to Key Questions 3 and/or 4]

Includes ONLY infants (children less than 1 year old)

Includes only subjects less than 19 years of age [article is NOT eligible fo rKey Questions 1 or 2, but 

MAY be eleigible for Key Qestins 3 and/or 4]

3. Choose article type: (Choose one)

Randomized controlled trial

Systematic review/meta-analysis

Non-randomized trial (with comparison group)

Narrative review

Cross-sectional study

Cohort study (with concurrent or historical historic group)

Case-control study

Nested case-control study

Case series ( 2 or more case reports

 Other post-market surveillance not otherwise specified

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Other

Clear Selection

 

Inclusion criteria

4. Specific EXCLUSION criteria for Key questions 1 and 2: 

QUESTION SCHEDULED FOR DELETION, DO NOT ANSWER 

Includes only subjects LESS than 18 years of age (article NOT eligible for Key questions 1 OR 2)

Is NOT a Randomized Controlled Trial, Sytematic Review, or Meta-analysis (article NOT eligible for Key questions 1 OR 2)

5. Select ONLY the Key Questions that this article applies to. 

Key Question 1: What is the efficacy determined in randomized controlled trials of supplementation with the single nutrients or

functionally related nutrient pairs listed below, each at a dose less than the upper limit determined by the Food and Nutrition Board, in the 

general adult population for the primary or secondary prevention of the chronic diseases/conditions listed below. (i.e., for those without 

clinically diagnosed disease, who could have risk factors or asymptomatic disease)?

Key Question 2: What is the efficacy determined in randomized controlled trials of multivitamin/mineral supplement use (defined as 3 

or more vitamins and/or minerals without herbs, hormones, or drugs), each at a dose less than the upper limit determined by the Food and 

Nutrition Board, in the general adult population for the primary or secondary prevention of the diseases/conditions listed below?

Key Question 3: What is known about the safety of use of multivitamin/mineral supplements (as defined in question 2), in the general 

population of adults and children, based primarily on data from randomized controlled trials and well-designed observational studies? We 

may also consider case-reports and post-marketing surveillance data.

Key Question 4: What is known about the safety of use of the following single nutritional supplements, selenium, iron, beta carotene, 

and vitamin A, in the general population of adults and children, based primarily on data from randomized controlled trials and well-designed 

observational studies? We may also consider case-reports and post-market surveillance data. (We will focus primarily on selenium, iron, 

beta carotene, and vitamin A. Vitamin E, calcium (with or without Vitamin D), vitamin D, and folate may also be considered.)

Does not apply to the KEY QUESTIONS

 

Nutrients:

Calcium, Folic acid (folate), Vitamin B6, Vitamin B12, Vitamin D, Vitamin E Vitamin C, Vitamin A, Iron, Zinc, Magnesium, Vitamin B1 

(thiamine), Vitamin B2 (riboflavin), Niacin. 

 

Diseases/conditions:

Oncologic: breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric (includes colorectal polyps) 

Cardiovascular: myocardial infarction, stroke 

Endocrine: type II diabetes 

Neurologic: Parkinson’s disease, dementia 

Age-related sensory loss: cataracts, macular degeneration, hearing loss 

Musculoskeletal: osteoporosis, rheumatoid arthritis, osteoarthritis, osteopenia 

Gastroenterologic: non-alcoholic steatohepatitis, non-alcoholic fatty-liver disease 

Renal: chronic renal insufficiency, chronic nephrolithiasis 

Infectious: HIV infection, hepatitis C, tuberculosis 

Pulmonary: chronic obstructive pulmonary disease 

 

DEFINITIONS 

“Primary prevention denotes an action taken to prevent the development of a disease in a person who is well and does not have the disease 

in question.”

“Secondary prevention denotes the identification of people who have already developed a disease, at an early stage in the disease’s natural 

history, through screening and early intervention.”

 

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State: Excluded, Level: 1

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GENERAL STUDY CHARACTERISTICS

This form is applicable to ALL Key Questions 

1. Study name and abbreviation (if applicable).Enlarge Shrink2. Study Design (choose one)

Please Select

3. Choose one type of RCT ONLY if you selected "Randomized Controlled Trial" in question 2:

Please Select

4. "Other" RCTEnlarge Shrink5. Choose one type of Observational Study ONLY if you selected "Observational Study" in question 2:

Please Select

6. "Other" Observational StudyEnlarge Shrink7. Choose one type of Case Series ONLY if you selected "Case series" in question 2:

Please Select

8. "Other" Case SeriesEnlarge Shrink9. Define "other" study designEnlarge Shrink10. Study period:

Start year

End year

Not reported (explain)

11. Follow-up period:

Start year

End year

Not reported (i.e., follow-up not reported)

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Not applicable

Years Months Weeks Not applicalbe Not reported

12. Total follow-up time:

13. Median follow-up duration:14. Mean follow-up duration:

Eligibility criteria of STUDY PARTICIPANTS--note: these are not study outcomes (only answer those that apply, be as explicite and comprehensive as possible).

Inclusion Exclusion

15. Age Clear

16. Male Clear17. Female Clear18. Cancer (specify type) Clear19. Myocardial infarction Clear20. Stroke Clear21. Type II diabetes Clear22. Parkinson's disease Clear23. Dementia Clear24. Cataracts Clear25. Macular degeneration Clear26. Hearing loss Clear27. Osteoporosis or ostepenia (specify) Clear28. Arthritis (osteo or rheumatiod) (specify) Clear29. Non-alcoholic steatohepatitis Clear30. Non-alcoholic fatty liver disease Clear31. Chronic renal insufficiency Clear32. Chronic nephrolithiasis Clear

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33. HIV infection Clear

34. Hepatitis C Clear35. Tuberculosis Clear36. Chronic obstructive pulmonary disease Clear37. Other disease (specify) Clear38. Other disease (specify) Clear39. Other disease (specify) Clear40. Other disease (specify) Clear41. Other disease (specify) Clear42. Other disease (specify) Clear43. Prior use of supplements (specify supplement) Clear44. Prior use of supplements (specify supplement) Clear45. Prior use of supplements (specify supplement) Clear46. Prior use of supplements (specify supplement) Clear47. Prior use of supplements (specify supplement) Clear48. Prior use of supplements (specify supplement) Clear49. OTHER inclusion/exclusion criteria (specify) Clear50. OTHER inclusion/exclusion criteria (specify) Clear51. OTHER inclusion/exclusion criteria (specify) Clear52. OTHER inclusion/exclusion criteria (specify) Clear

Study participants.

53. Total sample size at enrolment (N)

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Enlarge Shrink

54. Country, State, County, City, or other Geographic Area as reported.Enlarge Shrink55. Recruitment setting

Clinical

CommunityOther

Clear SelectionPatient Characteristics (these are OPTIONAL questions, please be as detailed as possible when filling out the following tables).

Range Mean Standard Deviation

56. Age (in years)

n %

57. 

Male58. Female

Race:

n %

59. White60. Black/ African American61. Native Hawaiian/other Pacific Islander62. Native American/Alaska Native63. Hispanic/Latino64. Asian

Other Race, not specified in above table (please specify below).

Specify n %

65. Other 1

66. Other 267. Other 3

Smoking status:

n %

68. Never smoked

69. Former smoker70. Current smoker71. Other smoker

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Alcohol use status:

n %

72. Never used/drank alcohol

73. Former alcohol user/drinker74. Current alcohol user/drinker75. Other alcohol user/drinker

Other patient characteristics:

Range Mean Median Standard Deviation

76. BMI <25

77. BMI 25-2978. BMI > 30

Define Range Mean Median Standard Deviation

79. Other study characterisitcs

80. Other study characterisitcs81. Other study characterisitcs82. Other study characterisitcs83. Other study characterisitcs84. Other study characterisitcs85. Other study characterisitcs86. Other study characterisitcs87. Other study characterisitcs88. Other study characterisitcs

Supplements used prior to this study.

n %

89. Calcium

90. Folic acid91. B 692. B 1293. Vitamin D94. Vitamin E95. Vitamin C96. Vitamin A97. beta-carotene98. Iron99. Zinc100. Magnesium101. B 1102. B 2103. Niacin

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104. Selenium

Specify n %

105. Other 1

106. Other 2107. Other 3108. Other 4

109. NOTES on General Study Characteristics please add any information that you believe will contribute to the outcome of the systematic reviewEnlarge Shrink110. Does this study include data on adverse events?

Yes, study covers BOTH efficacy and adverse events--Fill out BOTH OUTCOMES forms (Levels 13 and 14)

Yes, study covers ONLY adverse events--Fill out ONLY the OUTCOMES FORM for key questions 3 and 4 (Level 14)No, study covers ONLY efficacy --Fill out ONLY the OUTCOMES FORM for key questions 1 and 2 (Level 13)

Clear Selection

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State: Excluded, Level: 1

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1. Arm 1 (define)Enlarge ShrinkControl arms (answer these questions ONLY if no nutrient interveniton was provided):

Exposure--WEEKS Exposure--MONTHS Exposure--YEARS

2. Placebo

3. No dietary supplements or No standard care4. Standard care5. Nutritional/dietary education

Intervention arms (answer these questions ONLY if a nutrient interveniton was provided):

Calcium Folic acid Vitamin B6 Vitamin B12 Vitamin D Vitamin E Vitamin C Vitamin A Iron Zinc Magnesium Vitamin B1 Vitamin B2 Niacin Selenuim

6. Select ALL of the nutrients 

(those that apply to this study's key questions) represented in this arm

Identify ALL of the nutrients (those not listed in this study's key questions) represented in this arm.

7. Other

1 co-Qa

8. Other

2

9. Other

3

10. Other

4

11. Other

5

12. Other

6

13. Other

7

14. Other

8

INSTRUCTIONS FOR COMPLETING INTERVENTION ARM GENERAL DATA: 1. Include information on all forms and combinations of nutrients and other therapies in each arm of this study (example: if a study has 3 arms; placebo, calcium, and calcium/HRT, we need the information on calcium for BOTH in2. If more than one chemical form of the same nutrient is used in an arm, fill out the specific nutrient information for ONE of the chemical forms and use "other" at the end of this form for the remaining chemical forms. If you do no

immediately and more will be added.

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CALCIUM

15. Chemical form

Please Select

16. Chemical form "other"

Specify

17. Total Dose

Specify amount

18. Units

Please Select

19. Unit, "other"

Specify

20. Frequency of use

Please Select

21. Frequency of use, "other"

Specify

22. Timing of use

Please Select

23. Timing of use, "other"

Specify

24. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

FOLIC ACID (folate)

25. Chemical form

Please Select

26. Chemical form "other"

Specify

27. Total Dose

Specify amount

28. Units

Please Select

29. Unit, "other"

Specify

30. Frequency of use

Please Select

31. Frequency of use, "other"

Specify

32. Timing of use

Please Select

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33. Timing of use, "other"

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34. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

VITAMIN B6 (pyridoxine)

35. Chemical form

Please Select

36. Chemical form "other"

Specify

37. Total dose

Specify amount

38. Units

Please Select

39. Unit, "other"

Specify

40. Frequency of use

Please Select

41. Frequency of use, "other"

Specify

42. Timing of use

Please Select

43. Timing of use, "other"

Specify

44. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

VITAMIN B12 (cyanocobalamin)

45. Chemical form

Please Select

46. Chemical form "other"

Specify

47. Total dose

Specify amount

48. Units

Please Select

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49. Units, "other"

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50. Frequency of use

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51. Frequency of use, "other"

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52. Timing of use

Please Select

53. Timing of use, "other"

Specify

54. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

VITAMIN D

55. Chemical form

Please Select

56. Chemical form "other"

Specify

57. Total dose

Specify amount

58. Units

Please Select

59. Unit, "other"

Specify

60. Frequency of use

Please Select

61. Frequency of use, "other"

Specify

62. Timing of use

Please Select

63. Timing of use, "other"

Specify

64. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

VITAMIN E

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65. Chemical form

Please Select

66. Chemical form "other"

Specify

67. Total dose

Specify amount

68. Units

Please Select

69. Unit, "other"

Specify

70. Frequency of use

Please Select

71. Frequency of use, "other"

Specify

72. Timing of use

Please Select

73. Timing of use, "other"

Specify

74. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

VITAMIN C

75. Chemical form

Please Select

76. Chemical form "other"

Specify

77. Total does

Specify amount

78. Units

Please Select

79. Unit, "other"

Specify

80. Frequency of use

Please Select

81. Frequency of use, "other"

Specify

82. Timing of use

Please Select

83. Timing of use, "other"

Specify

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84. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

VITAMIN A

85. Chemical form

Please Select

86. Chemical form "other"

Specify

87. Total dose

Specify amount

88. Dose, units

Please Select

89. Unit, "other"

Specify

90. Frequency of use

Please Select

91. Frequency of use, "other"

Specify

92. Timing of use

Please Select

93. Timing of use, "other"

Specify

94. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

IRON

95. Chemical form

Please Select

96. Chemical form "other"

Specify

97. Total dose

Specify amount

98. Units

Please Select

99. Unit, "other"

Specify

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100. Frequency of use

Please Select

101. Frequency of use, "other"

Specify

102. Timing of use

Please Select

103. Timing of use, "other"

Specify

104. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

ZINC

105. Chemical form

Please Select

106. Chemical form "other"

Specify

107. Total dose

Specify amount

108. Units

Please Select

109. Units, "other"

Specify

110. Frequency of use

Please Select

111. Frequency of use, "other"

Specify

112. Timing of use

Please Select

113. Timing of use, "other"

Specify

114. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

MAGNESIUM

115. Chemical form

Please Select

116. Chemical form "other"

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117. Total dose

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118. Units

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119. Unit, "other"

Specify

120. Frequency of use

Please Select

121. Frequency of use, "other"

Specify

122. Timing of use

Please Select

123. Timing of use, "other"

Specify

124. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

VITAMIN B1 (thiamine)

125. Chemical form

Please Select

126. Chemical form "other"

Specify

127. Total dose

Specify amount

128. Units

Please Select

129. Unit, "other"

Specify

130. Frequency of use

Please Select

131. Frequency of use, "other"

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132. Timing of use

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133. Timing of use, "other"

Specify

134. Duration of use

Exposure--WEEKS

Exposure--MONTHS

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Exposure--YEARS

Not specified

VITAMIN B2 (riboflavin)

135. Chemical form

Please Select

136. Chemical form "other"

Specify

137. Total dose

Specify amount

138. Units

Please Select

139. Unit, "other"

Specify

140. Frequency of use

Please Select

141. Frequency of use, "other"

Specify

142. Timing of use

Please Select

143. Timing of use, "other"

Specify

144. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

NIACIN

145. Chemical form

Please Select

146. Chemical form "other"

Specify

147. Total dose

Specify amount

148. Units

Please Select

149. Unit, "other"

Specify

150. Frequency of use

Please Select

151. Frequency of use, "other"

Specify

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152. Timing of use

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153. Timing of use, "other"

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154. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

SELENIUM

155. Chemical form

Please Select

156. Chemical form "other"

Specify

157. Total dose

Specify amount

158. Units

Please Select

159. Unit, "other"

Specify

160. Frequency of use

Please Select

161. Frequency of use, "other"

Specify

162. Timing of use

Please Select

163. Timing of use, "other"

Specify

164. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

165. OTHER

1

166. Chemical form

Specify

Not specified

167. Total dose

Specify amount

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168. Units

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169. Unit, "other"

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170. Frequency of use

Please Select

171. Frequency of use, "other"

Specify

172. Timing of use

Please Select

173. Timing of use, "other"

Specify

174. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

175. OTHER

2

176. Chemical form

Specify

Not specified

177. Total dose

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178. Units

Please Select

179. Unit, "other"

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180. Frequency of use

Please Select

181. Frequency of use, "other"

Specify

182. Timing of use

Please Select

183. Timing of use, "other"

Specify

184. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

185. OTHER

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3

186. Chemical form

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Not specified

187. Total dose

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188. Units

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189. Unit, "other"

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190. Frequency of use

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191. Frequency of use, "other"

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192. Timing of use

Please Select

193. Timing of use, "other"

Specify

194. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

195. OTHER

4

196. Chemical form

Specify

Not specified

197. Total dose

Specify amount

198. Units

Please Select

199. Unit, "other"

Specify

200. Frequency of use

Please Select

201. Frequency of use, "other"

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202. Timing of use

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203. Timing of use, "other"

Specify

204. Duration of use

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Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

205. OTHER

5

206. Chemical form

Specify

Not specified

207. Total dose

Specify amount

208. Units

Please Select

209. Unit, "other"

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210. Frequency of use

Please Select

211. Frequency of use, "other"

Specify

212. Timing of use

Please Select

213. Timing of use, "other"

Specify

214. Duration of use

Exposure--WEEKS

Exposure--MONTHSExposure--YEARS

Not specified

215. Notes on ARM 1Enlarge Shrink

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Study Results (Outcomes) This form is ONLY to be used for studies applying to Key Questions 1 and/or 2.Study endpoints: Check all that apply, please be as complete as possible in your answers.

Primary endpoint Secondary endpoint

1. Any cancer Clear

2. Cancer other than non-melanoma skin cancer Clear3. Breast cancer Clear4. Colorectal cancer Clear5. Lung cancer Clear6. Prostate cancer Clear7. Gastric cancer Clear8. Myocardial infarction Clear9. Stroke Clear10. Cancer other than non-melanoma skin cancer Clear11. Type II diabetes Clear12. Parkinson's disease Clear13. Dementia Clear14. Cataracts Clear15. Macular degeneration Clear16. Hearing loss Clear17. Osteporosis Clear18. Bone mineral density Clear19. Rheumatiod arthritis Clear20. Osteoarthritis Clear21. Osteopenia Clear22. Non-alcoholic steatohepatitis Clear23. Non-alcoholic fatty-liver disease Clear24. Chronic renal insufficiency Clear25. Chronic nepholithiasis Clear26. HIV infection Clear27. Hepatitis C Clear28. Tuberculosis Clear29. Chronic obstructive pulmonary disease Clear

Define Primary endpoint Secondary endpoint

30. Other

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31. Other

32. Other33. Other34. Other35. Other36. Other37. Other38. Other39. Other40. Other41. Other42. Other

Study results (disease endpoints): Do not include BMD, or area of opacity results in this table, a seperate table has been supplied for this data. Check all that apply, please be as complete as possible in your answers.

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted esti

sp

43. 1.44. 2.45. 3.46. 4.47. 5.48. 6.49. 7.50. 8.51. 9.

Study results (Bone Mineral Density (BMD)): Do not include data on area of opacity in this table, a seperate table has been supplied for this data. Check all that apply, please be as complete as possible in your answers.

Randomized group Bone density site Median IQR change from Mean change from baseline Standard deviation Standard error 95% CI 

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baseline 

52. 1.

53. 2.54. 3.55. 4.56. 5.57. 6.58. 7.59. 8.60. 9.

Study results (area of opacity (% pixels opaque), cognitive function test results or results from other contour measurements): Do not include data on bone mineral density in this table, a sCheck all that apply, please be as complete as possible in your answers.

Randomized group Median IQR Mean change from baseline Standard deviation Standard error 95% CI Difference from placebo (

61. 1.62. 2.63. 3.64. 4.65. 5.66. 6.67. 7.68. 8.69. 9.

70. What subgroups were analyzed?

Gender (specify)

Age (specify)Ethnicity (specify)Other (specify)

71. Subgroup 1Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted esti

sp

72. 1.73. 2.74. 3.75. 4.76. 5.77. 6.78. 7.

SRS Form 

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79. 

8.

80. Subgroup 2Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted esti

sp

81. 1.82. 2.83. 3.84. 4.

85. Notes on Efficacy OutcomesEnlarge Shrink86. Subgroup 3Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted esti

sp

87. 1.88. 2.89. 3.90. 4.

91. Notes on Efficacy OutcomesEnlarge Shrink92. Subgroup 4Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted esti

sp

93. 1.94. 2.95. 3.96. 4.

97. Notes on Efficacy OutcomesEnlarge Shrink98. Subgroup 5Enlarge Shrink

Diseease endpoint Study supplement Total Number in study Number of disease events Person years (active/placebo) Incidence Unadjusted est

SRS Form 

https://www.clinical-analytics.com/d2d/ul1/review.asp?mode=previewMode&articleid=268&level=13 
(active/placebo) (active/placebo) sp

99. 1.

100. 2.101. 3.102. 4.

103. Notes on Efficacy OutcomesEnlarge Shrink104. Subgroup 6Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted est

sp

105. 1.106. 2.107. 3.108. 4.

109. Notes on Efficacy OutcomesEnlarge Shrink110. Subgroup 7Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted est

sp

111. 1.112. 2.113. 3.114. 4.

115. Notes on Efficacy OutcomesEnlarge Shrink116. Subgroup 8Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted est

sp

117. 1.118. 2.119. 3.120. 4.

SRS Form 

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121. Notes on Efficacy Outcomes

Enlarge Shrink122. Subgroup 9Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted est

sp

123. 1.124. 2.125. 3.126. 4.

127. Notes on Efficacy OutcomesEnlarge Shrink128. Subgroup 10Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted est

sp

129. 1.130. 2.131. 3.132. 4.

133. Notes on Efficacy OutcomesEnlarge Shrink134. Subgroup 11Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted est

sp

135. 1.136. 2.137. 3.138. 4.

139. Notes on Efficacy OutcomesEnlarge Shrink140. Subgroup 12

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Form took 3.265625 seconds to render

Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted est

sp

141. 1.142. 2.143. 3.144. 4.

145. Notes on Efficacy OutcomesEnlarge Shrink146. Subgroup 13Enlarge Shrink

Diseease endpoint Study supplement Total Number in study (active/placebo) Number of disease events (active/placebo) Person years (active/placebo) Incidence Unadjusted est

sp

147. 1.148. 2.149. 3.150. 4.

151. Notes on Efficacy OutcomesEnlarge Shrink

Submit Data

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Study Results (Outcomes) This form is ONLY to be used for studies applying to Key Questions 3 and/or 4.

Types of Outcomes

(Study Endpoints)

1. List ALL safety-related outcomes reported in this study

1.

2.3.4.5.6.

Criteria for causality (for outcome 1 listed above):

Yes No Not reported

2. Did supplement use take place prior to adverse events/effects (i.e., temporal relationships)? Clear

3. Did the original data reported in this article support a dose-respones relationship? Clear4. Did advers effects disappear after discontinuation of supplement use? Clear5. Was there evidence that serum levels of nutrients increased after supplementation? Clear6. Was there lack of alternative cause for the edverse effects other than supplemetn use? Clear7. Did adverse effectrs occur again after re-use of the supplements? Clear

Criteria for causality (for outcome 2 listed above):

Yes No Not reported

8. Did supplement use take place prior to adverse events/effects (i.e., temporal relationships)? Clear

9. Did the original data reported in this article support a dose-respones relationship? Clear10. Did advers effects disappear after discontinuation of supplement use? Clear11. Was there evidence that serum levels of nutrients increased after supplementation? Clear12. Was there lack of alternative cause for the edverse effects other than supplemetn use? Clear13. Did adverse effectrs occur again after re-use of the supplements? Clear

Criteria for causality (for outcome 3 listed above):

Yes No Not reported

14. Did supplement use take place prior to adverse events/effects (i.e., temporal relationships)? Clear

15. Did the original data reported in this article support a dose-respones relationship? Clear16. Did advers effects disappear after discontinuation of supplement use? Clear17. Was there evidence that serum levels of nutrients increased after supplementation? Clear18. Was there lack of alternative cause for the edverse effects other than supplemetn use? Clear19. Did adverse effectrs occur again after re-use of the supplements? Clear

Criteria for causality (for outcome 4 listed above):

SRS Form 

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Yes No Not reported

20. Did supplement use take place prior to adverse events/effects (i.e., temporal relationships)? Clear

21. Did the original data reported in this article support a dose-respones relationship? Clear22. Did advers effects disappear after discontinuation of supplement use? Clear23. Was there evidence that serum levels of nutrients increased after supplementation? Clear24. Was there lack of alternative cause for the edverse effects other than supplemetn use? Clear25. Did adverse effectrs occur again after re-use of the supplements? Clear

Criteria for causality (for outcome 5 listed above):

Yes No Not reported

26. Did supplement use take place prior to adverse events/effects (i.e., temporal relationships)? Clear

27. Did the original data reported in this article support a dose-respones relationship? Clear28. Did advers effects disappear after discontinuation of supplement use? Clear29. Was there evidence that serum levels of nutrients increased after supplementation? Clear30. Was there lack of alternative cause for the edverse effects other than supplemetn use? Clear31. Did adverse effectrs occur again after re-use of the supplements? Clear

Criteria for causality (for outcome 6 listed above):

Yes No Not reported

32. Did supplement use take place prior to adverse events/effects (i.e., temporal relationships)? Clear

33. Did the original data reported in this article support a dose-respones relationship? Clear34. Did advers effects disappear after discontinuation of supplement use? Clear35. Was there evidence that serum levels of nutrients increased after supplementation? Clear36. Was there lack of alternative cause for the edverse effects other than supplemetn use? Clear37. Did adverse effectrs occur again after re-use of the supplements? Clear

Study results (note that side effects may be presented as reasons for dropouts).

38. NutrientEnlarge

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39. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

40. Side effects or 

adverse events reported?

Please Select

41. Number 

of events in the active (nutrient) group. 

enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

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42. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

43. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

44. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

45. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

46. 95% 

No

applica

No

reporte

Re

48. NutrientEnlarge

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49. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

50. Side effects or 

adverse events reported?

Please Select

51. Number 

of events in the active (nutrient) group. 

enter "0" if no adverse effects occurred enter "not reported" if the 

52. Number of events in the control group. enter "0" if no adverse effects occurred 

53. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

54. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

55. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

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result was not 

reportedEnlarge

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enter "not reported" if the result was not reportedEnlarge

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Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

(SE)

Median

OtherNot 

applicable

Not 

reported

Not 

applicable

Not 

reported

58. 

NutrientEnlarge

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59. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

60. Side effects or 

adverse events reported?

Please Select

61. Number 

of events in the active (nutrient) group. 

enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

62. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

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63. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

64. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

65. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

66. 95% 

No

applica

No

reporte

Re

68. NutrientEnlarge

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69. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

70. Side effects or 

adverse events reported?

Please Select

71. Number 

of events in the active (nutrient) group. 

enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

72. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

73. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

74. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

75. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

76. 95% 

No

applica

No

reporte

Re

78. NutrientEnlarge

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79. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

80. Side effects or 

adverse events reported?

Please Select

81. Number 

of events in the active (nutrient) group. 

enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

82. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

83. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

84. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

85. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

86. 95% 

No

applica

No

reporte

Re

88. 89. Outcome 90. Side effects or 91. Number 92. 93. Change in active (nutrient) group 94. Change in control group 95. Point estimate 96. 95% 

SRS Form 

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Nutrient

Enlarge

Shrink

as adverse event/event (i.e., vomiting, hives). Enlarge Shrink

adverse events reported?

Please Select

of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

(e.g., cholesterol data) answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

No

applica

No

reporte

Re

98. NutrientEnlarge

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99. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

100. Side effects or 

adverse events reported?

Please Select

101. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

102. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

103. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

104. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

105. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

106. 95

No

applica

No

reporte

Re

108. NutrientEnlarge

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109. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

110. Side effects or 

adverse events reported?

Please Select

111. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

112. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

113. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

114. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

115. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

116. 95

No

applica

No

reporte

Re

118. NutrientEnlarge

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119. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

120. Side effects or 

adverse events reported?

Please Select

121. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reported

122. 

Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reported

123. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

Median

124. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOther

125. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

126. 95

No

applica

No

reporte

Re

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OtherNot 

reported

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applicable

Not 

applicable

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reported

reported

128. 

NutrientEnlarge

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129. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

130. Side effects or 

adverse events reported?

Please Select

131. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

132. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

133. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

134. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

135. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

136. 95

No

applica

No

reporte

Re

138. NutrientEnlarge

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139. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

140. Side effects or 

adverse events reported?

Please Select

141. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

142. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

143. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

144. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

145. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

146. 95

No

applica

No

reporte

Re

148. NutrientEnlarge

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149. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

150. Side effects or 

adverse events reported?

Please Select

151. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

152. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

153. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

154. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

155. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

156. 95

No

applica

No

reporte

Re

158. Nutrient

159. Outcome 

as adverse event/event (i.e., vomiting, hives). 

160. Side effects or 

adverse events reported?

Please Select

161. Number of events in the active (nutrient) 

162. Number of events in the control 

163. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

164. Change in control group answer all that apply

Mean 

(95% CI)

165. Point estimate

Relative 

Risk

Odds 

166. 95

No

applica

No

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group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

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group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

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(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

reporte

Re

168. NutrientEnlarge

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169. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

170. Side effects or 

adverse events reported?

Please Select

171. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

172. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

173. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

174. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

175. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

176. 95

No

applica

No

reporte

Re

178. NutrientEnlarge

Shrink

179. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

180. Side effects or 

adverse events reported?

Please Select

181. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

182. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

183. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

184. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

185. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

186. 95

No

applica

No

reporte

Re

188. NutrientEnlarge

Shrink

189. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

190. Side effects or 

adverse events reported?

Please Select

191. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

192. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reported

193. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

194. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

195. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

196. 95

No

applica

No

reporte

Re

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Enlarge

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applicable

Not 

reported

198. NutrientEnlarge

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199. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

200. Side effects or 

adverse events reported?

Please Select

201. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

202. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

203. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

204. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

205. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

206. 95

No

applica

No

reporte

Re

208. NutrientEnlarge

Shrink

209. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

210. Side effects or 

adverse events reported?

Please Select

211. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

212. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

213. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

214. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

215. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

216. 95

No

applica

No

reporte

Re

218. NutrientEnlarge

Shrink

219. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

220. Side effects or 

adverse events reported?

Please Select

221. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

222. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

223. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

224. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

225. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

226. 95

No

applica

No

reporte

Re

228. NutrientEnlarge

Shrink

229. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

230. Side effects or 

adverse events reported?

Please Select

231. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not 

232. Number of events in the control group. enter "0" if no adverse effects occurred 

233. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

234. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

235. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

236. 95

No

applica

No

reporte

Re

SRS Form 

https://www.clinical-analytics.com/d2d/ul1/review.asp?mode=previewMode&articleid=268&level=14 
reported" if the 

result was not reportedEnlarge

Shrink

enter "not reported" if the result was not reportedEnlarge

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Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

MedianOtherNot 

applicable

Not 

reported

Not 

applicable

Not 

reported

238. 

NutrientEnlarge

Shrink

239. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

240. Side effects or 

adverse events reported?

Please Select

241. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

242. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

243. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

244. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

245. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

246. 95

No

applica

No

reporte

Re

248. NutrientEnlarge

Shrink

249. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

250. Side effects or 

adverse events reported?

Please Select

251. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

252. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

253. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

254. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

255. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

256. 95

No

applica

No

reporte

Re

258. NutrientEnlarge

Shrink

259. Outcome 

as adverse event/event (i.e., vomiting, hives). 

Enlarge Shrink

260. Side effects or 

adverse events reported?

Please Select

261. Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

262. Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

263. Change in active (nutrient) group 

(e.g., cholesterol data) 

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

264. Change in control group answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

265. Point estimate

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

266. 95

No

applica

No

reporte

Re

268. 269. Outcome 270. Side effects or 271. 272. 273. Change in active (nutrient) group 274. Change in control group 275. Point estimate 276. 95

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Form took 14.8125 seconds to render

NutrientEnlarge

Shrink

as adverse event/event (i.e., vomiting, hives). Enlarge Shrink

adverse events reported?

Please Select

Number of events in the active (nutrient) group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

Number of events in the control group. enter "0" if no adverse effects occurred enter "not reported" if the result was not reportedEnlarge

Shrink

(e.g., cholesterol data) answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

reported

Not 

applicable

answer all that apply

Mean 

(95% CI)

Mean 

(SD)

Mean 

(SE)

MedianOtherNot 

applicable

Not 

reported

Relative 

Risk

Odds 

Ratio

Hazard 

Ratio

Not 

applicable

Not 

reported

No

applica

No

reporte

Re

278. NOTES: Add notes on this study regarding data that did not fit into the above form.Enlarge Shrink

Submit Data

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2005, p.566-75 

State: Excluded, Level: 1

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Quality Review Form 

(only for articles that apply to Key Questions 1 and/or 2) 

NOTE FOR SECOND REVIEWERS: 

All quality reviews should be done independantly. DO NOT follow the serial review instructions as you have for the outcomes data

NOTE: numbers in brackets () are the quality score

 

Representativeness of the Study Population

1. Did the study describe the setting and population from which the study sample was drawn, and the dates of the study?

 Please Select

2. Were detailed inclusion/exclusion criteria provided?

 Please Select

3. Was information provided on excluded or non-participating individuals?

 Please Select

4. 

Does the study describe key characteristics of study participants at enrollment? 

Demographics: age, gender, race/ethnicity, education

Medical risk factors: 

i. Oncologic (breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric, or any other malignancy, colorectal polyps): family history, medical conditions (e.g. benign prostatic 

hyperplasia, benign breast disease, inflammatory bowel disease).

ii. Cardiovascular (MI, stroke): family history of CVD, obesity, lipid profile, hypertension, diabetes

iii. Endocrine (type II diabetes): obesity

iv. Neurologic (Parkinson’s disease): 

Neurologic (Dementia):

v. Age-related sensory loss (cataracts, macular degeneration, hearing loss):

vi. Musculoskeletal (osteoporosis, rheumatoid arthritis, osteoarthritis, osteopenia): women, heredity, sex hormone deficiency (estrogen deficiency in women, testosterone deficiency in 

men), low body weight, physical inactivity, poor calcium intake, vitamin D deficiency, excessive alcohol drinking

vii. Gastroenterologic (non-alcoholic steatorrheic hepatitis, NAFLD): obesity, type 2 diabetes, elevated total cholesterol or triglyceride.

viii. Renal (chronic renal insufficiency, chronic nephrolithiasis): hypertension, diabetes, African American, hypercalciuria

ix. HIV infection:

 Hepatitis C:

TB: 

x. Pulmonary: COPD

Lifestyle risk factors: smoking, prior dietary supplement use, diet, physical activities 

Use of medication: any medication reported, particularly those used to prevent or treat the outcome of interest

 Please Select

 

Bias and Confounding

5. Was the assignment of patients to study group randomly determined?

 Please Select

6. 

Was concealment of allocation sequence adequate? 

 Please Select

* Centralized randomization by telephone; numbered or coded identical containers administered sequentially; on-site computer system which can only be accessed after entering the 

characteristics of an enrolled participant; sequentially numbered, sealed, opaque envelopes. 

** Sealed envelopes but not sequentially numbered or opaque; list of random numbers read by someone entering patient into trial (open list); a trial in which the description suggests adequate 

concealment, but other features are suspicious (for example: markedly unequal controls and trial groups; stated random, but unable to obtain further details. 

*** for example: an open list of random numbers, alternation, date of birth, day of week, case record number, not randomized or unclear.

7. 

Did the patient groups have any important differences in key patient characteristics? 

Demographics: age, gender, race/ethnicity, education, 

i. Oncologic (breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric, or any other malignancy, colorectal polyps): family history, medical conditions (e.g. benign prostatic 

hyperplasia, benign breast disease, inflammatory bowel disease).

ii. Cardiovascular (MI, stroke): family history of CVD, obesity, lipid profile, hypertension, diabetes

iii. Endocrine (type II diabetes): obesity

iv. Neurologic (Parkinson’s disease): 

Neurologic (Dementia):

v. Age-related sensory loss (cataracts, macular degeneration, hearing loss):

vi. Musculoskeletal (osteoporosis, rheumatoid arthritis, osteoarthritis, osteopenia): women, heredity, sex hormone deficiency (estrogen deficiency in women, testosterone deficiency in 

men), low body weight, physical inactivity, poor calcium intake, vitamin D deficiency, excessive alcohol drinking

vii. Gastroenterologic (non-alcoholic steatorrheic hepatitis, NAFLD): obesity, type 2 diabetes, elevated total cholesterol or triglyceride.

viii. Renal (chronic renal insufficiency, chronic nephrolithiasis): hypertension, diabetes, African American, hypercalciuria

ix. HIV infection:

 Hepatitis C:

TB: 

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x. Pulmonary: COPD

Lifestyle Factors: smoking, prior dietary supplement use, diet, physical activities 

Use of medication: any medication reported, particularly those used to prevent or treat the outcome of interest

 Please Select

8. 

Did study report adequate information about the use of vitamin/mineral supplements prior to study enrollment? 

 Please Select

9. 

Did the study groups differ in the use of vitamin/mineral supplements prior to study enrollment? 

 Please Select

10. 

Did the study describe medication use during the study period that may affect the net efficacy of the supplements of interest? 

 Please Select

11. 

Were there efforts made to blind study supplements? 

 Please Select

12. 

Did the study report evidence of success on blinding study subjects? 

 Please Select

13. 

Were diagnoses of clinical outcomes in the present study confirmed by medical charts, pathohistological data or registry? 

 Please Select

14. 

Was interpretation of clinical outcomes performed by two or more independent observers? 

 Please Select

15. 

Was there blinding to clinicians, study participants, outcome assessors and statisticians with regard to group assignment? 

 Please Select

16. 

Were all randomized arms blinded? 

 Please Select

 

Description of Study Supplements/Supplementation 17. 

How well were the details of the study supplements (including placebo)described? (i.e., types of supplements, chemical forms of supplements, and 

dosage, frequency, and duration of supplementation) 

 Please Select

18. 

How good was the assessment of adherence to supplemetnations? 

 Please Select

 

Adherence and Follow-up 

19. 

How did the study describe the flow of participants through each stage? For each group, the number of participants randomly assigned, receiving 

intended intervention, completing the study protocol and analyzed for the primary outcome. 

 Please Select

20. 

How was the participants’ adherence to study supplement use? 

 Please Select

21. 

Was there an unintended cross-over between/among randomized groups? (i.e. subjects in one arm taking what was assigned to another arm) 

 Please Select

22. 

Did the study report the numbers or reasons for withdrawals from the study protocol or for participants otherwise lost to follow-up? 

 Please Select

23. 

What was the percentage of participants who withdrew from the study protocol or were lost to follow-up? 

 Please Select

24. 

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Did the study stop the intervention earlier than as planned or describe other deviations from the study protocol together with reasons? 

 Please Select

* no deviations from the protocol OR deviations from the protocol with reasons given did not appear to have affected the estimate of the efficacy

** deviations from the protocol with reasons given BUT may have affected the estimate of the efficacy, e.g. inadequate follow-up

*** deviations from the protocol with no reasons given AND may have affected the efficacy of interest

 

Statistical Analysis

25. 

Was the statistical test of all analyses clearly identified? 

 Please Select

26. 

Was unintended cross-over handled appropriately in the analysis? 

 Please Select

27. 

Was loss-to-follow-up handled appropriately in the analysis? 

 Please Select

28. 

For primary endpoints of the evaluation, does the study report: (The magnitude of difference between groups OR magnitude of the association 

between outcomes and participant characteristics) AND (an index of variability e.g., test statistic, p value, standard error, confidence interval)? 

 Please Select

29. 

Was adequate adjustment made for potential confounding in the analysis from which the main findings were drawn? 

 Please Select

* adjusted for all potential confounding factors that differed between groups

** adjusted for some but not all potential confounding factors

*** did not adjust for confounding factors or unclear whether potential confounding factors differed between groups 

**** e.g., groups did not differ in important participant characteristics

30. 

Did the study report its statistical power? 

 Please Select

 

Conflicts of Interest

31. 

Did the study report identify the sources of funding and the type and degree of involvement of the funding agency? 

 Please Select

32. Notes on Quality

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Refid: 1, Cosman, F., Nieves, J., Zion, M., Woelfert, L., Luckey, M., and Lindsay, R., Daily and cyclic parathyroid hormone in women receiving alendronate, N Engl J Med, 353(6), 

2005, p.566-75 

State: Excluded, Level: 1

Submit Data

Quality Review Form 

(only for SYSTEMATIC REVIEWS) 

NOTE FOR SECOND REVIEWERS: 

All quality reviews should be done independantly. DO NOT follow the serial review instructions as you have for the outcomes data

NOTE: numbers in brackets () are the quality score

1. Did the authors clearly state the question addressed by the overview at the beginning of the article?

 Please Select

2. Did the authors describe the search methods used to find evidence (original research) on the primary question(s)?

 Please Select

3. Was the search for evidence reasonably comprehensive?

 Please Select

* Search included MEDLINE (or other electronic database), hand-searching of select journals or reference lists, AND query of 1 or more experts.

** Search included MEDLINE (or other electronic database), but did not include hand-searching of journals or reference lists AND/OR did not 

include a query of experts.

*** Search did not include an electronic database of journals

4. Did the authors report on the criteria they used for deciding which studies to include in the systematic review?

 Please Select

5. Were the inclusion criteria appropriate (aimed at avoiding bias in the selection of studies)?

 Please Select

6. Were analyses done to see whether efficacy varies according to dose and duration of the supplements, such as dose-response analyses?

 Please Select

7. Were analyses done to see whether efficacy varies according to the forms of the dietary supplements?

 Please Select

8. Did the authors assess study quality?

 Please Select

9. Was the quality assessment done appropriately?

 Please Select

* Quality assessment was done using a validated instrument (with citation) or the authors demonstrated validity of their methods

** Authors used their own quality assessment instrument without validation, or another instrument with unknown measurement properties.

10. Did the authors evaluate and consider the differences in defining outcomes across studies? (e.g., overall CVD vs. combination of specific 

cardiovascular events)

 Please Select

11. Did the authors take account of the different ways of reporting outcomes across studies in their analyses? 

 Please Select

12. Did the authors demonstrate that their methodology was reproducible?

 Please Select

* The investigators mostly (>50% of the time) agreed on selection of articles, on quality assessment, AND on the data that was extracted.

** Disagreement occurred the majority of the time either on the selection of articles, quality assessment, or data extraction (but not all 3).

*** Disagreement occurred the majority of the time on the selection of articles, quality assessment, AND data extraction.

13. Did the authors discuss whether variation in the results of the original research may be due to differences in study design or population?

 Please Select

* Text or tables provide comparative information on both study design, and population 

characteristics 

14. Were the results of the relevant studies combined appropriately relative to the primary question?

 Please Select

* The overview included some assessment of the qualitative and quantitative heterogeneity of study results AND used an accepted pooling method 

(i.e., more than simple addition).

15. Were the conclusions of the authors supported by the data and/or analysis reported in the overview?

 Please Select

Submit Data

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2005, p.566-75 

State: Excluded, Level: 1

Submit Data

Summary Result Form 

(for systematic reviews of calcium/vitamin D)

 

Study aim of the systematic review (check all that apply): 

1. To assess: 

calcium

vitamin D

2. In the prevention of: 

Bone density loss

Fracture

Colon Cancer

Colon polyps

Colorectal cancer

Other 

Years

Months

3. Exclusion criteria used in this systematic review article:

Enlarge Shrink 

 

Search Strategies 

4. Source databases (check all that apply):

Cochrane Library

MEDLINE

EMBASE

Cochrane Controlled Trial Register

Cancerlit

CABNAR

LILACS

CINAHL

BIOSIS

HealthSTAR

MANTIS

Allied & Complementary Medicine

CABHealth

TGG Health & Wellness

Unpublished Data

Hand search based on reference lists of relevant articles

Experts’ referral

Other (list all) 

5. Publication dates of included articles: 

From (Years)

From (Months)

To (Years)

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To (Months)

6. Search terms used (check all that apply): 

calcium

vitamin D

osteoporosis

post-menopause 

bone loss

fracture

cancer

polyps 

colorectal cancer

oncologic

other

7. Number of trials included in the review: 

Enlarge Shrink 

8. Total number of trial participants: 

In placebo group

In Calcium alone group 

In Vitamin D alone group

In Calcium + vitamin D group

9. Follow-up periods of the trials included in this systematic review:

Range____to____ (year) 

Not Reported

10. Range of proportion of participants who were lost to follow-up:

From

To

Not Reported

11. Trial Participants Characteristics:

Range of mean age: (___to___)

Range of % women: _____% to _____%

Race (range of %)

White

African-American

Hispanic

Other (specify)

Baseline BMD

Mean (including unit)

Median (including unit)

% post-menopausal in women

12. Chemical forms of vitamins/minerals used in included trials (check all that apply):

Ca1. calcium carbonate

Ca2. calcium citrate

Ca3. calcium citrate malate

Ca4. dibasic calcium phosphate

Ca5. unspecified

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Ca6. other

D1. cholecalciferol

D2. ergocalciferol

D3. unspecified

D4. other 

13. Range of doses used in trials:

Calcium (including unit)

Vitamin D (including unit)

Aggregate Results on Bone mineral density and bone mineral content

Result 1:

14. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

15. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

16. Number of trials for this result:

Enlarge Shrink 

17. Total sample size for this result: 

Enlarge Shrink 

18. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

19. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 2:

20. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

21. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

22. Number of trials for this result:

Enlarge Shrink 

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23. Total sample size for this result: 

Enlarge Shrink 

24. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

25. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 3:

26. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

27. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

28. Number of trials for this result:

Enlarge Shrink 

29. Total sample size for this result: 

Enlarge Shrink 

30. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

31. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 4:

32. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

33. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

34. Number of trials for this result:

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Enlarge Shrink 

35. Total sample size for this result: 

Enlarge Shrink 

36. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

37. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 5:

38. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

39. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

40. Number of trials for this result:

Enlarge Shrink 

41. Total sample size for this result: 

Enlarge Shrink 

42. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

43. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 6:

44. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

45. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

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1/3 distal radius

Other

46. Number of trials for this result:

Enlarge Shrink 

47. Total sample size for this result: 

Enlarge Shrink 

48. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

49. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 7:

50. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

51. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

52. Number of trials for this result:

Enlarge Shrink 

53. Total sample size for this result: 

Enlarge Shrink 

54. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

55. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 8:

56. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

57. Bone density site: 

Total body

L-spine (1-2 yrs) 

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L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

58. Number of trials for this result:

Enlarge Shrink 

59. Total sample size for this result: 

Enlarge Shrink 

60. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

61. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 9:

62. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

63. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

64. Number of trials for this result:

Enlarge Shrink 

65. Total sample size for this result: 

Enlarge Shrink 

66. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

Result 9:

67. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

68. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

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Combined hip 

1/3 distal radius

Other

69. Number of trials for this result:

Enlarge Shrink 

70. Total sample size for this result: 

Enlarge Shrink 

71. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

Result 9:

72. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

73. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

74. Number of trials for this result:

Enlarge Shrink 

75. Total sample size for this result: 

Enlarge Shrink 

76. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

Result 9:

77. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

78. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

79. Number of trials for this result:

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Enlarge Shrink 

80. Total sample size for this result: 

Enlarge Shrink 

81. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

Result 9:

82. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

83. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

84. Number of trials for this result:

Enlarge Shrink 

85. Total sample size for this result: 

Enlarge Shrink 

86. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

87. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Result 10:

88. Group comparison: 

Calcium compared to inactive comparison group

Vitamin D compared to inactive comparison group

Calcium + vitamin D compared to inactive comparison group

89. Bone density site: 

Total body

L-spine (1-2 yrs) 

L-spine (3-4 yrs)

Combined hip 

1/3 distal radius

Other

90. Number of trials for this result:

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Enlarge Shrink 

91. Total sample size for this result: 

Enlarge Shrink 

92. Weighted mean difference (active group – inactive group): 

Weighted mean difference (including unit)

95% CI

P-value for the mean difference

93. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Aggregate Results on Fractures 

94. Fracture Site: 

Vertebral

Hip

Nonvertebral (other than hip; specified)

95. Number of trials included for this result: 

Enlarge Shrink 

96. Total sample size for this result: 

Enlarge Shrink 

97. Cancer outcome (type in the cancer site): 

colon cancer

colorectal cancer

polyps

other 

98. Aggregate efficacy (active vs. inactive groups): 

Relative Risk

Odds Ratio

Hazard Ratio

Point estimate

95% confidence interval 

Not Reported (only individual study-results were 

reported)

99. P-value for test of heterogeneity:

p>0.05

p<=0.05

not reported

100. Fracture Site: 

Vertebral

Hip

Nonvertebral (other than hip; specified)

101. Number of trials included for this result: 

Enlarge Shrink 

102. Total sample size for this result: 

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Enlarge Shrink 

103. Cancer outcome (type in the cancer site): 

colon cancer

colorectal cancer

polyps

other 

104. Aggregate efficacy (active vs. inactive groups): 

Relative Risk

Odds Ratio

Hazard Ratio

Point estimate

95% confidence interval 

Not Reported (only individual study-results were 

reported)

105. P-value for test of heterogeneity:

p>0.05

p<=0.05

not reported

106. Fracture Site: 

Vertebral

Hip

Nonvertebral (other than hip; specified)

107. Number of trials included for this result: 

Enlarge Shrink 

108. Total sample size for this result: 

Enlarge Shrink 

109. Cancer outcome (type in the cancer site): 

colon cancer

colorectal cancer

polyps

other 

110. Aggregate efficacy (active vs. inactive groups): 

Relative Risk

Odds Ratio

Hazard Ratio

Point estimate

95% confidence interval 

Not Reported (only individual study-results were 

reported)

111. P-value for test of heterogeneity:

p>0.05

p<=0.05

not reported

112. Fracture Site: 

Vertebral

Hip

Nonvertebral (other than hip; specified)

113. Number of trials included for this result: 

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Enlarge Shrink 

114. Total sample size for this result: 

Enlarge Shrink 

115. Cancer outcome (type in the cancer site): 

colon cancer

colorectal cancer

polyps

other 

116. Aggregate efficacy (active vs. inactive groups): 

Relative Risk

Odds Ratio

Hazard Ratio

Point estimate

95% confidence interval 

Not Reported (only individual study-results were 

reported)

117. P-value for test of heterogeneity:

p>0.05

p<=0.05

not reported

118. Fracture Site: 

Vertebral

Hip

Nonvertebral (other than hip; specified)

119. Number of trials included for this result: 

Enlarge Shrink 

120. Total sample size for this result: 

Enlarge Shrink 

121. Cancer outcome (type in the cancer site): 

colon cancer

colorectal cancer

polyps

other 

122. Aggregate efficacy (active vs. inactive groups): 

Relative Risk

Odds Ratio

Hazard Ratio

Point estimate

95% confidence interval 

Not Reported (only individual study-results were 

reported)

123. P-value for test of heterogeneity:

p>0.05

p<=0.05

not reported

124. Fracture Site: 

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Vertebral

Hip

Nonvertebral (other than hip; specified)

125. Number of trials included for this result: 

Enlarge Shrink 

126. Total sample size for this result: 

Enlarge Shrink 

127. Cancer outcome (type in the cancer site): 

colon cancer

colorectal cancer

polyps

other 

128. Aggregate efficacy (active vs. inactive groups): 

Relative Risk

Odds Ratio

Hazard Ratio

Point estimate

95% confidence interval 

Not Reported (only individual study-results were 

reported)

129. P-value for test of heterogeneity:

p>0.05

p<=0.05

not reported

130. Fracture Site: 

Vertebral

Hip

Nonvertebral (other than hip; specified)

131. Number of trials included for this result: 

Enlarge Shrink 

132. Total sample size for this result: 

Enlarge Shrink 

133. Cancer outcome (type in the cancer site): 

colon cancer

colorectal cancer

polyps

other 

134. Aggregate efficacy (active vs. inactive groups): 

Relative Risk

Odds Ratio

Hazard Ratio

Point estimate

95% confidence interval 

Not Reported (only individual study-results were 

reported)

135. P-value for test of heterogeneity:

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Form took 1.96875 seconds to render

p>0.05

p<=0.05

not reported

136. Fracture Site: 

Vertebral

Hip

Nonvertebral (other than hip; specified)

137. Number of trials included for this result: 

Enlarge Shrink 

138. Total sample size for this result: 

Enlarge Shrink 

139. Cancer outcome (type in the cancer site): 

colon cancer

colorectal cancer

polyps

other 

140. Aggregate efficacy (active vs. inactive groups): 

Relative Risk

Odds Ratio

Hazard Ratio

Point estimate

95% confidence interval 

Not Reported (only individual study-results were 

reported)

141. P-value for test of heterogeneity:

p>0.05

p<=0.05

not reported

Submit Data

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Previewing Only: You cannot submit data from this form

Previewing at Level 18 

Refid: 1, Cosman, F., Nieves, J., Zion, M., Woelfert, L., Luckey, M., and Lindsay, R., Daily and cyclic parathyroid hormone in women receiving alendronate, N Engl J Med, 353(6), 

2005, p.566-75 

State: Excluded, Level: 1

Submit Data

Summary Result Form 

(for systematic reviews other than calcium/vitamin D) 

 

 

Study aim of the systematic review (check all that apply): 1. To assess: 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

calcium/magnesium

beta-carotene

selenium

Comments

2. In the prevention of: 

Oncologic (specify)

Cardiovascular (specify)

Endocrine (specify)

Neurologic (specify)

Age-related sensory loss (specify)

Musculoskeletal (specify)

Gastroenterologic (specify)

Renal (specify)

Infectious (specify)

Pulmonary (specify)

Comments

3. Exclusion criteria used in this systematic review article:

Enlarge Shrink 

 

Search Strategies 

4. Source databases (check all that apply):

Cochrane Library

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MEDLINE

EMBASE

Cochrane Controlled Trial Register

Cancerlit

CABNAR

LILACS

CINAHL

BIOSIS

HealthSTAR

MANTIS

Allied & Complementary Medicine

CABHealth

TGG Health & Wellness

Unpublished Data

Hand search based on reference lists of relevant articles

Experts’ referral

Other (list all) 

Comments

5. Search terms used (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

calcium/magnesium

beta-carotene

selenium

cancer

cardiovascular disease

other (specify)

6. Publication dates of included articles: 

FROM (year):

TO (year):

Comments

7. Number of trials included in the review: 

Enlarge Shrink 

Total number of trial participants: 

8. In Placebo group: 

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Enlarge Shrink 

9. In vitamin/mineral group (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

calcium/magnesium

beta-carotene

selenium

Not applicable

Comments

10. Follow-up range of periods of the trials included in this systematic review:

From ____to_____(year): 

Not Reported

Comments

11. Range of proportion of participants who were lost-to-follow up:

From:

To:

Not Reported

Comments

12. Trial Participants Characteristics:

Range of mean age: (___to___)

Range of % women: _____% to _____%

Race (range of %)

White

African-American

Hispanic

Other (specify)

Comments

13. Health Status:

All trials included apparent healthy individuals

Some trials included diseased individuals

Comments

14. Chemical forms of folic acid used in included trials (check all that apply):

F1: Folic acid

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F2: unspecified

F3: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

15. Chemical forms of vitamin B6 used in included trials (check all that apply): 

B6_1: Pyridoxine hydrochloride 

B6_2: Pyridoxol 5' phosphate 

B6_3: Pyridoxine alpha-ketoglutarate 

B6_4: unspecified 

B6_5: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

16. Chemical forms of vitamin E used in included trials (check all that apply):

E_1: d-alpha-tocopherol 

E_2: d-alpha-tocopherol acetate

E_3: d-alpha-tocopherol succinate

E_4: dl-alpha-tocopherol 

E_5: dl-alpha-tocopherol acetate 

E_6: dl-alpha-tocopherol succinate

E_7: d-beta-tocopherol 

E-8: d-gamma-tocopherol 

E_9: d-delta-tocopherol

E_10: unspecified 

E_11: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

17. Chemical forms of vitamin C used in included trials [4] (check all that apply):

C_1: Ascorbic acid

C_2: L-Ascorbic acid

C_3: Sodium Ascorbate

C_4: Unspecified

C_5: Other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

18. Chemical forms of beta-carotene used in included trials (check all that apply):

A_1: Beta-carotene

A_2: Retinyl acetate

A_3: Retinyl palmitate

A_4: Retinol

A_5: Unspecified

A_6: Other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

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19. Chemical forms of iron used in included trials (check all that apply):

Fe_1: Ferrous fumarate

Fe_2: Ferrous sulfate

Fe_3: Ferrous citrate

Fe_4: Ferrous glycinate

Fe_5: Iron carbonyl

Fe_6: Ferrous gluconate

Fe_7: Unspecified

Fe_8: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

20. Chemical forms of zinc used in included trials (check all that apply):

Z_1: Zinc acetate

Z_2: Zinc gluconate

Z_3: Zinc oxide

Z_4: Zinc pyrithione

Z_5: Zinc sulfate

Z_6: Zinc citrate

Z_7: Zinc taurinate

Z_8: Zinc monomethionine

Z_9: Zinc picolinate

Z_10: unspecified

Z_11: Other (Specified)

Range of doses used in trials (including units):

Not Applicable

Comments

21. Chemical forms of magnesium used in included trials (check all that apply):

Mg_1: Magnesium carbonate

Mg_2: Magnesium chloride

Mg_3: Magnesium hydroxide

Mg_4: Magnesium oxide

Mg_5: Magnesium trisilicate

Mg_6: Magnesium chloride hexahydrate

Mg_7: Magnesium citrate

Mg_8: Magnesium taurinate

Mg_9: Magnesium aspartate

Mg_10: Magnesium lactate gluconate

Mg_11: Magnesium gluconate

Mg_12: Unspecified

Mg_13: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

22. Chemical forms of vitamin B1 used in included trials (check all that apply):

B1_1: Thiamine hydrochloride

B1_2: Thiamine carboxylase

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B1_3: Thiamine mononitrate

B1_4: unspecified

B1_5: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

23. Chemical forms of vitamin B2 used in included trials (check all that apply):

B2_1: Riboflavin

B2_2: Riboflavin 5' phosphate

B2_3: unspecified

B2_4: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

24. Chemical forms of niacin used in included trials (check all that apply):

N_1: Niacin

N_2: Niacinamide

N_3: unspecified 

N_4: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

25. Chemical forms of selenium used in included trials (check all that apply):

S_1: Selenium sulfide

S_2: L-selenomethionine

S_3: Sodium selenate

S_4: selenium yeast

S_5: Selenite

S_6: Unspecified

S_7: other (specified)

Range of doses used in trials (including units):

Not Applicable

Comments

 

Aggregate Efficacy Results 

Result 1

26. Type of outcome: 

CVD incidence

CVD mortality

Total mortality

Cataract incidence

Cancer incidence (specify site) 

Cancer mortality (specify site) 

Non-fatal myocardial infarction

fatal myocardial infarction

fatal and non-fatal myocardial infarction

Other (specify) 

Not reported

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Comments

27. In vitamin/mineral group (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

magnesium

beta-carotene

selenium

Comments

28. Aggregate efficacy (active vs. inactive groups): 

Relative Risk 

Odds Ratio 

Hazard Ratio 

Point estimate (active compared to inactive)

95% confidence interval 

Not reported (only individual study-results were reported)

Comments

29. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Comments

Result 2

30. Type of outcome: 

CVD incidence

CVD mortality

Total mortality

Cataract incidence

Cancer incidence (specify site) 

Cancer mortality (specify site) 

Non-fatal myocardial infarction

fatal myocardial infarction

fatal and non-fatal myocardial infarction

Other (specify) 

Not reported

Comments

31. In vitamin/mineral group (check all that apply): 

iron

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vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

magnesium

beta-carotene

selenium

Comments

32. Aggregate efficacy (active vs. inactive groups): 

Relative Risk 

Odds Ratio 

Hazard Ratio 

Point estimate (active compared to inactive)

95% confidence interval 

Not reported (only individual study-results were reported)

Comments

33. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Comments

Result 3

34. Type of outcome: 

CVD incidence

CVD mortality

Total mortality

Cataract incidence

Cancer incidence (specify site) 

Cancer mortality (specify site) 

Non-fatal myocardial infarction

fatal myocardial infarction

fatal and non-fatal myocardial infarction

Other (specify) 

Not reported

Comments

35. In vitamin/mineral group (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

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vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

magnesium

beta-carotene

selenium

Comments

36. Aggregate efficacy (active vs. inactive groups): 

Relative Risk 

Odds Ratio 

Hazard Ratio 

Point estimate (active compared to inactive)

95% confidence interval 

Not reported (only individual study-results were reported)

Comments

37. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Comments

Result 4

38. Type of outcome: 

CVD incidence

CVD mortality

Total mortality

Cataract incidence

Cancer incidence (specify site) 

Cancer mortality (specify site) 

Non-fatal myocardial infarction

fatal myocardial infarction

fatal and non-fatal myocardial infarction

Other (specify) 

Not reported

Comments

39. In vitamin/mineral group (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

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folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

magnesium

beta-carotene

selenium

Comments

40. Aggregate efficacy (active vs. inactive groups): 

Relative Risk 

Odds Ratio 

Hazard Ratio 

Point estimate (active compared to inactive)

95% confidence interval 

Not reported (only individual study-results were reported)

Comments

41. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Comments

Result 5

42. Type of outcome: 

CVD incidence

CVD mortality

Total mortality

Cataract incidence

Cancer incidence (specify site) 

Cancer mortality (specify site) 

Non-fatal myocardial infarction

fatal myocardial infarction

fatal and non-fatal myocardial infarction

Other (specify) 

Not reported

Comments

43. In vitamin/mineral group (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

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magnesium

vitamin B12

vitamin A

vitamin B1

magnesium

beta-carotene

selenium

Comments

44. Aggregate efficacy (active vs. inactive groups): 

Relative Risk 

Odds Ratio 

Hazard Ratio 

Point estimate (active compared to inactive)

95% confidence interval 

Not reported (only individual study-results were reported)

Comments

45. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Comments

Result 6

46. Type of outcome: 

CVD incidence

CVD mortality

Total mortality

Cataract incidence

Cancer incidence (specify site) 

Cancer mortality (specify site) 

Non-fatal myocardial infarction

fatal myocardial infarction

fatal and non-fatal myocardial infarction

Other (specify) 

Not reported

Comments

47. In vitamin/mineral group (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

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vitamin B1

magnesium

beta-carotene

selenium

Comments

48. Aggregate efficacy (active vs. inactive groups): 

Relative Risk 

Odds Ratio 

Hazard Ratio 

Point estimate (active compared to inactive)

95% confidence interval 

Not reported (only individual study-results were reported)

Comments

49. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Comments

Result 7

 

50. Type of outcome: 

CVD incidence

CVD mortality

Total mortality

Cataract incidence

Cancer incidence (specify site) 

Cancer mortality (specify site) 

Non-fatal myocardial infarction

fatal myocardial infarction

fatal and non-fatal myocardial infarction

Other (specify) 

Not reported

Comments

51. In vitamin/mineral group (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

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magnesium

beta-carotene

selenium

Comments

52. Aggregate efficacy (active vs. inactive groups): 

Relative Risk 

Odds Ratio 

Hazard Ratio 

Point estimate (active compared to inactive)

95% confidence interval 

Not reported (only individual study-results were reported)

Comments

53. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Comments

Result 8

54. Type of outcome: 

CVD incidence

CVD mortality

Total mortality

Cataract incidence

Cancer incidence (specify site) 

Cancer mortality (specify site) 

Non-fatal myocardial infarction

fatal myocardial infarction

fatal and non-fatal myocardial infarction

Other (specify) 

Not reported

Comments

55. In vitamin/mineral group (check all that apply): 

iron

vitamin B2

folic acid/B12

folic acid

vitamin E

zinc

niacin

folic acid/B6

vitamin B6

vitamin C

magnesium

vitamin B12

vitamin A

vitamin B1

magnesium

beta-carotene

selenium

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Comments

56. Aggregate efficacy (active vs. inactive groups): 

Relative Risk 

Odds Ratio 

Hazard Ratio 

Point estimate (active compared to inactive)

95% confidence interval 

Not reported (only individual study-results were reported)

Comments

57. P-value for test of heterogeneity:

p>0.05

p<=0.05 

not reported

Comments

Submit Data

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Appendix F: Evidence Tables 

F 1 

Evidence Table 1a. Characteristics of the studies on the efficacy of multivitamins in preventing chronic disease 

Study 

name Nutrient(s) 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study 

 Linxian 

General 

Population 

Trial 64,66

Not 40-69; history of stomach or esophageal cancer; debilitating disease; does not live in one of 4 communes in Linxian 

29584 

Wang, 

199468

Groups of placebo, AB, AC, AD, BC, BD, CD, ABCD where A: Retinol palmitate 10000 IU + Zinc oxide 45 mg, B: Riboflavin 5.2 mg + Niacin 40 mg, C: Ascorbic acid 180 mg + Molybdenum Yeast complex 30 μg, D: Beta-carotene 15 mg + Selenium yeast 50 μg + alpha-tocopherol 60 mg 

RCT; Factorial design 

1986-1991 

Not 40-69; history of cancer; did not live in one of two villages in Rencun commune; did not complete 1st (1987) and end-of-trial (2nd 1991) cytology exam. 

 391 (in 1991) 

5.25 years (total) 

 LinxiaprovinChina 
Appendix F: Evidence Tables 

F 2 

Evidence Table 1a. Characteristics of the studies on the efficacy of multivitamins in preventing chronic disease (continued) 

Study 

name Nutrient(s) 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study 

Linxian 

cataract 

Study 65

Groups of placebo, AB, AC, AD, BC, BD, CD, ABCD where A: Retinol palmitate 10000 IU + Zinc oxide 45 mg, B: Riboflavin 5.2 mg + Niacin 40 mg, C: Ascorbic acid 180 mg + Molybdenum Yeast complex 30 μg, D: Beta-carotene 15 mg + Selenium yeast 50 μg + alpha-tocopherol 60 mg 

RCT; Factorial design 

1985-1991 Not 40-69; cancer; did 

not live in Linxian province. 

5390 6 years (total) Linxia

provinChina 

1994-2002 69 Disease was expected to hinder participation or 

threaten 5-year survival; participant was taking any supplement offered in this study; participant had extreme beliefs or behavior regarding diet. 

12741 8 years (total), 

7.5 years (median). 

SU.VI.MAX Franc

69,70 Vitamin C+ vitamin E+ beta carotene+ 

selenium+ zinc. 

RCT; placebo controlled 

1994-1995 70 Not 45-60 years old; female; cancer; not free 

of "severe health problems"; any use study supplements. 

 5141 (males) 8.9 years 

(median) 

 Franc
Appendix F: Evidence Tables 

F 3 

Evidence Table 1a. Characteristics of the studies on the efficacy of multivitamins in preventing chronic disease (continued) 

Study 

name Nutrient(s) 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study 

REACT 72 Beta-carotene + 

vitamin C+ vitamin E. 

RCT; placebo controlled 

1990-1995 History of iritis or 

amblyopia; glaucoma or elevated intraocular pressure; ocular corticosteroid use or glaucoma therapy; participation in other anti-cataract trial within last year; regular use of antioxidants. 

297 3 years (total), 

2.8 years (mean). 

BostoUSA; and BradfUK. 

4596 75 ARED 73,75 Beta-carotene+ 

vitamin C+ vitamin E. 

RCT; placebo controlled 

1992-2001 History of cancer with a 

poor 7-year prognosis; major cardiovascular or cerebrovascular event within the last year; hemachromatosis; persons bilaterally aphakic or pseudophakic were ineligible for AMD Category 1. 

3509 73

9 years (total), 6.3 years (mean). 

USA (multicente
Appendix F: Evidence Tables 

F 4 

Evidence Table 1a. Characteristics of the studies on the efficacy of multivitamins in preventing chronic disease (continued) 

Study 

name Nutrient(s) 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study 

ARMD 74 Beta-carotene; 

vitamin E; vitamin C; citrus bioflavenoid complex; quercitin; rutin; zinc; selenium; taurine; N-acetyl cysteine; glutathione; vitamin B2; chromium. 

RCT; Placebo controlled 

NR Did not have a one-time 

decrease of visual acuity not attributable to cataract, amblyopia, systemic or ophthalmic disease; eye findings not consistent with loss of macular reflex; former prisoner of war; chronic alcoholic with tobacco/nutritional amblyopia or gastrointestinal absorption disorder. 

71 3 years (total) USA 

(multicente

MONMD 71 Beta-carotene; 

vitamin E; vitamin C; citrus bioflavenoid complex; quercitin; rutin; zinc; selenium; taurine; N-acetyl cysteine; glutathione; vitamin B2; chromium. 

RCT; Placebo controlled 

NR Did not have a one-time 

decrease of visual acuity not attributable to cataract, amblyopia, systemic or ophthalmic disease; eye findings not consistent with loss of macular reflex; former prisoner of war; chronic alcoholic with tobacco/nutritional amblyopia or gastrointestinal absorption disorder; prior use vitamins >1 year. 

84 3 years (total) USA 

(multicente

SU.VI.MAX. (SUppléments en VItamines et Minéraux AntioXydants); REACT (Roche European American Cataract Trial); AREDS (Age-Related Ey

(Age-Related Macular Degeneration). 
Appendix F: Evidence Tables 

F 5 

Evidence Table 1b. Characteristics of the intervention in the studies of the efficacy of multivitamins/minerals in the prevention 

Study name Intervention Chemical form Dose/Frequency of use Timing of use 

Placebo Vitamin A Retinol palmitate 10000 IU/NS Zinc Zinc oxide 45 mg/NS Vitamin B2 Riboflavin 5.2 mg/NS Niacin Niacin 40 mg/NS Vitamin C Ascorbic acid 180 mg/NS Molybdenum Yeast complex 30 μg/NS Beta-carotene NS 15 mg/NS Selenium Selenium yeast 50 μg/NS 

Linxiana General 

Population study 66

Vitamin E alpha-tocopherol 60 mg/NS 

 NS 

Placebo NS Vitamin A + zinc Retinol palmitate, zinc oxide 5000 IU/daily, 22.5 mg/daily Riboflavin + niacin Riboflavin , niacin 3.2 mg/1x/day, 40 mg/1x/day Vitamin C + molybdenum 

Ascorbic acid, molybdenum 120 mg/1x/day, 30 mcg/1x/day 

Linxian General 

Population Study 64

Vitamin E + selenium + beta-carotene 

d-alpha-tocopherol, selenium yeast, beta-carotene 

30 mg/1x/day, 50 mcg/1x/day, 15 mg/1x/day 

 NS 

Placebo 1 Vitamin A Retinol palmitate 5000 IU/daily Zinc Zinc oxide 22.5 mg/daily Vitamin B2 Riboflavin 3.2 mg/1x/day Niacin Niacin 40 mg/1x/day Vitamin C Ascorbic acid 120 mg/1x/day Other Chemical Molybendum 30 mcg/1x/day Vitamin E d-alpha-tocopherol 30 mg/1x/day Selenuim Selenium yeast 50 mcg/1x/day 

Linxian General 

Population 

Study68

Other Chemical beta-carotene 15 mg/1x/day 

NS 

Placebo NS Calcium Dibasic calcium phosphate 324 mg/NS Folic Acid Folic aci 800 mcg/NS Vitamin B6 Pyridoxine hydrochloride 6 mg/NS Vitamin B12 Cyanocobalamin 18 mcg/NS Vitamin D NS 800 IU/NS Vitamin E 2-ambo-alpha-tocopherol 60 IU/NS Vitamin C Ascorbic acid 180 mg/NS Vitamin A Acetate 10000 IU/NS Iron Ferrous fumarate 54 mg/NS 

Linxian Cataract 

Study 65

Zinc Zinc sulfate 45 mg/NS 

NS 
Appendix F: Evidence Tables 

F 6 

Evidence Table 1b. Characteristics of the intervention in the studies of the efficacy of multivitamins/minerals in the prevention 

(continued) 

Study name Intervention Chemical form Dose/Frequency of use Timing of use 

Magnesium Magnesium oxide 200 mg/NS Vitamin B1 Thiamine mononitrate 5 mg/NS Vitamin B2 Riboflavin 5.2 mg/NS Niacin Niacinamide 40 mg/NS Selenuim Sodium selenate 50 mcg/NS Beta-carotene beta-carotene 15 mg/1x/day Biotin Biotin 90 mcg/1x/day Calcium Pantothenic acid/calcium 

pantothenate 

20 mg/1x/day 

Phosphorus and calcium 

Phophorous/dibasic calcium phosphate 

250 mg/1x/day 

Iodine Iodine/potassium iodide 300 mg/1x/day Copper Cupric oxide 6 mg/1x/day Potassium Potassium chloride 15.4 mg/1x/day Chloride Potassium chloride 14 mg/1x/day Chromium Chromium chloride 30 mcg/1x/day Molybendum Sodium molybdate 30 mcg/1x/day 

Linxian Cataract 

Study (cont’d) 

Manganese Manganese sulfate 15 mg/1x/day 

Placebo NS Vitamin E NS 30 mg/1x/day Vitamin C Ascorbic acid 120 mg/1x/day Vitamin A beta-carotene 6 mg/1x/day Zinc Zinc gluconate 20 mg/1x/day 

SU.VI.MAX 69

Selenuim Selenium yeast 100 mcg/1x/day 

 NS 

Placebo NS Vitamin E a-tocopherol 30 mg/1x/day Vitamin C NS 120 mg/1x/day Vitamin A beta-carotene 6 mg/1x/day Zinc NS 20 mg/1x/day 

SU.VI.MAX 70

Selenuim Selenium yeast 100 mcg/1x/day 

NS 
Appendix F: Evidence Tables 

F 7 

Evidence Table 1b. Characteristics of the intervention in the studies of the efficacy of multivitamins/minerals in the prevention 

(continued) 

Study name Intervention Chemical form Dose/Frequency of use Timing of use 

Placebo Vitamin E all rac-alpha-tocopherol acetate 200 mg/3x/day Vitamin C Ascorbic acid 250 mg/3x/day 

REACT 72

Vitamin A beta-carotene 6 mg/3x/day 

 With meals 

Placebo NS NS Vitamin E dl-alpha-tocopherol acetate 200 IU/2x/day/ (2 tablets in the 

morning, 2 in the evening) 

Vitamin C Ascorbic acid 250 mg/2x/day (2 tablets in the 

morning, 2 in the evening) 

Vitamin A beta-carotene 7.5 mg/2x/day (2 tablets in the 

morning, 2 in the evening) 

Zinc Zinc oxide 40 mg/2x/day (2 tablets in the 

morning, 2 in the evening) 

Copper Cupric copper 2 mg/2x/day (2 tablets in the 

morning, 2 in the evening) 

ARED 75

Combination above supplements 

With meals 

Placebo NS NS Vitamin E dl-alpha-tocopherol acetate 200 IU/2x/day (2 tablets in the 

morning, 2 in the evening) 

Vitamin C Ascorbic acid 250 mg/2x/day (2 tablets in the 

morning, 2 in the evening) 

Vitamin A beta-carotene 7.5 mg/2x/day (2 tablets in the 

morning, 2 in the evening) 

ARED 73

Zinc Zinc oxide 40 mg/2x/day (2 tablets in the 

morning, 2 n the evening) 

With meals 

Placebo Starch NS Vitamin E NS 200 IU/1x/day Vitamin C NS 750 IU/1x/day Vitamin A beta-carotene 20000 IU/1x/day Zinc Zinc picolinate 12.5 mg/1x/day 

MONMD 74

Selenuim Unspecified 60 mcg/1x/day 

NS 

SU.VI.MAX. (SUppléments en VItamines et Minéraux AntioXydants); REACT (Roche European American Cataract Trial); AREDS (Age-Related Ey

(Age-Related Macular Degeneration); NS = Not specified; mg = milligram; mcg = microgram; IU = international unit
Appendix F: Evidence Tables 

F 8 

Evidence Table 1c. Characteristics of participants in studies of the efficacies of multivitamins 

Study name 

Mean age (SD), and/or range 

Women, n (%); Ethnicity, n (%) Smokers, n (%) 

Alcohol consumption, n (%) 

Mean BMI in kg/m2 

Linxian 

General 

Population 

Study 66

Median (female) 51; median (male): 53; range: 44-60. 

16271 (55); ethnicity NR 

Current (female): 3254 (20); current (male): 8929 (67) 

Current (female): (10); current (male): (40). 

Median BMI (female): 21median BMI 21.6. 

Linxian 

General 

Population 

Study 64

<50: 12425 (42%); 50-59: 10354 (35%); ≥60: 6804 (23%). 

16271 (55); ethnicity NR 

Never: 20709 (70); ever smoked for >6 months: 8875 (30). 

Never: 22780 (77); any use in past 12 months: 6804 (23). 

NR 

Wang,1994 53 196 (50); 

ethnicity NR 

Current: 141 (36.0). Current: 145 (37.0). NR 

Linxian 

Cataract 

Study 65

57.5 2872 (53.3); 

ethnicity NR 

Ever smoked for >6 months: 1748 (32.4). NR NR 

SU.VI.MAX 

69

Women: 46.6 (6.6); men: 51.3 (4.7). 

7713; ethnicity NR 

Never (women, placebo): (54.8); never (women, intervention): (54.6); never (men, placebo): (34.5); never (men, intervention): (33.7); former (women, placebo): (29.1); former (women, intervention) (28.9); former (men, placebo): (50.2); former (men, intervention): (50.9); current (women, placebo): (16.1); current (women, intervention): (16.5); current (men, placebo): (15.3); current (men, intervention): (15.4). 

NR Placebo (wo

22.9 (3.0); intervention (women): 22(0.5); placeb(men): 25.2 intervention 25.2 (3.0). 

SU.VI.MAX 

70 51.3 (4.6) 0 (0) ; ethnicity NR Current: 4818 (15.4) NR BMI≥27 (pla

25.23%; BM

(supplement25.21%. 

REACT 72 UK: 67.55 

(8.47); US: 64.2 (8.49). 

UK: 33 (47.1); US 52 (59.2); ethnicity NR 

Never (UK): 13 (18.8); never (US): 15 (17.1). NR NR 
Appendix F: Evidence Tables 

F 9 

Evidence Table 1c. Characteristics of participants in studies of the efficacies of multivitamins (continued) 

Study name 

Mean age (SD), and/or range 

Women, n (%); Ethnicity, n (%) Smokers, n (%) 

Alcohol consumption, n (%) 

Mean BMI in kg/m2 

ARED 75 Median: 56 2551 (56); 

Caucasian, 4412 (96); Latino 185 (4) 

Former: 2184 (48); current: 345 (7.5). NR NR 

ARED 73 Median: 69 2021 (56); 

Caucasian, 3483 (96); Latino 153 (3) 

Former: 1751 (49); current: 298 (8.0). NR NR 

MONMD 71 68.6-72.4 5 (6) NR 0.69-1.00 

ounce/day 

NR 

SU.VI.MAX. (SUppléments en VItamines et Minéraux AntioXydants); REACT (Roche European American Cataract Trial); AREDS (Age-Related Ey

(Age-Related Macular Degeneration); BMI = Body mass index; NR (not recorded); UK = United Kingdom; US = United States
Appendix F: Evidence Tables 

F 10 

Evidence Table 1d. Results of studies of the efficacy of multivitamins/minerals in preventing chronic disease 

Study name Disease endpoint Study supplement * 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pval

Cancer 

Retinol + zinc RR 1.00 (0.89-1.11) Riboflavin + niacin RR 0.95 (0.85-1.06) Vitamin C + molybdenum 

RR 1.06 (0.95-1.18) 

Total cancer incidence 

Beta-carotene +selenium+ alpha-tocopherol 

Total 1298 

RR 0.93 (0.83-1.03) 

Retinol + zinc RR 0.96 (0.81-1.14) Riboflavin + niacin RR 1.04 (0.88-1.23) Vitamin C + molybdenum 

RR 1.10 (0.92-1.30) 

Gastric cancer incidence 

Beta-carotene +selenium+ alpha-tocopherol 

 Total 539 

RR 0.84 (0.71-1.00) 

Retinol + zinc RR 1.07 (0.92-1.25) Riboflavin + niacin RR 0.86 (0.74-1.01) Vitamin C + molybdenum 

RR 1.06 (0.91-1.24) 

Esophageal cancer incidence 

Beta-carotene +selenium+ alphatocopherol 

Total 640 

RR 1.02 (0.87-1.19) 

Retinol + zinc RR 1.05 (0.93-1.19) Riboflavin + niacin RR 0.94 (0.83-1.06) Vitamin C + molybdenum 

RR 1.06 (0.94-1.20) 

Esophageal/cardia incidence 

Beta-carotene +selenium+ alphatocopherol 

Total 1075 

RR 0.94 (0.84-1.06) 

Retinol + zinc RR 0.97 (0.85-1.12) Riboflavin + niacin RR 0.98 (0.85-1.13) 

Linxian General Population Study 64

Total cancer death 

Vitamin C + molybdenum 

Total 29,584 

Total 792 

RR 1.06 (0.92-1.21) 
Appendix F: Evidence Tables 

F 11 

Evidence Table 1d. Results of studies of the efficacy of multivitamins/minerals in preventing chronic disease (continued) 

Study name Disease endpoint Study supplement * 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pval

Cancer (continued) 

Total cancer death Beta-carotene 

+selenium+ alphatocopherol 

Total 792 RR 0.87 (0.75-1.00) 

Retinol + zinc RR 1.03 (0.83-1.28) Riboflavin + niacin RR 1.00 (0.81-1.24) Vitamin C + molybdenum 

RR 1.09 (0.88-1.36) 

Stomach cancer death 

Betacarotene+selenium+ alpha-tocopherol 

Total 331 

RR 0.79 (0.64-0.99) 

Retinol + zinc RR 0.93 (0.76-1.15) Riboflavin + niacin RR 0.90 (0.73-1.11) Vitamin C + molybdenum 

RR 1.05 (0.85-1.29) 

Esophageal cancer death 

Betacarotene+selenium+ alpha-tocopherol 

Total 360 

RR 0.96 (0.78-1.18) 

Retinol + zinc RR 1.04 (0.89-1.22) Riboflavin + niacin RR 0.95 (0.81-1.11) Vitamin C + molybdenum 

RR 1.06 (0.90-1.24) 

Linxian General Population Study 64

Esophageal/gastric cardia death 

Betacarotene+selenium+ alpha-tocopherol 

Total 613 

RR 0.90 (0.77-1.05) 
Appendix F: Evidence Tables 

F 12 

Evidence Table 1d. Results of studies of the efficacy of multivitamins/minerals in preventing chronic disease (continued) 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pval

Cancer (continued) 

Retinol + zinc 197/194 28/32 OR 0.83 (0.47-1.46) Riboflavin + niacin 194/197 34/26 OR 1.39 (0.79-2.44) Ascorbic acid + molybdenum 

206/185 37/23 OR 1.61 (0.91-2.86) 

Esophageal and gastric cancer and dyaplasia 

Beta-carotene + selenium + alphatocopherol 

177/214 25/35 OR 0.83 (0.47-1.46) 

Retinol + zinc 197/194 13/18 OR 0.61 (0.29-1.31) Riboflavin + niacin 194/197 18/13 OR 1.46 (0.68-3.11) Ascorbic acid + molybdenum 

206/185 21/10 OR 1.99 (0.90-4.41) 

Linxian General Population Study68

Esophageal and gastric cancer 

Beta-carotene + selenium + alphatocopherol 

177/214 12/19 OR 0.79 (0.36-1.69) 

2522/2512 49/54 0.88 (0.60-1.29) 0.72293/2270 18/33 0.52 (0.29-0.92) 0.0

SU.VI.MAX 70

Prostate cancer Vitamin C + vitamin E 

+ beta-carotene + selenium + zinc 

149/143 31/19 1.54 (0.87-2.72) 0.4

6364/6377 267/295 RR 0.90 (0.76-1.06) 0.13844/3869 women only 

179/171 RR 1.04 (0.85-1.29) 0.5

SU.VI.MAX 69

Cancer Vitamin C + vitamin E 

+ beta-carotene + selenium + zinc 

2520/2508 men only 

88/124 RR 0.69 (0.53-0.91) 0.0
Appendix F: Evidence Tables 

F 13 

Evidence Table 1d. Results of studies of the efficacy of multivitamins/minerals in preventing chronic disease (continued) 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pval

Cardiovascular Disease 

Retinol + zinc + riboflavin + niacin 

66/77 3.5/4.1 per 

1000 

RR 0.85 (0.61-1.18) 

Retinol + zinc + vitamin C + molybdenum 

71/77 3.8/4.1 per 

1000 

RR 0.91 (0.66-1.27) 

Retinol + zinc + betacarotene +selenium+ alpha-tocopherol 

55/77 2.9/4.1 per 

1000 

RR 0.71 (0.50-1.00) 

Riboflavin + niacin + vitamin C + molybdenum 

60/77 3.2/4.1 per 

1000 

RR 0.78 (0.55-1.09) 

Riboflavin + niacin + beta-carotene + selenium + alphatocopherol 

58/77 3.1/4.1 per 

1000 

RR 0.75 (0.53-1.05) 

Vitamin C + molybdenum + betacarotene + selenium+ alpha-tocopherol 

67/77 3.6/4.1 per 

1000 

RR 0.86 (0.62-1.20) 

retinol + zinc + riboflavin + niacin + vitamin C + molybdenum + betacarotene + selenium + alpha-tocopherol 

69/77 3.7/4.1 per 

1000 

RR 0.88 (0.64-1.22) 

Retinol + zinc RR 0.99 (0.84-1.18) Riboflavin + niacin RR 0.94 (0.79-1.11) Vitamin C + molybdenum 

 RR 1.04 (0.88-1.24) 

Linxian General Population Study 66

Stroke deaths 

Beta-carotene + selenium + alphatocopherol vs. placebo 

Total 29,584 

 RR 0.91 (0.76-1.07) 
Appendix F: Evidence Tables 

F 14 

Evidence Table 1d. Results of studies of the efficacy of multivitamins/minerals in preventing chronic disease (continued) 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pvalu

Cardiovascular Disease (continued) SU.VI.MAX 69

Ischemic cardiovascular disease 

Vitamin C + vitamin E + beta-carotene + selenium + zinc 

6364/6377 134/137 RR 0.97 (0.77-1.20) 0.8 

Eye Disease 

Retinol + zinc 1628/ 

1621 

0.120/ 0.151 

OR 0.77 (0.58-1.02) 

Riboflavin + niacin 1623/ 

1626 

0.107/ 0.169 

OR 0.59 (0.45-0.79) 

Vitamin C + molybdenum 

1654/ 1595 

0.121/ 0.150 

OR 0.78 (0.59-1.04) 

Prevalence of nuclear cataracts 

Beta-carotene + selenium + alpha-tocopherol 

1617/ 1632 

0.146/ 0.125 

OR 1.19 (0.90-1.59) 

Retinol + zinc 1628/ 

1621 

0.342/ 0.325 

OR 1.08 (0.92-1.27) 

Riboflavin + niacin 1623/ 

1626 

0.342/ 0.325 

OR 1.08 (0.92-1.27) 

Vitamin C + molybdenum 

1654/ 1595 

0.325/ 0.342 

OR 0.92 (0.79-1.09) 

Prevalence of cortical cataracts 

Beta-carotene + selenium + alpha-tocopherol 

1617/ 1632 

0.330/ 0.338 

OR 0.96 (0.82-1.13) 

Retinol + zinc 1628/ 

1621 

0.008/ 0.013 

OR 0.59 (0.31-1.14) 

Riboflavin + niacin 1623/ 

1626 

0.016/ 0.006 

OR 2.64 (1.31-5.35) 

Vitamin C + molybdenum 

1654/ 1595 

0.011/ 0.009 

OR 1.25 (0.65-2.38) 

Linxian Cataract Study 65

Prevalence of posterior subcapsular cataracts 

Beta-carotene + selenium + alpha-tocopherol 

1617/1632 0.013/ 

0.008 

OR 1.56 (0.81-3.00) 
Appendix F: Evidence Tables 

F 15 

Evidence Table 1d. Results of studies of the efficacy of multivitamins/minerals in preventing chronic disease (continued) 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pval

Eye Disease (continued) REACT 72 Anterior % pixel 

opaque†

Beta-carotene + vitamin C + vitamin E 

81/77 Not 

applicable 

Mean ± 95% CI Placebo: baseline 5.0 ± 1.4, last 8.3 ± 2.2, mean change from baseline: 3.3 ± 1.4; supplement: baseline 5.7± 1.6, last 7.3± 2.0 

mean change from baseline: 1.7± 1.0; 

Difference from placebo: -1.6 

.05 

Total lens event Vitamin C + vitamin E + 

beta-carotene 

2286/2310 756/785 

(in 5 years) 

OR 0.97 (0.84-1.11) 0.5

Cataract surgery Vitamin C + vitamin E + 

beta-carotene 

2286/2310 675 in 

total 

OR 0.94 (0.77-1.14) 0.4

Severe lens event Vitamin C + vitamin E + 

beta-carotene 

2286/2310 991 in 

total 

OR 0.92 (0.76-1.12) 0.2

Vitamin C + vitamin E + beta-carotene 

4331 1674 

in total 

Nuclear event OR 0.98 (0.84-1.14) 0.7

Antioxidants only (vitamin C + vitamin E+ betacarotene) 

2715 1027 

in total 

OR 1.00 (0.82-1.22) 0.9

Vitamin C + vitamin E + beta-carotene 

4329 1058 

in total 

Cortical event OR 0.99 (0.82-1.19) 0.84 

Antioxidants only (vitamin C + vitamin E+ betacarotene) 

2715 625 

in total 

OR 0.91 (0.71-1.15) 0.2

Vitamin C + vitamin E + beta-carotene 

4329 888 

in total 

OR 0.94 (0.78-1.14) 0.3

AREDS 73

cataract 

Posterior subcapsular event 

Antioxidants only (vitamin C + vitamin E+ betacarotene) 

2715 535 

in total 

OR 0.91 (0.70-1.17) 0.3
Appendix F: Evidence Tables 

F 16 

Evidence Table 1d. Results of studies of the efficacy of multivitamins/minerals in preventing chronic disease 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pval

Eye Disease (continued) 

Lens event in eyes without opacities 

Vitamin C + vitamin E + beta-carotene 

823 NR OR 0.85 (0.55-1.33) NR 

AREDS 73

cataract (continued) 

Loss of visual acuity score of 15 letters or more 

Antioxidants only (vitamin C + vitamin E+ betacarotene) 

537/580 Total 172 OR 1.03 (0.63-1.66) 0.8

Antioxidants vs. no antioxidants 

OR 0.87(0.70-1.09) 0.1

Zinc vs. no zinc OR 0.82 (0.66-1.03) 0.0Antioxidants OR 0.80 (0.59-1.09) 0.0Zinc OR 0.75 (0.55-1.03) 0.0

Progression to advanced AMD (among participants in AMD categories 2,3,4) 

Antioxidants + zinc 

Total 3609 Total 803 

OR 0.72 (0.52-0.98) 0.0

Antioxidants vs. no antioxidants 

OR 0.90 (0.74-1.09) 0.14 

Zinc vs. no zinc OR 0.88 (0.73-1.07) 0.0Antioxidants OR 0.88 (0.67-1.15) 0.2Zinc OR 0.87 (0.66-1.13) 0.1

Loss of visual acuity score of >=15 letters from baseline (among participants in AMD categories 2,3,4) Antioxidants + zinc 

Total 3597 Total 1197 

OR 0.79 (0.60-1.04) 0.0

Antioxidants vs. no antioxidants 

OR 0.83 (0.66-1.06) 0.0

Zinc vs. no zinc OR 0.79 (0.69-0.99) 0.0Antioxidants OR 0.76 (0.55-1.05) 0.0Zinc OR 0.71 (0.52-0.99) 0.0

AREDS 75

age-related macular degeneration 

Progression to advanced AMD (among participants in AMD categories 3,4) 

Antioxidants + zinc 

Total 2556 Total 775 

OR 0.66 (0.47-0.91) 0.0
Appendix F: Evidence Tables 

F 17 

Evidence Table 1d. Results of studies of the efficacy of multivitamins/minerals in preventing chronic disease (continued) 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pval

Eye Disease (continued) 

Antioxidants vs. no antioxidants 

OR 0.86 (0.70-1.07) 0.0

Zinc vs. no zinc OR 0.84 (0.68-1.04) 0.0Antioxidants OR 0.85 (0.63-1.14) 0.1Zinc OR 0.83 (0.62-1.11) 0.1

AREDS 75

age-related macular degeneration (continued) 

Loss of visual acuity score of >=15 letters from baseline (among participants in AMD categories 3,4) Antioxidants + zinc 

Total 2549 Total 1022 

OR 0.73 (0.54-0.99) 0.0

MONMD 74 Macular 

degeneration 

Beta-carotene + vitamin E+vitamin C+ citrus bioflavenoid complex+ quercitin+ rutin+ zinc+ selenium+ taurine+ Nacetyl cysteine+ glutathione+ vitamin B2+ chromium 

39/32 Not 

applicable 

 

* comparisons were made between groups receiving the combination of the listed nutrients and the groups receiving combinations of placebo/nutrient

listed, unless otherwise specified. 

† primary endpoint ‡ secondary endpoint 

SU.VI.MAX. (SUppléments en VItamines et Minéraux AntioXydants); MONMD = Multicenter ophthalmic and nutritional age-related macular degen

(Roche European American Cataract Trial); AREDS (Age-Related Eye Disease Study); OR = odds ratio; RR = relative risk; 95% CI = 95 confidencspecific antigen; py = person-years; AMD = age-related macular degeneration.
Appendix F: Evidence Tables 

F 18 

Evidence Table 1e. Total mortality in studies multivitamins/minerals used to prevent chronic disease 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) P-v

Retinol + zinc + riboflavin + niacin 

265/280 14.1/15.0 

per 1000 py 

RR 0.94 (0.79-1.11) 

Retinol + zinc + vitamin C + molybdenum 

296/280 15.8/15.0 

per 1000 py 

RR 1.05 (0.89-1.24) 

Retinol + zinc + betacarotene +selenium+ alpha-tocopherol 

250/280 13.3/15.0 

per 1000 py 

RR 0.89 (0.75-1.05) 

Riboflavin + niacin + vitamin C + molybdenum 

268/280 14.3/15.0 

per 1000 py 

RR 0.95 (0.81-1.13) 

Riboflavin + niacin + beta-carotene +selenium+ alphatocopherol 

263/280 14.0/15.0 

per 1000 py 

RR 0.93 (0.79-1.11) 

Vitamin C + molybdenum + betacarotene + selenium+ alpha-tocopherol 

249/280 13.2/15.0 

per 1000 py 

RR 0.88 (0.74-1.05) 

Retinol + zinc + riboflavin + niacin + vitamin C + molybdenum + betacarotene + selenium + alpha-tocopherol 

256/280 13.6/15.0 

per 1000 py 

RR 0.91 (0.76-1.07) 

Retinol + zinc RR 1.00 (0.92-1.09) Riboflavin + niacin RR 0.98 (0.90-1.06) Vitamin C + molybdenum 

RR 1.01 (0.92-1.10) 

Linxian General Population Study 66

Total mortality 

Beta-carotene +selenium+ alpha-tocopherol 

29,584 (total) 

NR NR 

RR 0.91 (0.84-0.99) 

NR 
Appendix F: Evidence Tables 

F 19 

Evidence Table 1e. Total mortality in studies multivitamins/minerals used to prevent chronic disease (continued) 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) P-v

Retinol + zinc 1.03 Riboflavin + niacin 0.96 Vitamin C + molybdenum 

0.93 

Total mortality In men 

Beta-carotene +selenium+ alpha-tocopherol 

0.93 

Retinol + zinc 0.97 Riboflavin + niacin 0.99 Vitamin C + molybdenum 

1.12 

Total mortality In women 

Beta-carotene +selenium+ alpha-tocopherol 

0.89 

Retinol + zinc 0.96 Riboflavin + niacin 1.02 Vitamin C + molybdenum 

0.90 

NR 

Total mortality In those aged <55 years 

Beta-carotene +selenium+ alpha-tocopherol 

0.87 <.0

Retinol + zinc 1.02 Riboflavin + niacin 0.96 Vitamin C + molybdenum 

1.05 

Linxian General Population Study 71

Total mortality In those aged ≥55 years 

Beta-carotene +selenium+ alpha-tocopherol 

NR NR NR 

0.93 

NR 

SU.VI.MAX 69 Total mortality Vitamin C + vitamin E + beta-carotene + zinc 

+selenium vs. placebo 

6364/6377 76/98 NR RR 0.77 (0.57-1.00) .09 
Appendix F: Evidence Tables 

F 20 

Evidence Table 1e. Total mortality in studies multivitamins/minerals used to prevent chronic disease. 

Study name Disease endpoint Study supplement* 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence or prevalence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) P-v

Vitamin C + vitamin E + beta-carotene 

AREDS 2370/2387 251/240 RR 1.06 (0.84-1.33) .53 73

cataract study vitamin C + vitamin E+ 

beta-carotene only vs. placebo 

2965 313 RR 1.05 (0.78-1.40) .68 

Vitamin C + vitamin E + beta-carotene 

1833/1807 216/194 RR 1.10 (0.85-1.42) .35 

Zinc vs. no zinc 1792/1848 178/232 RR 0.79 (0.61-1.02) .02 Vitamin C + vitamin E + beta-carotene vs. placebo 

945/903 125/107 RR 1.12 (0.80-1.57) .39 

Zinc vs. placebo 904/903 87/107 RR 0.81 (0.56-1.17) .14 

AREDS 75

age-related macular degeneration 

Vitamin C + vitamin E + beta-carotene + zinc vs. placebo 

888/903 91/107 RR 0.87 (0.60-1.25) .32 

REACT 72

Total mortality 

Beta-carotene + vitamin C + vitamin E vs. placebo 

81/77 9/3 NR NR 

* comparisons were made between groups receiving the combination of the listed nutrients and the groups receiving combinations of placebo/nutrient

listed, unless otherwise specified. CI = confidence interval; SU.VI.MAX. = SUppléments en VItamines et Minéraux AntioXydants; RR = relative risk; AREDS = Age-Related Eye Dise

European American Cataract Trial; NR = not reported.
Appendix F: Evidence Tables 

F 21 

Evidence Table 2a. Characteristics of the interventions in studies of the safety of multivitamin supplements Author, year 

Study design 

Control arm (duration of use) INTERVENTION ARMS 

Nutrient/supplement Chemical form(s) Dose/frequency of use 

Tu

Chylack, 

200272

RCT Placebo-corn 

oil (3 years) 

Multivitamin (beta-carotene, vitamin C, vitamin E) 

All-rac alpha-tocopherol acetate; ascorbic acid; beta-carotene 

200 mg; 250 mg; 6 mg 3

(w

Multivitamin (vitamin E, vitamin C, vitamin A, zinc, copper) 

Dl-alpha-tocopherol acetate; ascorbic acid; beta-carotene; zinc oxide; cuprix oxide 

200 IU; 250 mg; 7.5 mg; 40 mg; 1 mg 

Multivitamin (vitamin E, vitamin C, vitamin A) 

Dl-alpha-tocopherol acetate; ascorbic acid; beta-carotene 

200 IU; 250 mg; 7.5 mg 

ARED, 

2001a, b73, 

75

RCT Placebo (6.3 

years) 

Zinc, copper Zinc oxide; cupric oxide 40 mg; 1 mg 

2 min ew

Richer, 1996 

74

RCT Placebo 

(starch), (18 months) 

 Multivitamin (Vitamin E, Vitamin C, Vitamin A, Zinc, Vitamin B2, Selenuim, citrus bioflavonoid complex; quercitin (bioflavonoid); biberry extract (bioflavonoid); rutin (bioflavonoid); taurine; n-acetyl cysteine; l-glutathione; chromium) 

 NS; NS; betacarotene; Zinc picolinate; NS; NS; NS; NS; NS; NS; NS;taurine; n-acetyl cysteine; l-glutathione 

 200 IU; 750 IU; 20000 IU; 12.5 mg; 25 mg; 60 mcg; 125 mg; 50 mg; 5 mg; 50 mg; 100 mg; 100 mg; 100mg; 5 mg 

 2

Xuan, 1991 78RCT Vitamin A; beta-carotene; 

vitamin E; selenium 

Retinol; beta-carotene; d-alphatocopherol; selenium yeast 25,000 IU, 30 mg; 50 mg; 800 IU; 400 mcg 1

Ohtake 79 Case 

report 

 Multivitamin (Calcium, Vitamin 

D, Vitamin C), laxatives and aspirin 

Calcium lactate; NS; ascorbic acid 

1000 mg; 250 IU; 6000 mg 1

Grouhi, 2000 

80

Case report 

 Multivitamin (Calcium, Vitamin 

E, Vitamin C, niacin, selenium), echinacia; barley green; licorice root; Chinese herbs; B complex 

NS; NS; NS; niacin; NS 100 mg; 800 IU; 300 mg; 240 

mg (niacin comes from multivitamin (40mg), B-complex (40mg) and anti-nausea drug(150mg)); 200 mcg 

N

Gulati, 1999 

81

Case report 

 Multivitamin/minerals (Vitamin E 

Vitamin C Vitamin A Zinc Vitamin B2 Selenuim + copper) 

Vitamin E acetate; NS; vitamin A acetate; NS; NS; selenium dioxide monohydrate; copper sulfate 

NS 1
Appendix F: Evidence Tables 

F 22 

Evidence Table 2b. Results of studies with information on clinical adverse effects of multivitamin supplements in the preventioAuthor, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type 

Statistsignifi(p-valu

Intercurrent illness 107 84 NS Deaths/serious events 9 deaths (2 from coronary 

thrombosis, lead from renal cell cancer, throat cancer, carcinomatosis, esophagitis, sudden death, aneurysm, pulmonary fibrosis) 

3 deaths (coronary thrombosis, bile duct cancer, lung cancer) 

0.07 fodeaths 

Chylack, 

200272

Vitamins A, C, E 

Skin yellowing 6 NR 

NR 

Hospitalizations (due to mild to moderate symptoms) 

173 (7.3%) 221(9.3%) 0.01 

Primary adverse effect (caused by skin, subcutaneous tissue problems) 

56 (2.4%) 21(.9%) <0.001 

Change in skin color 203 (8.6%) 146 (6.1%) <0.001 Chest pain 467 (19.8%) 541 (22.8%) 

NR 

0.01 

ARED, 2001a 

73

Antioxidants 

Mortality 251 240 1.06 (0.84-

1.33) 

0.53 
Appendix F: Evidence Tables 

F 23 

Evidence Table 2b. Results of studies with information on clinical adverse effects of multivitamin supplements in the preventio(continued) Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type 

Statistsignifi(p-valu

Yellow skin 151 (8.3%) in antioxidant 

arm 

106 (6.0%) in non antioxidant arms 

NR 0.008 

Hospitalizations due to infections 

29 (1.6%) in antioxidant arms 

15 (0.8%) in non antioxidant arns 

NR 0.04 

Mortality NR NR 1.10 (0.85-

1.42) 

0.35 

Antioxidants 

Skin and subcutaneous tissue conditions 

41 (2.2%) 18 (1.0)% NR 0.003 

Anemia 236 (13.2%) in zinc arms 187 (10.2%) in non zinc 

arms 

0.004 

Genitourinary hospitalizations (eg, unspecified urinary tract infection, prostatic hyperplasia in men, stress incontinence in women) 

134 (7.5%) in zinc arms 90 (4.9%) in non zinc 

arms 

0.001 

Hospitalizations for mild/moderate symptoms (e.g. chest pain, fever) 

173 (9.7%) in zinc arms 143 (7.8%) in non zinc 

arms 

0.04 

ARED, 

2001b75

Zinc 

Circulatory adverse experience 

16 (0.9%) 5 (0.3%) 

NR 
Appendix F: Evidence Tables 

F 24 

Evidence Table 2b. Results of studies with information on clinical adverse effects of multivitamin supplements in the preventio(continued) Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type 

Statistsignifi(p-valu

Diffuse whole body maculopapular rash 

1 0.06 fo

interatbetweetime acaPsuwithin Patien

Transient diarrhea 

Richer, 

199674

Beta-carotene; vitamin E; vitamin C; bioflavonoid; zinc picolinate; selenium; taurine; nacetyl cysteine; lglutathione; vitamin B2; chromium 

Diarrhea, constipation, nausea/vomiting, dyspeptic symptoms 

NR 

NR NR 
Appendix F: Evidence Tables 

F 25 

Evidence Table 2b. Results of studies with information on clinical adverse effects of multivitamin supplements in the preventio(continued) Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type 

Statistsignifi(p-valu

See comments See comments See comments 

Xuan, 1991 78 Vitamin E, 

selenium 

Stroke 1 (vitamin E + selenium) 1 (placebo) 

NR 

Ohtake, 2005 

79

Ascorbic acid; calcium lactate; vitamin D, laxatives; laxatives 

Severe proximal tubular dysfunction, calcified lesion, hypokalemic nephropathy 

1 0 NR 

Grouhi, 2000 

80 Niacin Pseudoallergic toxic reaction 1 NA NA 
Appendix F: Evidence Tables 

F 26 

Evidence Table 2b. Results of studies with information on clinical adverse effects of multivitamin supplements in the preventio(continued) Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type 

Statistsignifi(p-valu

Gulati, 1999 

81

Vitamin A acetate; vitamin E acetate; vitamin C; vitamin B2; copper sulfate; zinc sulfate; selenium dioxide monohydrate 

Fixed drug eruption 1 0 NA 

NR = Not reported; NS = Not significant; NA = Not applicable 
Appendix F: Evidence Tables 

F 27 

Evidence Table 2c. Results of Studies with information on lipid profiles associated with the use of multivitamin supplements Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Change in active group (indicate mean (95% CI)), mean (SD), mean (SE), median or other measurements 

Change in inactive group (indicate mean (95% CI)), mean (SD), mean (SE), median or other measurements 

Vitamin E Mean (SD) pre/post: 

Cholesterol 4.97 (1.09)/4.73 (0.87); LDL 3.44 (0.88)/3.06 (0.96l); HDL 1.44 (0.42)/1.23 (0.37); TG 0.84 (0.15)/0.92 (0.28) 

Mean (SD) pre/post: Cholesterol 4.68 (0.84)/4.60 (0.80); LDL 2.40 (0.53)/2.84 (0.79) HDL 1.01 (0.3)/1.22 (0.48) TG 1.44 (0.99)/1.18 (0.55) 

Vitamin C Mean (SD) pre/post: 

Cholesterol 5.23 (0.97)/5.30 (1.00); LDL 2.82 (0.65)/3.17(0.72); HDL 1.58 (0.41)/1.50 (0.79); TG 1.31 (1.00)/1.33 (0.79) 

Mean (SD) pre/post: Cholesterol 4.68 (0.84)/4.60 (0.80); LDL: 2.40 (0.53)/2.84 (0.79); HDL: 1.01 (0.3)/1.22 (0.48); TG: 1.44 (0.99)/1.18 (0.55) 

BetaCarotene Mean (SD) pre/post: Cholestrol 4.83 (0.65)/4.87 

(0.55); LDL 2.88 (0.24)/3.14 (0.52); HDL 1.28 (0.21)/1.12 (0.22); TG 1.01 (0.41)/1.29 (0.96) 

Mean (SD) pre/post: Cholesterol 4.68(0.84)/4.60 (0.80); LDL 2.40 (0.53)/2.84 (0.79); HDL 1.01 (0.30)/1.22 (0.48); TG 1.44 (0.99)/1.18 (0.55) 

Sacco, 2003 

181

Combined 

Lipid profiles: Cholesterol (mM), LDL (mM), HDL (mM), triglycerides (mM) 

NA NA 

Mean (SD) pre/post: Cholestrol 5.04 (1.32)/4.98 (1.27); LDL 2.97 (1.75)/3.19 (0.34); HDL 1.39 (0.34)/1.30 (0.37); TG 1.06 (0.75)/1.08 (0.89) 

Mean (SD) pre/post: Cholesterol 4.68 (0.84)/4.60 (0.80); LDL 2.40 (0.53)/2.84 (0.79); HDL 1.01 (0.30)/1.22 (0.48); TG 1.44 (0.99)/1.18 (0.55) 

 NA = Not applicable; NR = Not Reported; LDL = low-density lipoprotein; HDL = high-density lipoprotein; SD = Standard Deviation; SE = Standard 
Appendix F: Evidence Tables 

F 28 

Evidence Table 2d. Assessment of the likelihood that reported adverse effect were caused by use of a multivitamin/mineral sup

Author, year Nutrient Adverse effect 

Temporal relationship 

Doseresponse relationship 

Adverse effects disappeared after discontinuation of supplementation 

Evidence of supplement use 

Intercurrent illness Deaths/serious events 

Chylack, 

200272

Vitamins A, C, E 

Skin yellowing 

Yes NR NR Yes 

Hospitalizations (due to mild to moderate symptoms) Primary adverse effect (caused by skin, subcutaneous tissue problems) Change in skin color 

ARED, 

2001a73

Antioxidants 

Chest pain 

Yes NR NR Yes 

Yellow skin Hospitalizations due to infections 

Antioxidants 

Skin and subcutaneous tissue conditions 

Yes NR NR Yes 

Anemia Genitourinary hospitalizations Hospitalizations for mild/moderate symptoms (e.g. chest pain, fever) 

 ARED, 

2001b 75

Zinc 

Circulatory adverse experience 

Yes NR NR Yes 

Diffuse whole body maculopapular rash 

Yes NR NR Yes 

Transient diarrhea Yes NR NR Yes Cholesterol No NR NR Yes 

Richer, 

1996 74

Beta-carotene; vitamin E; vitamin C; bioflavonoid; zinc picolinate; selenium; taurine; n-acetyl cysteine; lglutathione; vitamin B2;chromium 

Diarrhea, constipation, nausea/vomiting, dyspeptic symptom 

Yes NR NR Yes 
Appendix F: Evidence Tables 

F 29 

Evidence Table 2d. Assessment of the likelihood that reported adverse effect were caused by use of a multivitamin/mineral sup

Author, year Nutrient Adverse effect 

Temporal relationship 

Doseresponse relationship 

Adverse effects disappeared after discontinuation of supplementation 

Evidence of supplement use 

Xuan, 

1991 78

Vitamin E, selenium Stroke Yes NR NR Yes 

Ohtake, 

2005 79

Ascorbic acid; calcium lactate; vitamin D, laxatives; laxatives 

Severe proximal tubular dysfunction, calcified lesion, hypokalemic nephropathy 

NR No Yes NR 

Grouhi, 

2000 80 Niacin Pseudoallergic toxic reaction NR Yes NR Yes 

Gulati, 

1999 81

Vitamin A acetate; vitamin E acetate; vitamin C; vitamin B2; copper sulfate; zinc sulfate; selenium dioxide monohydrate 

Fixed drug eruption NR NR NR No 

NR = Not reported 
Appendix F: Evidence Tables 

F 30 

Evidence Table 3a. Characteristics of the studies on the efficacy of vitamin A and/or beta-carotene (singly or paired) in prevent

Author, 

year 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study site 

ATBC 

ATBC, 

199497 1985-1988 Not 50-69; female; any cancer except non-melanoma skin; chronic renal 

insufficiency; liver cirrhosis; chronic alcoholism; medical condition limiting participation; severe angina; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses 

29133 6.1 years 

(median) 

Albanes, 

199698 1985-1993 Not 50-69; female; any previous or current cancer; symptomatic CV disease, CHD or 

major ischemic change in their ECG; atrophic gastritits at baseline or after 3-yr follow-up; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; not smoking 5 or more cigarettes/day at entry; anti-coagulant use 

1344 5-8 years 

(total), 3.9 years (median, Helsinki), 5.8 years (median, outside Helsinki) 

Rautalahti, 

199999

1985-1993 Not 50-69; female; cancer; serious 

diseases; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; nonsmokers) 

29133 5-8 years 

(total), 6.1 years (media 

Varis, 199890 1985-1993 Not 50-69; female; any previous or current 

cancer; symptomatic CV disease, CHD or major ischemic change in their ECG; atrophic gastritits at baseline or after 3-yr follow-up; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; not smoking 5 or more cigarettes/day at entry; anti-coagulant use 

1344 5-8 years 

(total), 3.9 years (median, Helsinki), 5.8 years (median, outside Helsinki) 

Rapola, 

1996106

RCT; Factorial design 

1985-1993 MI; any history of CHD at baseline and 

same criteria as general ATBC trial 

22265 4.7 years 

(median) 

 Finland 
Appendix F: Evidence Tables 

F 31 

Evidence Table 3a. Characteristics of the studies on the efficacy of vitamin A and/or beta-carotene (singly or paired) in prevent

(continued) 

Author, 

year 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study site 

ATBC (continued) 

Leppala, 2000107 1985-1993 Not 50-69; female; cancer; serious diseases; vitamin E, vitamin A, and/or 

beta carotene in excess of predefined doses; not smoking 5 or more cigarettes/day at entry; anti-coagulant use 

28519 6.0 years 

(median) 

Teikari, 

1997109

1985-1993 Not 50-69; female; cancer; serious 

diseases; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; nonsmokers) 

1828 6.6 years 

(median) 

CARET 

Omenn, 

1996a105 1985-1993 1845 8 years (total) 

Omenn, 

1996b 

93 

RCT; Placebo controlled 

1985-1995 18314 4 years 

(mean), 3.7 years (median). 

Gooodman, 

200494 RCT ( Post- intervention 

follow up) 

1985-1996 

Asbestos arm: not 45-74 years old in pilot period or 45-69 yrs in vanguard; smoking arm: not 50-69 yrs, male; any history of cancer except non-melanoma skin cancer in past 5 years; NASH; NAFLD; asbestos arm: no chest X-ray evidence of asbestos interstitial lung disease or not greater than or equal to 5 years high risk trade, SGOT or alkaline phosphate greater than 2.5x and 1.5x 95th percentile of normal, respectively, history of liver disease in past 12 months, any beta-carotene supplementation; smoking arm: < 20 pack-year smoking history, current or quit in past 6 years; smoking arm: premenopausal; asbestos arm: < 15 years since first occupational exposure. 

17140 5.9 years 

(total) 

Seattle, WashingtoPortland, Oregon; SFranciscoCA; Baltimore, MD; New Haven Conn; IrvinCA. 

NCSP 

Green, 

199984

RCT; Factorial design 

1992-1996 Skin cancer 809 4.5 years 

(total) 

 Australia 
Appendix F: Evidence Tables 

F 32 

Evidence Table 3a. Characteristics of the studies on the efficacy of vitamin A and/or beta-carotene (singly or paired) in prevent

(continued) 

Author, 

year 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study site 

SCP 

Greenberg, 

199685

RCT; Parallel arms 

1983-1993 85 years old or greater; any cancer other 

than nonmelanoma skin cancer diagnosed during the prior 5 years; debilitating cardiovascular conditions; known genetic predisposition to cancer; had not had at least one biopsy proved basal cell or squamous cell skin cancer treated after January 1, 1980; medical conditions that would limit participation in the study. 

1720 8.2 years 

(median) 

USA 

PHS 

Cook, 

2000104

Frieling, 

200086

Female; cancer; MI; stroke; current use of vitamin A supplements; taking aspirin. 

22071 12.9 years 

(mean) 

Liu, 1999108 Female; cancer; MI; stroke; type II 

diabetes 

21468 12.9 years 

(mean) 

Hennikens, 

199695

RCT; Factorial design 

1982-1995 

Female; cancer except nonmelanoma skin cancer; MI; stroke; transient cerebral ischema 

22071 12 years 

(mean) 

 USA 

WHS 

Lee, 199996 RCT; 

Factorial design 

1993-1996 Male; cancer; MI; stroke; serious illness 

that might preclude participation; participants in the Nurses Health Study; taking supplements of vitamin A, E, or beta-carotene more than once per week; taking aspirin or aspirin containing medications and not willing to forego use; NSAID more than once a week and not willing to forego use; taking anticoagulants; taking corticosteroids. 

39876 4.1 years 

(median) 

USA (natiowide) 
Appendix F: Evidence Tables 

F 33 

Evidence Table 3a. Characteristics of the studies on the efficacy of vitamin A and/or beta-carotene (singly or paired) in prevent

(continued) 

Author, 

year 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study site 

Linxian General Population Study 

Mark, 199866 Not 40-46 years old; history of cancer; 

history of debilitating diseases. 

5 years (total) 

Blot, 199364

 RCT; factorial design 

 1986-1991 

Not 40-69; stomach or esophageal; debilitating disease; does not live in one of 4 communes in Linxian 

29584 

5.25 years (total) 

 Linxian province, China 

ATBC = Alpha-tocopherol Bata-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; NSCP = Nambour Skin Cancer Prev

Cancer Prevention Study; PHS = Physicians Health Study; WHS = Womens Health Study.
Appendix F: Evidence Tables 

F 34 

Evidence Table 3b. Characteristics of the intervention in the studies of the efficacy of vitamin A and/or beta-carotene in the predisease 

Author, year Control arm Intervention Chemical form Dose/Frequency of use 

Tiof 

ATBC 

ATBC, 199497 

Albanes, 199698 

Rautalahti, 

199999 

Varis, 199890 

Rapola, 1996106 

Leppala, 2000 107 

Teikari, 1997109

Placebo Vitamin E; beta-carotene dl-alpha-tocopherol 

acetate; beta-carotene 

50 mg/1x/day; 20 mg/1x/day NS 

CARET 

Omenn, 

1996a105 Vitamin A Retinol in pilot phase (1985-1988) then retinyl 

palmitate in Vanguard (1988-1996) 

25000 IU/1x/day 

Omenn, 1996b 

93 Vitamin A Retinyl palmitate 25000 IU/1x/day 

Gooodman, 

200494

Placebo 

Vitamin A; beta-carotene 25000 IU/1x/day; 30 

mg/1x/day 

NS 
Appendix F: Evidence Tables 

F 35 

Evidence Table 3b. Characteristics of the intervention in the studies of the efficacy of vitamin A and/or beta-carotene in the predisease (continued) 

Author, year Control arm Intervention Chemical form Dose/Frequency of use 

Tiof 

NSCP 

Green, 199984 Placebo Beta-carotene Beta-carotene 30 mg/1x/day W

me

SCP 

Greenberg, 

199685

Placebo Beta-carotene Beta-carotene 50 mg/1x/day N

PHS 

Cook, 2000104 

Frieling, 200086 

Liu, 1999108 

Hennikens, 

199695

Placebo Beta-carotene Beta-carotene 50 mg/every other day NS 

WHS 

Lee, 199996 Placebo Beta-carotene Beta-carotene 50 mg/every other day N

Linxian General Population Study 

Vitamin A; zinc Retinol palmitate; zinc 

oxide 

10,000 IU/NS; 45 mg/NS 

Vitamin B2; niacin Riboflavin; niacin 5.2 mg/NS; 40 mg/NS 

Mark, 199866 Placebo 

Vitamin C; molybdenum Ascorbic acid; yeast 

complex 

180 mg/NS; 30 μg/NS 

 N

Vitamin A; zinc Retinol palmitate; zinc 

oxide 

 5000 IU/daily; 22.5 mg/daily 

Vitamin B2; niacin Riboflavin; niacin 3.2 mg/1x/day; 40 

mg/1x/day 

Blot, 199364 Placebo 

Vitamin C; molybdenum Ascorbic acid; yeast 

complex 

12 mg/NS; 30 μg/NS 

 N

ATBC = Alpha-tocopherol Bata-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; NSCP = Nambour Skin Cancer Prev

Cancer Prevention Study; PHS = Physicians Health Study; WHS = Women Health Study; NS = Not specified; mg = milligram; mcg = microgram; IU 
Appendix F: Evidence Tables 

F 36 

Evidence Table 3c. Characteristics of participants in studies of the efficacies of Vitamin A and/or beta-carotene (singly or in nu

Author, year 

Mean age (SD), and/or range 

Women, n (%); Ethnicity, n (%) Smokers, n (%) 

Alcohol consumption, n (%) 

Mean Bkg/m2 

ATBC 

ATBC, 

199497 Median: 57; range: 50- 69. Current: 29133 (100) Mean intake (grams/day): 11.0. 26.0 

Albanes, 

199698 Median: 57; range: 50- 69. Current: 29133 (100) Mean intake (grams/day): 11.0. 26.0 

Rautalahti, 

199999 57.7 Current: (100.0) Mean intake (grams/day): 18.0. 26.3 

Varis, 199890 58.8 Current: 1344 (100) Mean intake (grams/day): 

8.9. 

NR 

Rapola, 

1996106 Median: 56.9 Current: 22269 (100) NR 26.0 

Leppala, 2000 107 Mean: 57.7 Current: 28519 (100) Mean intake (grams/day): 18.0. 26.3 

Teikari, 

1997109

64.8 

0 (0); ethnicity NR 

Current: 1828 (100) Mean intake (grams/day): 

12.5. 

25.5 

CARET 

Omenn, 

1996a105 NR Gender, NR; ethnicity NR NR NR 

Omenn, 

1996b 

93 

58 6289 (34.3); 

Caucasian, 17067 (93.2); AfricanAmerican, 530 (2.9); Latino 275 (1.5) 

Never: 132 (0.7); former: 7174 (39.2); current: 11008 (60.1). 

Never: 6121 (33.4). 

Gooodman, 

200494 62 6007 (35); Caucasian, 15988 

(93.3) 

Never: 116 (0.7); former: 8988 (52.4); current: 8036 (46.9). 

NR 

NR 

NSCP 

Green, 

199984 48.8 913 (56.3); ethnicity NR NR NR NR 
Appendix F: Evidence Tables 

F 37 

Evidence Table 3c. Characteristics of participants in studies of the efficacies of Vitamin A and/or beta-carotene (singly or in nu

Author, year 

Mean age (SD), and/or range 

Women, n (%); Ethnicity, n (%) Smokers, n (%) 

Alcohol consumption, n (%) 

Mean Bkg/m2 

SCP 

Greenberg, 

199685 63.2 532 (31); ethnicity NR Never: 625 (36.3); former: 780 (45.3); current: 315 

(18.3). 

NR BMI <23

(26.8); B27: 813 BMI>27(27.1). 

PHS 

Cook, 

2000104

Frieling, 

200086

Liu, 1999108

Hennikens, 

199695

 53.0 (9.5); range: 40-84. 

0 (0); ethnicity NR Never: 11036 (50); former: 

8608 (39); current 2428 (11.0). 

Rare: 3222 (14.6%); monthly: 2428 (11.0); weekly: (49.5); daily: 5518 (25.0). 

24.9 

WHS 

Lee, 199996 53.9 (7.1) 39876 (100); 

Caucasian, 37802 (94.8); Latino, 917 (2.3),; Asian, 558 (1.4) 

Never: 20377 (51.1); former: 14355 (36); current: 5224 (13.1). 

Never: 17984 (45.1). 26.0; BM

13119 (

Linxian General Population Study 

Mark, 199866 Median (female) 51; 

median (male): 53; range: 44-60. 

Current (female): 3254 (20); current (male): 8929 (67). 

Current (female): (10); current (male): (40). 

Median (female)median (male): 

Blot, 199364 <50: 12425 (42%); 50-

59: 10354 (35%); ≥60: 6804 (23%). 

16271 (55); ethnicity NR 

Never: 20709 (70); ever smoked for >6 months: 8875 (30). 

Never: 22780 (77); any use in past 12 months: 6804 (23). 

NR 

 ATBC = Alpha-tocopherol Bata-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; NSCP = Nambour Skin Cancer PrevCancer Prevention Study; PHS = Physicians Health Study; WHS = Womens Health Study; BMI = Body Mass Index; NR not reported 
Appendix F: Evidence Tables 

F 38 

Evidence Table 3d. Results of studies of the efficacy of vitamin A and/or beta-carotene in preventing chronic disease. 

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pvalue Comment 

Cancer 

ATBC 

Lung cancer Beta-carotene 474/402 56.3/47.5 

per 10000 py 

ATBC, RR 1.18 (1.03-1.36) .01 199497

Lung cancer mortality 

Beta-carotene 

14564/ 14564 

302/262 35.6/30.8 

per 10000 py 

RR 1.08 (1.01-1.16) .02 

Albanes, 199698 Lung cancer Beta-carotene vs. no beta-carotene 14560/ 14573 482/412 58.0/41.2 per 10000 py RR 1.16 (1.02-1.33) .01 RR 1.39, 9

aged 65-6RR 1.25, 9smoker 20RR 1.23, 9who alwayRR 1.17, 9exposed to RR 1.40, 9with dietarRR 1.35, 9drank ethaRR 1.33, 9with basel11.6-13.1 Non signifcancer in tbaseline dcarotene, by serum 

Beta-carotene 7282/7287 39/37 RR 1.06 (0.68-1.66) Beta-carotene vs. no beta-carotene 

14560/ 14573 

69/66 RR 1.05 (0.75-1.47) .78 P-value fro

Colorectal cancer 

Alpha-tocopherol +beta-carotene 

7278/7287 30/37 RR 0.82 (0.50-1.31) 

Albanes, 2000102

Colorectal cancer mortality 

Beta-carotene vs. no beta-carotene 

14564/ 14569 

22/24 

NR 

RR 1.01 (0.56-1.79) 
Appendix F: Evidence Tables 

F 39 

Evidence Table 3d. Results of studies of the efficacy of vitamin A and/or beta-carotene in preventing chronic disease. 

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pvalue Comment 

Cancer (continued) 

ATBC (continuted) 

Malila, 1999 100

Colorectal Adnomas 

Beta-carotene vs. no beta-carotene 

7761/7777 81/56 NR RR 0.98 (0.71-1.35) .89 P-value fro

not change with a prior 

Beta-carotene 7282/7287 80/67 RR 1.20 (0.87-1.66) Alpha-tocopherol +beta-carotene 

7278/7287 56/67 RR 0.84 (0.59-1.20) 

Prostate cancer 

Beta-carotene vs. no beta-carotene 

14560/ 14573 

136/110 RR 1.23 (0.96-1.59) 

Heinonen, 1998101

Prostate cancer mortality 

Beta-carotene vs. no beta-carotene 

14560/ 14573 

33/29 

NR 

RR 1.15 (0.70-1.89) 

Pancreatic cancer 

Beta-carotene vs. no beta-carotene 

14573/ 14560 

38/51 0.45/0.60 

per 1000 py 

RR 0.75 (0.49-1.14) 

Carcinoma of the pancreas 

Beta-carotene 7282/7287 12/26 NR RR 0.46 (0.23-0.92) 

Rautalahti, 199999

Pancreatic cancer mortality 

Beta-carotene vs. no beta-carotene 

14573/ 14560 

35/48 NR RR 0.81 (0.53-1.26) 

Beta-carotene 329/333 13/18 Alpha-tocopherol + beta-carotene 

361/333 19/18 

Varis, NR 199890

Gastric dysplasia, carcinoma, or carcinoid Beta-carotene vs. 

no beta-carotene 

690/654 32/31 

NR 

RR 0.98 (0.59-1.62) Adjusted R

CARET 

Lung Cancer 9420/8894 229/159 5.9/4.6 per 

1000 

RR 1.28 (1.04-1.57) .02 

Lung cancer mortality 

9420/8894 NR RR 1.46 (1.07-2.00) .02 

Leukemia 9420/8894 18/8 RR 2.18 (0.95-5.03) .06 Mesothelioma 9420/8894 14/9 RR 1.52 (0.66-3.52) .32 Breast Cancer 3208/3081 59/65 RR 0.78 (0.55-1.12) .18 Colorectal cancer 9420/8894 56/50 RR 1.02 (0.70-1.50) .91 Head/neck cancer 9420/8894 32/22 RR 1.26 (0.73-2.19) .41 Lymphoma 9420/8894 13/13 RR 0.91 (0.42-1.98) .81 Prostate cancer 9420/8894 161/139 RR 1.01 (0.80-1.27) .95 

Omenn, 1996a 105

Bladder cancer 

Retinyl palmitate + beta-carotene 

9420/8894 42/36 RR 1.08 (0.69-1.70) .73 
Appendix F: Evidence Tables 

F 40 

Evidence Table 3d. Results of studies of the efficacy of vitamin A and/or beta-carotene in preventing chronic disease. (continue

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence of disease endpoint (active/inactive) 

Unadjusted estimates (95% CI) 

Pvalue Comment 

Cancer (continued) 

CARET (continued) 

Lung Cancer Total 388, 

Confirmed: 286 

RR 1.28 (1.04-1.57) .02 

Lung Cancer death 

 NR RR 1.46 (1.07-2.0) 

Omenn, 1996b 93

Mesothelioma 

Retinyl palmitate + beta-carotene 

9420/8894 

14/9 

Total 5.4 per 1000 py; Active:confirmed: 5.92 per 1000 py; Placebo 4.62 per 1000 py 

 NR Described 

significant 

Lung Cancer Active group follow 

up (had received vitamin A and betacarotene) 

Goodman, 376/311 RR 1.12 (0.97-1.31) 199392

Lung cancer mortality 

Active group follow up (had received vitamin A and betacarotene) 

8744/8396 

294/227 RR 1.20 (1.01-1.43) 

.13 

NCSP 

Basal-cell carcinoma 

Beta-carotene 102/93 3954/3806 

per 100,000 

RR 1.04 (0.73-1.27) Data base

without a h

Green, 199984

Squamous-cell carcinoma 

Beta-carotene 

820/801 

40/28 1508/1146 

per 100,000 

RR 1.35 (0.84-2.19) 

PHS 

Nonmelanoma skin cancer 

10941/ 10943 

1786/1821 RR 0.98 (0.92-1.05) 

Basal cell carcinoma 

10941/ 10943 

1574/1598 RR 0.99 (0.92-1.06) 

Frieling, 200086

Squamous cell carcinoma 

Beta-carotene 

10941/ 10943 

340/352 RR 0.97 (0.84-1.13) 

 Adjusted f

Hennikens, All cancer 1273/1293 RR 0.98 (0.91-1.06) .65 199695 All cancer 

mortality 

Beta-carotene 11036/11035 

386/380 RR 1.02 (0.89-1.18) .76 
Appendix F: Evidence Tables 

F 41 

Evidence Table 3d. Results of studies of the efficacy of vitamin A and/or beta-carotene in preventing chronic disease. (continue

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pvalue Comment 

Cancer (continued) 

SCP

Greenberg, 199685

Cancer deaths Beta-carotene 38/44 NR HR 0.86 (0.56-1.32) .48, 

adjusted .41 

Adjusted fquetelet inHR 0.83 (0

Non-melanoma skin cancer 

1314/1353 RR 1.0 (0.9-1.0) .41 

Prostate cancer 551/566 RR 1.0 (0.9-1.1) .62 Colon cancer 128/139 RR 0.9 (0.7-1.2) .48 Rectal cancer 42/37 RR 1.1 (0.7-1.8) .58 Lung cancer 85/93 RR 0.9 (0.7-1.2) .54 Lymphoma 89/85 RR 1.0 (0.8-1.4) .77 Leukemia 36/45 RR 0.8 (0.5-1.2) .31 Melanoma 68/77 RR 0.9 (0.6-1.2) .45 Brain cancer 25/33 RR 0.8 (0.5-1.3) .29 Bladder cancer 62/41 RR 1.5 (1.0-2.2) .04 Stomach cancer 20/21 RR 0.9 (0.5-1.8) .87 Thyroid cancer 19/2 RR 9.5 (2.2-40.7) .003 All cancer incidence 1314/1353 RR 1.0 (0.9-1.0) .41 

Cook, 2000104

All cancer mortality 

Beta-carotene 11036/ 

11035 

414/406 RR 1.0 (0.9-1.2) .71 

WHS 

All cancers not non-melanoma skin cancer 

Lee, 378/369 RR 1.03 (0.89-1.18) .73 199996

Cancer mortality 

Beta-carotene 19939/ 

19937 

31/28 RR 1.11 (0.67-1.85) .69 

Adjusted faspirin assrandomize

Linxian General Population Study 

Gastric cancer incidence 

RR 0.96 (0.81-1.14) 

Esophageal cancer incidence 

RR 1.07 (0.92-1.25) 

Stomach cancer death 

RR 1.03 (.83-1.28) 

Stomach cancer incidence 

RR 1.02 (.85-1.24) 

Blot, 199364

Total cancer incidence 

Retinol + zinc 

RR 1.00 (.89-1.11) 
Appendix F: Evidence Tables 

F 42 

Evidence Table 3d. Results of studies of the efficacy of vitamin A and/or beta-carotene in preventing chronic disease. (continue

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence of disease endpoint (active/ inactive) 

Unadjusted estimates (95% CI) 

Pvalue Comment

Cancer (continued) 

ATBC 

Beta-carotene vs. no beta-carotene 

11348/ 11119 

1020/963 21.2/20.0 per 

1000 py 

RR 1.05 (0.97-1.16) 

Beta-carotene alone 

5602/5549 548/487 22.8/20.2 per 

1000 py 

RR 1.13 (1.00-1.27) 

Rapola, 1996106 Angina 

Alpha-tocopherol + beta-carotene 

5548/5549 472/487 19.6/20.2 per 

1000 py 

RR 0.96 (0.85-1.09) 

Cardiovascular Disease 

ATBC (continued) 

Intracerebral hemorrhage 

69/43 8.4/5.2 per 

10000 yr 

RR 1.62 (1.10-2.36) .01 

Death from Intracerebral hemorrhage 

29/21 3.5/2.5 per 

10000 yr 

RR 1.39(0.79-2.44) .25 

Subarachoid hemorrhage 

45/40 5.5/4.9 per 

10000 yr 

RR 1.13 (0.74-1.73) .57 

Death from Subarachoid hemorrhage 

15/23 1.8/2.8 per 

/61/1 per 10000 yr 

RR 0.65 (0.34-1.25) .20 

Cerebral infarction 

415/392 50.7/47.6 

per 10000 yr 

RR 1.07 (0.93-1.22) .36 

Death from Cerebral infarction 

35/30 4.3/3.6 per 

10000 yr 

RR 1.17 (0.72-1.91) .52 

All strokes 554/503 67.7/61.1 

per 10000 yr 

RR 1.29 (0.94-1.76) .11 

Leppala, 2000 107

Death from all strokes 

Beta-carotene vs. no beta-carotene 

14246/ 14273 

82/78 10.0/9.5 per 

10000 yr 

RR 1/06 (0.78-1.44) .72 

CARET 

Omenn, 1996b93

CV death Vitamin A + betacarotene 9420/8894 NR RR 1.26 (0.99-1.61) ICD codes 

revision 
Appendix F: Evidence Tables 

F 43 

Evidence Table 3d. Results of studies of the efficacy of vitamin A and/or beta-carotene in preventing chronic disease. (continue

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence of disease endpoint (active /inactive) 

Unadjusted estimates (95% CI) 

Pvalue Comment 

Cardiovascular Disease (continued) 

SCP 

Greenberg, 199685

CV deaths Beta-carotene 68/59 NR HR 1.15 (0.81-

1.63), adjusted HR 1.16 (0.82-1.64) 

0.44, Adjusted 0.41 

Adjusted for asmoking; Percarotene in thrisk of CV dea

PHS 

Liu, 1999108 Type 2 DM Beta-carotene 10756/ 10712 396/402 NR RR 0.98 (0.85-1.12) NR 

MI 468/489 RR 0.96 (0.84-1.09) .50 Stroke 367/382 RR 0.96 (0.83-1.11) .60 All CV events 967/972 RR 1.00 (0.91-1.09) .90 

Hennekens, 199695

Death; CV causes 

Beta-carotene 11036/11035 

338/313 

NR 

RR 1.09 (0.93-1.27) .28 

PHS 

Liu, 1999108 Type 2 DM Beta-carotene 10756/ 10712 396/402 NR RR 0.98 (0.85-1.12) NR 

MI 468/489 RR 0.96 (0.84-1.09) .50 Stroke 367/382 RR 0.96 (0.83-1.11) .60 All important CV events 

967/972 RR 1.00 (0.91-1.09) .90 

Hennekens, 199695

Death from CV causes 

Beta-carotene 11036/11035 

338/313 

NR 

RR 1.09 (0.93-1.27) .28 

WHS 

MI 42/50 RR 0.84 (0.56-1.27) .41 Stroke 61/43 RR 1.42 (0.96-2.10) .08 All important CV events combined 

116/102 RR 1.14 (0.87-1.49) .34 

Lee, 199996

Death from CV causes 

Beta-carotene 19939/ 

19937 

14/12 RR 1.17 (0.54-2.53) .69 

Linxian General Population Study 

 Mark, 199866

Stroke deaths Retinol + zinc RR 0.99 (0.84-

1.18) 

NA 
Appendix F: Evidence Tables 

F 44 

Evidence Table 3d. Results of studies of the efficacy of vitamin A and/or beta-carotene in preventing chronic disease. (continue

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ inactive) 

Number of disease events (active/ inactive) 

Incidence of disease endpoint (active /inactive) 

Unadjusted estimates (95% CI) 

Pvalue Comment

Eye Disease 

ATBC 

Nuclear Beta-carotene 469/428 55/51 OR 0.9 (0.5-1.6) cataract Alpha-tocopherol + 

beta-carotene 

475/428 65/51 OR 1.2 (0.7-2.1) 

Cortical Beta-carotene 469/428 102/86 OR 1.2 (0.8-1.9) cataract Alpha-tocopherol + 

beta-carotene 

475/428 108/86 OR 1.3 (0.8-1.9) 

Beta-carotene 469/428 21/25 OR 0.7 (0.3-1.5) 

Teikari, 1997109

Posterior subcapsular cataract 

Alpha-tocopherol + beta-carotene 

475/428 34/25 

 NA 

OR 1.1 (0.5-2.2) 

 All ORs ad

Teikari, 1997 110

ARM Beta-carotene vs. 

no beta-carotene 

491/450 141/128 NA 1.04 (0.74-1.47) 

Linxian General Population Study 

Nuclear cataracts 

OR 0.77 (0.58-1.02) 

Posterior subcapsular cataracts 

OR 0.59 (0.31-1.14) 

Sperduto, 199365

Cortical cataracts 

Retinol and zinc NA 

OR 1.08 (0.92-1.27) 

ATBC = Alpha-tocopherol Bata-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; NSCP = Nambour Skin Cancer preve

Cancer prevention Study; PHS = Physicians Health Study; WHS = Women’s Health Study; OR = odds ratio; RR = relative risk; HR = hazard ratio; 95

interval; CV = cardiovascular; cum = cumulative; MI = myocardial infraction; DM = diabetes mellitus; ARM = age-related maculopathy; ANOVA = person-year
Appendix F: Evidence Tables 

F 45 

Evidence Table 3e. Total mortality in studies of vitamin A and/or beta-carotene used to prevent chronic disease Author, year Study supplement 

Total number in study (active/ placebo) 

Number of disease events (active/ placebo) 

Incidence per 1000 personyears (active/placebo) 

Unadjusted estimates (point estimate and 95% CI) P-va

ATBC 

ATBC, 199497 Beta-carotene 14573/14560 NR NR RR 1.08 (1.01-1.16) .02 

SCP 

Greenberg, 

199685 Beta-carotene NR 146/139 NR HR 1.05 (0.83-1.32) .71 

WHS 

Omenn, 1996b 

93

Beta-carotene 19939/19937 59/55 NR RR 1.07 (0.74-1.56) .7 

CARET 

Omenn, 1996b 

93

Vitamin A; beta-carotene. 9420/8894 NR 14.45/11.91 RR 1.17 (1.03-1.33) .02 

Gooodman, 

200494

Vitamin A; beta-carotene. 8744/8396 1225/1047 NR RR 1.08 (0.99-1.17) .07 

Linxian General Population Study 

Retinol + zinc 265/280 14.1/15.0 per 

1000 py 

RR 0.94, CI (0.79-1.11) 

Retinol + zinc vs. placebo 296/280 15.8/15.0 per 

1000 py 

RR 1.05, CI (0.89-1.24) 

Mark, 199866

Retinol + zinc RR 1.00 (.92-1.09) NA 

ATBC = Alpha-tocopherol Bata-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; SCP = Skin Cancer prevention Study

Study; CI = confidence interval; RR = relative risk; AREDS = Age-Related Eye Disease Study; NR = not reported; HR = hazard ratio; ATBC = AlphCancer Prevention Trial; CARET = Beta Carotene and Retinol Efficacy Trial. 
Appendix F: Evidence Tables 

F 46 

Evidence Table 3f. Characteristics of the studies on the efficacy of vitamin E (singly or paired) in preventing chronic disease

Author, year 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study 

ATBC 

Varis, 199890 Not 50-69; female; any previous or current 

cancer; symptomatic CV disease, CHD or major ischemic change in their ECG; atrophic gastritits at baseline or after 3-yr follow-up; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; not smoking 5 or more cigarettess/day at entry; anti-coagulant use. 

1344 5-8 years 

(total), 3.9 years (median, Helsinki), 5.8 years (median, outside Helsinki). 

Albanes, 

199698 Not 50-69; female; any previous or current cancer; symptomatic CV disease, CHD or major 

ischemic change in their ECG; atrophic gastritits at baseline or after 3-yr follow-up; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; not smoking 5 or more cigarettess/day at entry; anti-coagulant use. 

1344 5-8 years 

(total), 3.9 years (median, Helsinki), 5.8 years (median, outside Helsinki). 

Albanes, 

2000102 Not 50-69; female; not smoking 5 or more cigarettess/day at entry; cancer; serious illness; 

vitamin E, vitamin A, and/or beta carotene in excess of predefined doses (>20 mg, >20000 IU, or >6mg); anti-coagulant use. 

29133 5-8 years 

(total) 

ATBC, 

199497 Not 50-69; female; any cancer except non- melanoma skin; chronic renal insufficiency; liver 

cirrhosis; chronic alcoholism; medical condition limiting participation; severe angina; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses. 

29133 6.1 years 

(median) 

Rautalahti, 

199999

Not 50-69; female; cancer; serious diseases; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; nonsmokers). 

29133 5-8 years 

(total), 6.1 years (median). 

Heinonen, 

1998101

Not 50-69; female; cancer; serious diseases; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; not smoking 5 or more cigarettess/day at entry 

29133 5-8 years 

(total), 6.1 years (median). 

Rapola, 

1996106

RCT; Factorial design 

1985-1993 

MI; any history of CHD at baseline and same criteria as general ATBC trial. 

22269 4.7 years 

(median) 

 Finla
Appendix F: Evidence Tables 

F 47 

Evidence Table 3f. Characteristics of the studies on the efficacy of vitamin E (singly or paired) in preventing chronic disease (c

Author, year 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study 

ATBC (continued) 

Lappala,2000 107 Not 50-69; female; cancer; serious diseases; vitamin E, vitamin A, and/or beta carotene in 

excess of predefined doses; not smoking 5 or more cigarettes/day at entry; anti-coagulant use 

28519 6.0 years 

(median) 

Teikari, 

1997109

Not 50-69; female; cancer; serious diseases; vitamin E, vitamin A, and/or beta carotene in excess of predefined doses; nonsmokers). 

1828 6.6 years 

(median) 

WHS 

Lee, 200587 RCT, 

factorial design 

1992-2004 All cancers except nonmelanoma skin cancer; all 

other major chronic disease; vitamin A , vitamin E, beta-carotene, aspirin, or NSAID use greater than once weekly; history of adverse effects from aspirin; use of anticoagulants; use of corticosteroids. 

39876 10.1 years 

(mean) 

USA (natiowide) 

Lee, 199996 RCT, 

placebo controlled trial 

1993-1999 Male; <45 years; cancer; coronary disease or 

cerebrovascular disease 

39876 4.1 years 

(median) 

USA (natiowide) 

PPP 

DeGaetano, 

2001112 4495 3.6 years (mean) 

Sacco, 

2003181

RCT; factorial design 

1994-1998 Disease with poor short-term prognosis; history 

of vascular events or or disease; chronic use of vitamin E, antiinflammatory agents, anticoagulants, aspirin; predictable psychological or logistical difficulties affecting compliance. 

1031 3.7 years 

(median) 

 Italy 

 VECAT 

McNeil, 

2004113

RCT; placebo controlled trial 

1995-2000 MI or type II diabetes in the previous 6 months; 

prior cataract surgery; advanced cataract in both eyes; glaucoma; major psychiatric illness; uncontrolled hypertension; terminal illness; continued use of vitamin E supplements; vitamin E sensitivity; long-term steroid or anticoagulation treatment; bilateral intraocular pressure >22; inadequate pupillary dilation (<6.5mm). 

1193 4 years (total) Melbo

Austra
Appendix F: Evidence Tables 

F 48 

Evidence Table 3f. Characteristics of the studies on the efficacy of vitamin E (singly or paired) in preventing chronic disease+ (

Author, year 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time Study 

CARET 

Goodman, 

200494

RCT (Postintervention follow up) 

1985-1996 Asbestos arm: not 45-74 years old in pilot period 

or 45-69 yrs in vanguard; smoking arm: not 50-69 yrs, male; any history of cancer except nonmelanoma skin cancer in past 5 years; NASH; NAFLD; asbestos arm: no chest X-ray evidence of asbestos interstitial lung disease or not greater than or equal to 5 years high risk trade, SGOT or alkaline phosphate greater than 2.5x and 1.5x 95th percentile of normal, respectively, history of liver disease in past 12 months, any betacarotene supplementation; smoking arm: < 20 pack-year smoking history, current or quit in past 6 years; smoking arm: premenopausal; asbestos arm: < 15 years since first occupational exposure. 

17140 5.9 years 

(total) 

SeattleWash; PortlaOregoSan FranciCA; BaltimMD; NHaven Conn; Irvine, 

ATBC = Alpha-tocopherol Beta-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; WHS = Womens Health Study; PPP 

Project; VECAT = Vitamin E and Cataract Randomized Controlled Trial.
Appendix F: Evidence Tables 

F 49 

Evidence Table 3g. Characteristics of the intervention in the studies of the efficacy of vitamin E in the prevention of chronic dis

Author, year Control arm Intervention Chemical form Dose/Frequency of use 

Timing of use 

ATBC 

Varis, 199890 

Albanes, 199698

Placebo Vitamin E; beta-carotene dl-alpha-tocopherol; 

beta-carotene 

 50 mg/1x/day; 20 mcg/1x/day 

 NS 

Albanes, 2000102 Placebo Vitamin E; beta-carotene dl-alpha-tocopherol; 

beta-carotene 

 50 mg/1x/day; 20 mcg/1x/day 

 NS 

ATBC, 199497 

Rautalahti, 

199999 

Heinonen, 

1998101 

Rapola, 1996106 

Lappala,2000 107 

Teikari, 1997109 

WHS 

Lee, 200587 Placebo Vitamin E alpha-tocopherol 600 IU/every other day NS Lee, 199996 Placebo beta-carotene NS 50mg/every other day NS 

PPP 

DeGaetano, 

2001112 Vitamin E synthetic alpha tocopherol 

Sacco, 2003181

Placebo 

Vitamin E alpha tocopherol 

300 mg/1x/day NS 

VECAT 

McNeil, 2004113 Placebo Vitamin E d-alpha-tocopherol 335 mg/1x/day NS 

CARET 

Goodman, 

200494 Placebo Vitamin A; beta-carotene 25000 IU/1x/day; 30 mg/1x/day NS 

 ATBC = Alpha-tocopherol Beta-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; WHS = Womens Health Study; PPP 

Project; VECAT = Vitamin E and Cataract Randomized Controlled Trial; NS = Not specified; mg = milligram; mcg = microgram; IU = international u
Appendix F: Evidence Tables 

F 50 

Evidence Table 3h. Characteristics of participants in studies of the efficacies of Vitamin E (singly or in nutrient pairs) 

Author, year 

Mean age (SD), and/or range 

Women, n (%); Ethnicity, n (%) Smokers, n (%) 

Alcohol consumption, n (%) 

Mean BMI in kg/m2 Prior supplem

ATBC 

Varis, 199890 64.8 0 (0); ethnicity 

NR 

Current: 1828 (100) Mean intake 

(grams/day): 12.5. 

25.5 Vitamin E: 0 (0

carotene: 0 (0)

Albanes, 

199698 Median: 56.9 0 (0); ethnicity NR Current: 22269 (100) NR 26.0 Vitamin E: 0 (0

carotene: 0 (0)

Albanes, 

2000102 57.2 0 (0); ethnicity NR Current: 29133 (100) Mean intake (grams/day): 11.0 26.0 Vitamin E: 0 (0

carotene: 0 (0)

ATBC, 

199497 64.2 (7.5) 534 (51.8); ethnicity NR Former: 257 (25.2); current: 168 (16.5). NR 29.0 NR 

Rautalahti, 

199999 53.0 (9.5); range: 40-

84. 

0 (0); ethnicity NR 

Never: 11036 (50); former: 8608 (39); current 2428 (11.0). 

Rare: 3222 (14.6%); monthly: 2428 (11.0); weekly: (49.5); daily: 5518 (25.0). 

24.9 Current multivi

Heinonen, 

1998101 57.2 0 (0); ethnicity NR Current: 29133 (100) Mean intake (grams/day): 11.0 26.0 Vitamin E: 0 (0

carotene: 0 (0)

Rapola, 

1996106

Median: 57; range: 50-69. 

0 (0); ethnicity NR 

Current: 29133 (100) Mean intake 

(grams/day): 11.0 

26.0 Vitamin E: 0 (0

carotene: 0 (0)

Lappala,2000 107 57.7 0 (0); ethnicity NR Current: 28519 (100) Mean intake (grams/day): 18.1 26.3 Vitamin E: 0 (0

carotene: 0 (0)

Teikari, 

1997109

Median: 57; range: 50-69. 

0 (0); ethnicity NR 

Current: 29133 (100) Mean intake 

(grams/day): 11.0. 

26.0 Vitamin E: 0 (0

carotene: 0 (0)

WHS 

Lee, 200587 58.8 0 (0); ethnicity 

NR 

Current: 1344 (100) Mean intake 

(grams/day): 8.9. 

NR Vitamin E: 0 (0

carotene: 0 (0)

Lee, 199996 NA 39876 (100); 

ethnicity NR 

NA NA NA NA 
Appendix F: Evidence Tables 

F 51 

Evidence Table 3h. Characteristics of participants in studies of the efficacies of Vitamin E (singly or in nutrient pairs) (continue

Author, year 

Mean age (SD), and/or range 

Women, n (%); Ethnicity, n (%) Smokers, n (%) 

Alcohol consumption, n (%) 

Mean BMI in kg/m2 Prior supplem

PPP 

DeGaetano, 

2001112 Median: 48 (50); ethnicity NR Current: (36) Current: (37.0) NR NR 

Sacco, 

2003181 64.4 (7.6) 1912 (42); ethnicity NR Former: 1080 (24); current: 667 (15). NR 27.6 NR 

VECAT 

McNeil, 

2004113 65.7 670 (56); ethnicity NR Current: 24 (2); ever: 577(48) NA >=27: 468 (39) Vitamin E: 289 

CARET 

Goodman, 

200494 62 6007 (35); Caucasian, 

15988 (93.3) 

Never: 116 (0.7); former: 8988 (52.4); current: 8036 (46.9). 

NR NR NR 

ATBC = Alpha-tocopherol Bata-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; WHS = Womens Health Study; PPP 

Project; VECAT = Vitamin E and Cataract Randomized Controlled Trial; BMI = Body Mass Index; NR = not reported 
Appendix F: Evidence Tables 

F 52 

Evidence Table 3i. Results of studies of the efficacy of vitamin E in preventing chronic disease. 

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ non-active) 

Number of disease events (active/ non-active) 

Incidence of disease endpoint (active/ non-active) 

Unadjusted estimates (95% CI) 

Pvalue C

Cancer 

ATBC 

Alpha-tocopherol 321/333 13/18 Alpha-tocopherol + beta-carotene 

361/333 19/18 

Varis, NR 199890

Gastric dysplasia, carcinoma, or carcinoid Alpha-tocopherol 

vs. no alphatocopherol 

682/662 32/31 

NR 

RR 1.00 (0.60-1.66) A

1

Albanes, 199698 Lung cancer Alpha-tocopherol vs. no alphatocopherol 14564/ 14569 444/450 53.2/54.5 per 10000 person years RR 0.99 (0.87-1.13) .86 N

sccsev

vao

a

Alpha-tocopherol vs. placebo 

7286/7287 29/37 NR RR 0.79 (0.48-1.28) 

Alpha-tocopherol vs. no alphatocopherol 

14564/ 14569 

59/76 NR RR 0.78 (0.55-1.09) .15 P

Colorectal cancer 

Alpha-tocopherol + beta-carotene 

7278/7287 30/37 NR RR 0.82 (0.50-1.31) 

Albanes, 2000102

Colorectal cancer mortality 

Alpha-tocopherol vs. no alphatocopherol 

14564/ 14569 

22/24 NR RR 0.92 (0.51-1.64) 

Lung cancer Alpha-tocopherol 14564/ 

14564 

433/443 51.3/52.4 

per 10000 person year 

ATBC, RR 0.98 (0.86-1.12) .8 199497

Lung cancer mortality 

Alpha-tocopherol 14564/ 

14564 

285/279 33.6/32.6 

per 10000 person year 

 RR 1.03 C
Appendix F: Evidence Tables 

F 53 

Evidence Table 3i. Results of studies of the efficacy of vitamin E in preventing chronic disease. (continued) 

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/nonactive) 

Number of disease events (active/nonactive) 

Incidence of disease endpoint (active/ non-active) 

Unadjusted estimates (95% CI) 

Pvalue C

Cancer (continued) 

ATBC (continued) 

Pancreatic cancer 

Alpha-tocopherol vs. no alphatocopherol 

14564/ 14569 

51/38 0.60/0.45 

per 1000 person year 

RR 1.34 (0.88-2.05) 

Carcinoma of the pancreas 

Alpha-tocopherol 7286/7287 25/26 NR RR 0.94 (0.56-1.67) 

Rautalahti, 199999

Pancreatic cancer mortality 

Alpha-tocopherol vs. no alphatocopherol 

14564/ 14569 

49/34 NR RR 1.11 (0.72-1.72) 

Malila, 1999 100

Colorectal Adnomas 

Alpha-tocopherol vs. no alphatocopherol 

7768/7770 81/56 NR RR 1.66 (1.19-2.32) .003 R

ep1

Alpha-tocopherol 7286/7287 43/67 NR RR 0.64 (0.44-0.94) Alpha-tocopherol + beta-carotene 

7278/7287 56/67 NR RR 0.84 (0.59-1.20) 

Prostate cancer 

Alpha-tocopherol vs. no alphatocopherol 

14564/ 14569 

99/147 NR RR 0.68 (0.53-0.88) .002 

Heinonen, 1998101

Prostate Cancer mortality 

Alpha-tocopherol vs. no alphatocopherol 

14564/ 14569 

23/39 NR RR 0.59 (0.35-0.99) 

WHS 

Total invasive cancer 

1437/1428 RR 1.01 (0.94-1.08) .87 

Breat cancer 616/614 RR 1.00 (0.90-1.12) .95 Lung cancer 107/98 RR 1.09 (0.83-1.44) .52 Colon cancer 

107/107 RR 1.00 (0.77-1.31) .99 

Lee, 200587

Cancer death 

Vitamin E 19937/ 

19939 

308/275 

NR 

RR 1.12 (0.95-1.32) .17 
Appendix F: Evidence Tables 

F 54 

Evidence Table 3i. Results of studies of the efficacy of vitamin E in preventing chronic disease. (continued) 

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ non-active) 

Number of disease events (active/ non-active) 

Incidence of disease endpoint (active/ non-active) 

Unadjusted estimates (95% CI) 

Pvalue C

Cardiovascular Disease 

ATBC 

Alpha-tocopherol vs. no alphatocopherol 

11118/ 11351 

948/1035 19.6/21.5 

per 1000 py 

RR 0.91 (0.83-0.99) 

Alpha-tocopherol alone 

5570/5549 476/487 19.7/20.2 

per 1000 py 

RR 0.97 (0.85-1.10) 

Rapola, 1996106 Angina 

Alpha-tocopherol + beta-carotene 

5548/5549 472/487 19.6/20.2 

per 1000 py 

RR 0.96 (0.85-1.09) 

Intracerebral hemorrhage 

57/55 7.0/6.7 per 

10000 py 

RR 1.04 (0.72-1.51) .84 

Death from Intracerebral hemorrhage 

31/19 3.8/2.3 per 

10000 py 

RR 1.64 (0.93-2.90) .09 

Subarachoid hemorrhage 

51/34 6.2/4.1 per 

10000 py 

RR 1.50 (0.97-2.32) .07 

Death from Subarachoid hemorrhage 

28/10 3.4/2.1 per 

10000 py 

RR 2.81 (1.37-5.79) .005 

Cerebral infarction 

373/434 45.5/52.8 

per 10000 py 

RR 0.86 (0.75-0.99) .03 

Death from Cerebral infarction 

29/36 3.5/4.4 per 

10000 py 

RR 0.81 (0.49-1.32) .39 

All strokes 509/548 62.1/66.6 

per 10000 py 

RR 0.93 (0.83-1.05) 0.25 

Lappala, 2000 107

Death from all strokes 

Alpha-tocopherol vs.no alphatocopherol 

14238/ 14281 

90/70 11.0/8.5 per 

10000 py 

RR 1.29 (0.94-1.76) 0.11 
Appendix F: Evidence Tables 

F 55 

Evidence Table 3i. Results of studies of the efficacy of vitamin E in preventing chronic disease. (continued) 

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ non-active) 

Number of disease events (active/ non-active) 

Incidence of disease endpoint (active/ non-active) 

Unadjusted estimates (95% CI) 

Pvalue C

Cardiovascular Disease (continued) 

WHS 

Combined first major CV event 

482/517 RR 0.93 (0.82-1.05) 0.26 

MI 196/195 RR 1.01 (0.82-1.23) 0.96 Nonfatal MI 184/181 RR 1.02 (0.83-1.25) 0.87 Fatal MI 12.0/14 RR 0.86 (0.40-1.85) 0.70 Stroke 241/246 RR 0.98 (0.82-1.17) 0.82 Nonfatal stroke 220/222 RR 0.99 (0.82-1.19) 0.93 Fatal stroke 21/24 RR 0.88 (0.49-1.57) 0.66 Ischemic stroke 

194/197 RR 0.99 (0.81-1.20) 0.88 

Hemorrhagic stroke 

44/48 RR 0.92 (0.61-1.38) 0.68 

Lee, 200587

Cardiovascular death 

Vitamin E 19937/ 

19939 

106/140 

NR 

RR 0.76 (0.59-0.98) 0.03 

PPP 

CV deaths, nonfatal MI and nonfatal stroke 

56/53 RR 1.07 (0.74-1.56) 

Total CV events/ diseases 

158/170 RR 0.94 (0.77-1.16) 

CV Deaths 22/26 RR 0.86 (0.49-1.52) Non-CV deaths 50/42 RR 1.21 (0.80-1.81) All MI 22/25 RR 0.89 (0.52-1.58) Non-fatal MI 19/18 RR 1.01 (0.56-2.03) All Stroke 22/18 RR1.24 (0.66-2.31) Nonfatal Stroke 20/13 RR 1.56 (0.77-3.13) TIA 33/35 RR 0.96 (0.60-1.53) PAD 16/30 RR 0.54 (0.30-0.99) .043 Revascularization procedures 

27/22 RR 1.25 (0.71-2.18) 

DeGaetano, 2001112

Angina pectoris 

Vitamin E 

66/55 RR 1.22 (0.86-1.73) 
Appendix F: Evidence Tables 

F 56 

 Evidence Table 3i. Results of studies of the efficacy of vitamin E in preventing chronic disease. (continued) 

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/nonactive) 

Number of disease events (active/nonactive) 

Incidence of disease endpoint (active/nonactive) Unadjusted estimates (95% CI) P- value C

Cardiovascular Disease (continued) 

CV deaths, nonfatal MI and nonfatal stroke 

22/20 RR 1.13 (0.62-2.04) 

Total CV events 

51/61 RR 0.86 (0.60-1.22) 

CV deaths 10/8 RR 1.28 (0.51-3.22) Non CV deaths 

13/14 RR 0.95 (0.45-2.01) 

All MI 7/8 RR 0.90 (0.33-2.46) All stroke 8/11 RR 0.75 (0.30-1.83) Angina pectoris 

14/15 RR 0.93 (0.45-1.90) 

TIA 6/11 RR 0.54 (0.21-1.43) PAD 10/14 RR 0.71 (0.32-1.58) 

Sacco, 2003182

Revascularisation procedure 

Vitamin E vs. placebo In persons with type 2 diabetes 

509/522 

9/9 RR 1.00 (0.40-2.48) 

 N

pbin a9
Appendix F: Evidence Tables 

F 57 

Evidence Table 3i. Results of studies of the efficacy of vitamin E in preventing chronic disease. (continued) 

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/nonactive) 

Number of disease events (active/ non-active) 

Incidence of disease endpoint (active/nonactive) Unadjusted estimates (95% CI) P- value C

Eye Disease 

VECAT 

Cortical cataract 

442/442 19/22 4.5%/5% 0.9(0.5-1.6) 0.75 

Nuclear cataract 

480/486 62/59 12.9%/12.1% 1.1(0.8-1.5) 0.77 

Posterior subcapsular cataract 

479/486 8/17 1.7%/3.5% 0.5(0.2-1.1) 0.08 

Any cataract 409/430 70/72 17.1%/16.7% 1.0(0.8-1.4) 0.92 

In

Cortical cataract 

156/147 26/27 16.7%/18.4% 0.9(0.5-1.6) 0.76 

Nuclear cataract 

501/503 57/60 11.4%/11.9% 0.9(0.7-1.3) 0.84 

Posterior subcapsular cataract 

18/18 5/2 28%/10% 2.5(0.6-11.2) 0.20 

McNeil, 2004113

Any cataract 

Vitamin E 

504/508 83/85 16.5%/16.7% 1.0(0.7-1.3) 0.93 

P

ATBC 

Nuclear Alpha-tocopherol 456/428 51/51 OR 0.8 (0.4-1.4) cataract Alpha-tocopherol + 

beta-carotene 

475/428 65/51 OR 1.2 (0.7-2.1) 

Cortical Alpha-tocopherol 456/428 90/86 OR 0.9 (0.6-1.4) cataract Alpha-tocopherol + 

beta-carotene 

475/428 108/86 OR 1.3 (0.8-1.9) 

Alpha-tocopherol 456/428 25/25 OR 0.9 (0.4-1.8) 

Teikari, 1997109

Posterior subcapsular cataract 

Alpha-tocopherol + beta-carotene 

475/428 34/25 

 NA 

OR 1.1 (0.5-2.2) 

 A

Teikari, 1998 110 Age-related maculopathy Alpha-tocopherol vs. no alphatocopherol 492/447 148/121 OR 1.13 (0.81-1.59) 

ATBC = Alpha-tocopherol Bata-carotene Prevention Study; CARET = Beta-carotene and Retinol Efficacy Trial; WHS = Women’s Health Study; PPP Project; VECAT = Vitamin E and Cataract Randomized Controlled Trial; OR = odds ratio; 95% CI = 95 confidence interval; py = person years; CV = cumulative; PSA = prostate-specific antigen; MI = myocardial infraction; ANOVA = analysis of variance; TIA = Transient ischemic attacks; PAD = p
Appendix F: Evidence Tables 

F 59 

Evidence Table 3j. Total mortality in studies of vitamin E used to prevent chronic disease Author, year Study supplement 

Total number in study (active/ placebo) 

Number of disease events (active/ placebo) 

Person years (active/ placebo) 

Incidence per 1000 person-years (active/placebo) 

Unadjusted estimestimate and 95% 

ATBC, 199497 Alpha-tocopherol vs. 

placebo 

14564/14564 NR NR NR RR 1.02 (0.95-1.0

Lee, 200587 Vitamin E 19937/19939 636/615 NR NR 1.04 (0.93-1.16) 

DeGaetano, 

2001112 Vitamin E 2231/2264 72/68 NR NR RR 1.07 (0.77-1.4

Sacco, 2003181 Vitamin E 509/522 23/22 NR NR RR 1.07 (0.61-1.9

CI = confidence interval; RR = relative risk; NR = not reported; WHS = Women's Health Study; ATBC = Alpha-Tocopherol, Beta Carotene Cancer PPrimary Prevention Project. 
Appendix F: Evidence Tables 

F 60 

Evidence Table 3k. Characteristics of the studies on the efficacy of selenium, B vitamins, or other single nutrients (singly or pa

chronic disease 

Author, year Nutrient(s) 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time S

NCP 

Calrk, 

1996133

Calrk, 

1998134

History of 2 or more BCC or 1 SCC of the skin, with 1 of these carcinomas occurring within the prior year; liver or kidney disease history; internal malignancies treated within the previous 5 years; life expectancy not greater than 5 years; female; no non-melanoma skin cancer; life expectancy not greater than 5 years; reported internal malignancies treated within the previous 5 years 

974-1312 10 years 

(total), 6.4 years (mean). 

EU

Reid, 

2002135 Not having valid baseline plasma selenium value collected on day of 

randomization +/-4 days; no noncutaneous malignancy within previous 5 years. 

1250 13 years 

(total), 7.9 years (mean) 

 EU

DuffieldLillico, 

2002136

 Selenium RCT; 

Placebo controlled 

1983-1993 

History of 2 or more BCC or 1 SCC of the skin, with 1 of these carcinomas occurring within the prior year; liver or kidney disease history; internal malignancies treated within the previous 5 years; life expectancy not greater than 5 years; Not having valid baseline plasma selenium value collected on day of randomization +/-4 days; no noncutaneous malignancy within previous 5 years; not NPC participant; female; Initial blood not drawn within first 4 days of randomization; history of prostate cancer 

927-1250 13 years 

(total), selenium 7.6 years (mean), placebo 7.3 years (mean), 7.4 years (mean). 

EU
Appendix F: Evidence Tables 

F 61 

Evidence Table 3k. Characteristics of the studies on the efficacy of selenium, B vitamins, or other single nutrients (singly or pa

chronic disease (continued) 

Author, year Nutrient(s) 

Study design 

Study period Exclusion criteria 

Total sample size enrolled 

Mean/ median follow-up time S

Linxian General Populatiton Study 

Mark, 199866 Not 40-46 years old; history of cancer; 

history of debilitating diseases. 

5 years (total) 

Sperduto, 

199364

Vitamin A + zinc; riboflavin + niacin; vitamin C + molybdenum 

RCT; Factorial design 

1986-1991 

Not 40-69; stomach or esophageal; debilitating disease; does not live in one of 4 communes in Linxian 

29584 29584 

5.25 years (total) 

 LpC

Other Study 

Yu, 1991139 Not in Qidong county; Not HBVsAg 

carrier; Abnormal liver function; not a member of family with hereditary predisposition to cancer 

226-2474 2-4 years 

(total) 

QCC

NPC = Nutritional Prevention of Cancer Study Group; ARED = Age-related Eye Disease Study Group. 
Appendix F: Evidence Tables 

F 62 

Evidence Table 3l. Characteristics of the intervention in the studies of the efficacy of other nutrients in the prevention of chron

Author, year 

Contorl Arm Interventnion Chemical form Dose/Frequency of use 

Timing of use 

NPC 

Clark, 1996133 Placebo Selenium Selenium yeast NS NS Clark, 1998134 Placebo Selenium Selenium yeast NS NS 

Reid, 2002 NS 135 Placebo Selenium Selenium yeast 200 mcg/1x/day 

NS 

Duffield-Lillico, Placebo Yeast NS NS 

2002136 Selenium Selenium yeast 200 mcg/1x/day NS 

Duffield-Lillico, Placebo Yeast NS NS 

2003137 Selenium Selenium yeast 200 mcg/1x/day NS 

Linxian General Population Study 

Placebo 1 Vitamin A Retinol palmitate 10000 IU/NS Zinc Zinc oxide 45 mg/NS Vitamin B2 Riboflavin 5.2 mg/NS Niacin Niacin 40 mg/NS Vitamin C Ascorbic acid 180 mg/NS 

Mark, 199866 Placebo 

Molybdenum Yeast complex 30 mg/NS 

 NS 

Vitamin A Retinol palmitate 5000 IU/daily Zinc Zinc oxide 22.5 mg/daily Vitamin B2 Riboflavin 3.2 mg/1x/day Niacin Niacin 40 mg/1x/day Vitamin C Ascorbic acid 120 mg/1x/day 

Sperduto, 

199364

Placebo 1 

Molybdenum Molybendum 30 mcg/1x/day 

NS 
Appendix F: Evidence Tables 

F 63 

Evidence Table 3l. Characteristics of the intervention in the studies of the efficacy of other nutrients in the prevention of chron

Author, year 

Contorl Arm Interventnion Chemical form Dose/Frequency of use 

Timing of use 

ARED 

 NS NS Vitamin E Dl-alpha-tocopherol acetate 200 IU/2x/day (2 tablets 

in the morning, 2 in the evening) 

Vitamin C Ascorbic acid 250 mg/2x/day (2 tablets 

in the morning, 2 in the evening) 

Vitamin A Beta-carotene 7.5 mg/2x/day (2 tablets 

in the morning, 2 in the evening) 

Zinc Zinc oxide 40 mg/2x/day (2 tablets 

in the morning, 2 n the evening) 

AREDS, 

2001b75

Placebo 1 

Selenium Selenium yeast 200 mcg/1x/day 

With meals 

Other Study 

Placebo 1 Trial 2 control group (plain 

yeast tablet) 

NS NS 

Placebo 2 Trial 3 control group (placebo, 

undefined) 

NS NS 

Yu, 1991139

 Selenium Selenium yeast 200 mcg/1x/day NS 

NPC = Nutritional Prevention of Cancer Study Group; ARED = Age-related Eye Disease Study Group; NS = Not specified; mg = milligram; mcg = m

unit. 
Appendix F: Evidence Tables 

F 64 

Evidence Table 3m. Characteristics of participants in studies of the efficacies of selenium, B vitamins or other nutrients (singly 

Author, year 

Mean age (SD), and/or range 

Women, n (%); Ethnicity, n (%) Smokers, n (%) 

Alcohol consumption, n (%) 

Mean BMI in kg/m2 

Pty

NPC 

Clark, 

1996133 63.2; range: 18-80. 332 (25.3); ethnicity, NR Never: 428 (32.6); former: 514 (39.2); current: 369 (28.2). NR NR 

Clark, 

1998134 63.8 0 (0); ethnicity, NR NR NR NR 

Reid, 

2002135 63.2 (10.0) 316 (25.0); ethnicity, NR Never: 398 (31.8); former: 497 (39.8); current: 355 (28.4). Mean drinks/week: 

12.9. 

NR 

DuffieldLillico, 

2002136

 63.2; range: 18-80. selenium: 63.4 (10.2); placebo 63 (9.9) 

332 (25.3); ethnicity, NR 

Never: 428 (32.6); former: 514 (39.2); current: 369 (28.2). 

NR 25.5 

DuffieldLillico, 

2003137

64.4; selenium: 64.9 (8.8); placebo 63.7 (9.4) 

0 (0); ethnicity, NR Never: 213 (23); former: 431 (46.5); 

current: 283 (30.5). 

NR 25.9 

N

Linxian General Population Study 

Mark, 199866 Median (female) 

51; median (male): 53; range: 44-60. 

Current (female): 3254 (20); current (male): 8929 (67). 

Current (female): (10); current (male): (40). 

Median BMI (female): 21.9; median BMI (male): 21.6. 

Sperduto, 

199364 <50: 12425 (42%); 50-59: 10354 

(35%); ≥60: 6804 (23%). 

16271 (55); ethnicity, NR 

Never: 20709 (70); ever smoked for >6 months: 8875 (30). 

Never: 22780 (77); any use in past 12 months: 6804 (23). 

NR 

N
Appendix F: Evidence Tables 

F 65 

Evidence Table 3m. Characteristics of participants in studies of the efficacies of selenium, B vitamins or other nutrients (singly (continued) 

Author, year 

Mean age (SD), and/or range 

Women, n (%); Ethnicity, n (%) Smokers, n (%) 

Alcohol consumption, n (%) 

Mean BMI in kg/m2 

Pty

ARED 

AREDS, 

2001b75 Median: 69 2021 (56); Caucasian, 3483 

(96); AfricanAmerican, 153 (3) 

Former: 1751 (49); current: 298 (8.0). 

NR NR M

ss(5

Other Study 

Yu, 1991139 Range: 21-63; 

Range: 15-75 

NR; Asian (100) NR NR NR 

NPC = Nutritional Prevention of Cancer Study Group; ARED = Age-related Eye Disease Study Group; BMI = Body Mass Index; NR = not reported. 
Appendix F: Evidence Tables 

F 66 

Evidence Table 3n. Results of studies of the efficacy of other single or paired nutrients in preventing chronic disease. 

Author, year Disease endpoint 

Study supplement 

Total Number in study (active/ placebo) 

Number of disease events (active/ placebo) 

Incidence of disease endpoint (arm1/arm2) 

Unadjusted estimates (95% CI) P-val

Cancer 

NPC 

Lung cancer 17/31 HR 0.56 (0.31-1.01) .05 Prostate cancer 13/35 HR 0.35 (0.18-.65) .001 Colorectal cancer 8/19 HR 0.39 (0.17-0.90) .03 Head and neck 6/8 HR 0.77 (0.27-2.24) .64 Bladder 8/6 HR 1.27 (0.44-3.67) .66 Esophageal 2/6 HR 0.30 (0.06-1.49) .14 Breast 9/3 HR 2.95 (0.80-10.9) .11 Other specific carcinomas 

5/9 HR 0.54 (0.18-1.62) .27 

Total carcinomas 59/104 HR 0.54 (0.39-0.75) <.001 Melanomas 8/8 HR 0.92 (0.34-2.45) .87 Leukemia/ lymphomas 

8/5 HR 1.50 (0.49-4.60) .48 

Other specific noncarcinomas 3/3 HR 0.99 (0.20-4.94) .99 Total noncarcinomas 19/16 HR 1.16 (0.60-2.27) .65 Total cancer 77/119 HR 0.61 (0.46-0.82) <.001 Total cancer mortality 

29/57 HR 0.48 (0.31-0.76) .001 

Lung cancer mortality 

12/25 HR 0.47 (0.23-0.93) .03 

Clark, 1996133

Other carcinoma mortality 

Selenium 653/659 

15/25 HR 0.56 (0.30-1.07) .08 

Clark, 1998134

Prostate cancer Selenium 479/495 13/35 RR 0.37 .002 
Appendix F: Evidence Tables 

F 67 

Evidence Table 3n. Results of studies of the efficacy of other single or paired nutrients in preventing chronic disease. (continu

Author, year Disease endpoint 

Study supplement 

Total Number in study (active/ placebo) 

Number of disease events (active/ placebo) 

Incidence of disease endpoint (arm1/arm2) 

Unadjusted estimates (95% CI) P-val

Cancer (continued) 

NPC (continued) 

Reid, 2002135 All lung cancer Selenium 621/629 25/35 0.063/0.085 RR 0.70 (0.40-1.21); HR 0.74 (0.44-1.24) .18 fo

RR; .2for HR 

Prostate Cancer 22/42 RR 0.51 (0.29-0.87) .009 Lung Cancer 25/35 RR 0.7 (0.4-1.21) .18 Colorectal Cancer 9/19 RR 0.46 (0.19-1.08) .055 Cancer mortality 40/66 RR 0.59 (0.39-0.89) .008 Head and neck cancer 

9/7 RR1.27 (0.42-4.01) .65 

Bladder cancer 10/8 RR 1.24 (0.44-3.61) .66 Esophageal cancer 2/5 RR 0.39 (0.04-2.41) .28 Breast 11/6 RR 1.82 (0.62-6.01) .24 Other specific carcinomas 

6/9 RR 0.66 (0.19-2.07) .44 

Melanomas 11/9 RR 1.21 (0.46-3.3) .68 

DuffieldLillico, 2003136

Leukemia/ lymphomas 

Selenium 621/629 

40/66 RR 1.32 (0.4-4.61) .62 

DuffieldLillico, 2002137

Prostate cancer Seleniu 457/470 22/42 RR 0.51 (0.29-0.88) .009 
Appendix F: Evidence Tables 

F 68 

Evidence Table 3n. Results of studies of the efficacy of other single or paired nutrients in preventing chronic disease. (continu

Author, year Disease endpoint 

Study supplement 

Total Number in study (active/ placebo) 

Number of disease events (active/ placebo) 

Incidence of disease endpoint (arm1/arm2) 

Unadjusted estimates (95% CI) P-val

Cancer (continued) 

Linxian General Population Study 

Retinol + zinc RR 0.96 (0.81-1.14) Riboflavin + niacin 

RR 1.04 (0.88-1.23) 

Gastric cancer incidence 

Vitamin C + molybdenum 

 539 total 

RR 1.10 (0.92-1.30) 

Retinol + zinc RR 1.07 (0.92-1.25) Riboflavin + niacin 

RR 0.86 (0.74-1.01) 

Esophageal cancer incidence 

Vitamin C + molybdenum 

640 total 

RR 1.06 (0.91-1.24) 

Retinol + zinc RR 1.03 (0.83-1.28) Riboflavin + niacin 

RR 1.00 (0.81-1.24) 

Stomach cancer death 

Vitamin C + molybdenum 

331 total 

RR 1.09 (0.88-1.36) 

Retinol + zinc RR .73 (0.49-1.08) Riboflavin + niacin 

RR .92 (0.63-1.35) 

Blot, 199367

Stomach cancer incidence (noncardia) 

Vitamin C + molybdenum 

331 total 

RR 1.21 (0.82-1.78) 

Other studies 

Yu, 1991139 Primary liver cancer Selenium 1444/1030 10/16 0.69% vs 1.26% <.05 
Appendix F: Evidence Tables 

F 69 

Evidence Table 3n. Results of studies of the efficacy of other single or paired nutrients in preventing chronic disease. (continu

Author, year Disease endpoint 

Study supplement 

Total Number in study (active/ placebo) 

Number of disease events (active/ placebo) 

Incidence of disease endpoint (arm1/arm2) 

Unadjusted estimates (95% CI) P-v

Cardiovascular Disease 

NPC 

CVD and cerebrovascular diseases mortality 

47/46 HR 0.96 (0.64-1.44) .83 

All other causes mortality 

32/26 HR 1.16 (0.69-1.95) .57 

Respiratory disease mortality 

14/11 HR 1.26 (0.57-2.77) .57 

Clark, 1996133

All cause mortality 108/129 HR 0.79 (0.61-1.02) .07 

Linxian General Population Study 

Retinol + zinc + riboflavin + niacin 

RR .85 (.61-1.18) 

Retinol + zinc + vitamin C + molybdenum 

RR .91 (.66-1.27) 

Riboflavin + niacin, vitamin C + molybdenum 

RR .78 (.55-1.09) 

Retinol + zinc RR .99 

(.84-1.18) 

Riboflavin + niacin 

RR .94 (.79-1.11) 

Mark, 199866

Stroke deaths 

Vitamin C + molybdenum 

NA 

RR 1.04 (.88-1.24) 

NA 
Appendix F: Evidence Tables 

F 70 

Evidence Table 3n. Results of studies of the efficacy of other single or paired nutrients in preventing chronic disease. (continu

Author, year Disease endpoint 

Study supplement 

Total Number in study (active/ placebo) 

Number of disease events (active/ placebo) 

Incidence of disease endpoint (arm1/arm2) 

Unadjusted estimates (95% CI) P-v

Eye Disease 

Linxian Cataract Study 

Retinol + zinc OR 1.08 (0.92-1.27) Riboflavin + niacin 

OR 1.08 (0.92-1.27) 

Sperduto, 199364

Cortical cataracts 

Vitamin C + molybdenum 

OR .92 (0.79-1.09) 

 NPC = Nutritional Prevention of Cancer Study Group; ARED = Age-related Eye Disease Study Group; OR = odds ratio; RR = relative risk; HR = haz

confidence interval; MVM = cum = cumulative; ANOVA = analysis of variance; py = person-years; AMD = age-related macular degeneration 
Appendix F: Evidence Tables 

F 71 

Evidence Table 3o. Total mortality in studies of the efficacy of other single or paired nutrients in preventing chronic disease

Author, year 

Disease endpoint Study supplement 

Total Number in study (active/ placebo) 

Number of disease events (active/ placebo) 

Incidence of disease endpoint (arm1/arm2) 

Unadjus(95% CI) 

Clark, 

1996133

All cause mortality 

 108/129 HR 0.79 Retinol + zinc RR 1.00 Riboflavin + niacin RR .98 (.

Mark, 

199866

Total mortality 

Vitamin C + molybdenum 

 NA 

RR 1.01 

NPC = Nutritional Prevention of Cancer Study Group 
Appendix F. Evidence Tables 

F 72 

Evidence Table 3p. Systematic reviews on calcium and/or vitamin D: supplement information. 

Author, Year Study aim Trials included, n 

Publication yrs (range of dates) 

Supplements/ other therapies in treated groups Chemical forms 

Range of daily doses 

Prevention of Bone Loss

Shea, 

200447

Assess effects of calcium supplementation on bone loss and postmenopausal women. 

10 1978-1998 Calcium

Vitamin D: - In 2 trials, (n=140), vitamin D given to both treatment & control groups. Exercise: In 2 trials (n=121), exercise prescribed for both treatment & control groups 

Calcium carbonate, Calcium gluconate ± lactate Calcium citrate ± malate, Calcium (salt form not stated. Vitamin D forms not stated. 

Ca carbonate 52000 mg Ca gluconate ± 1000 mg Ca c± malate 500-1000mg Ca(no salt) 501000mg Vitam300,000 IU at sof 1.5 yr study (=~550 IU/day) Vitamin D 400 

Papadimitriopoulos, 

200449

vitamin D in preventing osteoporosis in postmenopausal women with bone density in the normal or nearnormal range. 

25 total trials -10 of which involved vitamin D doses ≤2000 IU/day ("standard vit D"). Of these 10 trials, 4 measured BMD fracture reduction ± BMD changes, and 6 monitored BMD changes only. 

1980-1999 Vitamin D ± 

calcium 

Cholecalciferol (vitamin D3); 

Calcium salts not described 

Cholecalciferol 300-2000 IU; Calcium 377 m1000 mg; 

Mackerras, 

199752 Separate analyses of first- and 

second-year effects of calcium of bone mineral density in postmenopausal women 

8 1987-1995 Calcium; 

Milk Powder 

calcium carbonate, calcium citrate malate, lactogluconate, lactategluconate, combination, milk powder 

Ca carbonate 52000 mg; Ca lactate gluconate 10002000 mg; Ca citrate male500 mg Ca in milk pow1000 mg 
Appendix F. Evidence Tables 

F 73 

Evidence Table 3p. Systematic reviews on calcium and/or vitamin D: supplement information. (continued) 

Author, Year Study aim Trials included, n 

Publication yrs (range of dates) 

Supplements/ other therapies in treated groups Chemical forms 

Range of daily doses 

Prevention of Bone Loss & Fractures

Shea, 

200447

Assess effects of calcium supplementation on bone loss and fractures in postmenopausal women. 

5 1978-1998 Calcium 

Vitamin D 

Calcium carbonate, Calcium gluconate Calcium citrate Calcium (salt form not stated); Vitamin D formulations not described. 

Ca carb 1000-2mg Ca gluc 1000 mCalcium 1000 Calcium citrate 1600 mg 

Papadimitriopoulos, 

200449

vitamin D in preventing osteoporosis in postmenopausal women 

25 total trials, 10 eligible for our review. 4 of these 10 evaluiated fracture reduction. 

1980-1999 Vitamin D ± 

calcium 

Cholecalciferol (vitamin D3); 

Neither calcium nor phosphate salt forms described 

Cholecalciferol - 800 IU Calcium 300-1mg; Phosphate 600 

Avenell, 

2005143

Vitamin D for preventing fractures associated with involutional and post-menopausal osteoporosis 

Of total 38 trials, 11 eligible for our review (involved rx with vitamin D in doses <2000 IU (upper limit advised by the Food & Nutrition Board. 

1983-2005 Vitamin D ± 

calcium 

Cholecalciferol (vitamin D3); 

Ca carbonate; Tricalcium phosphate; Calcium lactate; Calcium 

Cholecalciferol 400-1000 IU; Calcium salts tprovide 500-12mg; 
Appendix F. Evidence Tables 

F 74 

Evidence Table 3q. Systematic reviews on calcium and/or vitamin D: participant characteristics 

Author, Year 

Inclusion/ exclusion criteria 

Treatment, n 

Controls, n 

Ca alone, n 

Ca + Vit D, n 

Ca + exercise, n 

Vit D alone, n 

Exercise alone, n 

Dietary calcium intake/ fall prevention, couseling 

PBO Total 

Range mean ages (SD) 

Prevention of Bone Loss 

Shea, 

200447

Inclusison: RCT;  PMP women >45 yrs old with amenorrhea ≥ 6 months; Treatment in which intervention was calcium supplementation or usual dietary calcium intake; Vit D supplementation ≤400 IU/day & equivalent in Rx & control grps. Exclusion: Males Calcium <400mg/d; Vit D rx >400 IU/d and/or that differed between rx & pbo groups; Trial duration <1 yr; BMD measured only at ultra-distal forearm site; BMD measurement by technique other than SPA, DPA, or DXA; Failure of contacted authors of eligible studies to provide requested data; A priori selected out-comes not included 

745 497 629 69 47 71 52 0 374 46-72

(0.6) 
Appendix F. Evidence Tables 

F 75 

Evidence Table 3q. Systematic reviews on calcium and/or vitamin D: participant characteristics (continued) 

Author, Year 

Inclusion/ exclusion criteria 

Treatment, n 

Controls, n 

Ca alone, n 

Ca + Vit D, n 

Ca + exercise, n 

Vit D alone, n 

Exercise alone, n 

Dietary calcium intake/ fall prevention, couseling 

PBO Total 

Range mean ages (SD) 

Prevention of Bone Loss (continued) 

Papadimitriopoulos, 

200449

Inclusion: PMP women >45 yrs old with amenorrhea ≥ 6 mos; included studies with interventions of vitamin D ± calcium and control grp intakes of vitamin D ≤100 IU/day ± 

calcum. Exclusion: Males; Women < 45 y/o and/or amenorrheic < 6 mos; vitamin D daily intake ≤400 IU/d; follow-up < 1 year;BMD (g/cm or g/cm2) not measured by single-photon absorptiometry, dualphoton absroptiometry, or dual x-ray absroptiometry in at least 1 of several designated sites (femoral neck, total hip, trochanter, lumbar spine, total body ,or combined forearm); reporting total number of fractures for a group as opposed to reporting fracture results on individual patients; studies that compared different types or doses of vitamin D 

445 511 373 387 NA 578 NA 0 275 49.9-

71.5 
Appendix F. Evidence Tables 

F 76 

Evidence Table 3q. Systematic reviews on calcium and/or vitamin D: participant characteristics (continued) 

Author, Year 

Inclusion/ exclusion criteria 

Treatment, n 

Controls, n 

Ca alone, n 

Ca + Vit D, n 

Ca + exercise, n 

Vit D alone, n 

Exercise alone, n 

Dietary calcium intake/ fall prevention, couseling 

PBO Total 

Range mean ages (SD) 

Prevention of Bone Loss (continued) 

Mackerras, 

199752

Inclusion: PMP women; any indication that study was randomized. Exclusion: report not in English; less than 2 years of follow-up; no group received calcium supplement or dairy products; no randomized control group; no intention-totreat analysis reported and/or reconstructable from the data given; a crossover study using subjects as their own controls; obviously nonrandomized studies; combination therapy arms involving calcium and another drug with known strong effects on bone; not postmenopausal women 

999 387 612 34 

Aloia study) 

75 36 35 352 352 51-66 
Appendix F. Evidence Tables 

F 77 

Evidence Table 3q. Systematic reviews on calcium and/or vitamin D: participant characteristics (continued) 

Author, Year 

Inclusion/ exclusion criteria 

Treatment, n 

Controls, n 

Ca alone, n 

Ca + Vit D, n 

Ca + exercise, n 

Vit D alone, n 

Exercise alone, n 

Dietary calcium intake/ fall prevention, couseling 

PBO Total 

Range mean ages (SD) 

Prevention of Fractures 

Shea, 

200447

Inclusion: PMP women >45 years old with amenorrhea ≥ 6 

months; Vit D supplementation ≤400 

IU & same in Rx & control groups Exclusion: Males; calcium <400mg/d; vit D rx >400 IU/d and/or that differed between rx & pbo groups; trial duration <1 yr; BMD measured only at ultra-distal forearm site; BMD measurement by technique other than SPA, DPA, or DXA; Failure of contacted authors of eligible studies to provide requested data; A priori selected outcomes not included 

270 279 270 0 0 0 0 279 279 50(2.8

to 73.(7.1) 
Appendix F. Evidence Tables 

F 78 

Evidence Table 3q. Systematic reviews on calcium and/or vitamin D: participant characteristics (continued) 

Author, Year 

Inclusion/ exclusion criteria 

Treatment, n 

Controls, n 

Ca alone, n 

Ca + Vit D, n 

Ca + exercise, n 

Vit D alone, n 

Exercise alone, n 

Dietary calcium intake/ fall prevention, couseling 

PBO Total 

Range mean ages (SD) 

Prevention of Fractures (continued) 

Papadimitriopoulos, 

200449

Inclusion: PMP women >45 yrs old with amenorrhea ≥ 6 mos; Included studies with interventions of vitamin D ± calcium and control grp intakes of vitamin D ≤100 IU/day ± 

calcum. Exclusion: Males; women < 45 y/o and/or amenorrheic < 6 mos; vitamin D daily intake ≤400 IU/d; follow-up < 1 year; BMD (g/cm or g/cm2) not measured by single-photon absorptiometry, dual-photon absroptiometry, or dual xray absoroptiometry in at least 1 of several designated sites (femoral neck, total hip, trochanter, lumbar spine, total body ,or combined forearm); reporting total number of fractures for a group as opposed to reporting fracture results on individual patients; studies that compared different types or doses of vitamin D. 

2892 2888 123 1636 

received vit D together with ca 1200 mg and phosphate 600 mg per day 

0 2210 0 2765 2765 49.9 t

84.0 
Appendix F. Evidence Tables 

F 79 

Evidence Table 3q. Systematic reviews on calcium and/or vitamin D: participant characteristics (continued) 

Author, Year 

Inclusion/ exclusion criteria 

Treatment, n 

Controls, n 

Ca alone, n 

Ca + Vit D, n 

Ca + exercise, n 

Vit D alone, n 

Exercise alone, n 

Dietary calcium intake/ fall prevention, couseling 

PBO Total 

Range mean ages (SD) 

Prevention of Fractures (continued) 

Avenell, 

2005143

Inclusion; Men & PMP women ≥ age 65; either community-living & institutionalized; Included trials whose subjects had previous fractures and neurologic disorders impairing mobility (e.g. Parkinson's); Included both randomized & pseudorandomized trials Exclusion; Women and men younger than 65 years of age; cognitive impairment;cancer within previous 10 yr of type likely to metastasize to bone; life expectancy <6 months; trials in which subjects were on glucocor- ticoid Rx; interventions that included agents other than vitamin D & calcium; disorders (e.g. nephrolithiasis, hyperparathyroidism) or drugs (e.g. bisphosphonates, HRT, vitamin D >200 IU/day) known to affect bone metabolism 

12653 15485 3918 9935 0 2718 0 7042 7042 52.7-8
Appendix F. Evidence Tables 

F 80 

Evidence Table 3q. Systematic reviews on calcium and/or vitamin D: participant characteristics (continued) 

Ca = calcium; vit = vitamin; PBO = placebo; SD = standard deviation; RCT = randomized controlled trial; PMP = post-menopausal; BMD = bone mi

photon absorbency; DPA = double-photon absorbency; DXA = dual x-ray absorbency 
Appendix F: Evidence Tables

F 81 

Evidence Table 3r. Systematic reviews on calcium and/or vitamin D for prevention of bone loss and fractures: efficacy measur

BMD Measurements Fracture Risk

Author, 

year 

Outcome Inter- vention BMD Site Trials (n) WMD (95% CI) 1

Heterogeneity 

p-value FX Site 

Trials (n) 

Weighted RR2

Hegep-

L-spine (2 y) 

9 (845) 

1.66 (0.92, 2.39) p<0.01 

0.02 Vert. 5 

(576) 

0.79 (0.55, 1.13) p= 0.14 

0.4

L-spine (3-4 y) 

2 (218) 

1.13 (-0.11, 2.38) p=0.07 

0.71 NonVert. 2 (222) 0.86 (0.43, 1.72) 

p=0.66 

0.

Combined hip 

8 (830) 

1.64 (0.70, 2.57) p<0.01 

0.04 

1/3 distal radius 

6 (615) 

1.91 (0.33, 3.50) p=0.02 

<0.01 

Shea, 

200447

Effect of calcium on BMD & FXs in PMP women. Followup 1 to 4 yr 

Calcium500-2000 mg/d ± Vit. D3

Total body 

4 (358) 

2.05 (0.24, 3.86) p=0.03 

<0.01 

L-spine (1 y) 

4 (563)) 

0.86 (0.17, 1.54) p=0.01 

0.10 Vert. 1 

(160) 

0.33 (0.01, 8.05) p= 0.49 

L-spine (2-5 y) 

4 (608) 

-0.40 (-2.06, 1.25) p=0.63 

<0.00 NonVert. 3 (5399) 0.78 (0.55, 1.09) 

p=0.15 

Femoral neck (1-5 y) 

5 (862) 0.98 (0.10, 1.85) p=0.03 0.22 

Combined forearm (1-2 y) 

5 (597) 

-0.48 (-1.18, 0.22) p=0.18 

0.42 

Papadimitriopoulos, 

200449

Effect of Vit. D on BMD & FXs in pmp women. Followup 1 to 5 yr 

Vit. D3, 300-2000 IU/day  ± Ca 

Total body (1-3 y) 

3 (508) 

0.40 (-0.25, 1.05) p=0.23 

<0.01 
Appendix F: Evidence Tables

F 82 

Evidence Table 3r. Systematic reviews on calcium for prevention of bone loss (upper panel) and vitamin D for prevention of falmeasures (continued) 

Year-by-year differences in rate of bone loss1 

Author, 

year 

Outcome Inter- vention BMD Site First yr (95% CI) Second yr (95% CI) 2 yr total 

L-spine 1.9 (0.9, 2.8) p<0.001 0.00 (-1.2, 1.1) p=1.0 1.9 (0.8, 2,9) p=0Femoral neck 2.2 (1.0, 3.5) p=0.001 0.1 (-1.4, 1.6) p=0.9 2.3 (1.0, 3.6) p=0Trochante 2.9 (1.5, 4.2) p<0.001 -0.4 (-2.0, 1.3) p=0.7 2.5 (1.1, 3.9) p=0.Distal forearm 0.9 (-1.2, 3.1) p=0.04 1.1 (-1.6, 3.7) p=0,04 1.9 (-0.3, 4.3) p=0

Mackerras, 

199752 Yearby-year 

effect of calcium on BMD in postmenopausal women. Followup 2 to 3 yr. 

Calcium, 500-2000 mg/d ± Vit. D3

400 IU/d 

Proximal forearm 2.1 (0.8, 3.4) p=0.002 0.5 (-1.0, 2.1) p=0.5 2.6 (1.3, 4.0) p=<
Appendix F: Evidence Tables

F 83 

Evidence Table 3r. Systematic reviews on calcium for prevention of bone loss (upper panel) and vitamin D for prevention of falmeasures (continued) 

Author, 

year Outcome 

Interventtion Trials (n) Corrected pooled odds ratio for prevention of falls by vitamin D supplementation Pooled risk difference 

5  (1237) 0.78 (95% CI 0.64-0.92) 7% (95% CI 2%-12%; p=0.00

NNT 15 (95% CI 8-53) 

Subgroup analysesTrials using vitamin D3 400-800 IU/day 

(active vitamin D trials excluded) 

Trials using only vitamin D3 8

IU/day (400 IU/day vitamin D trial excluded) 

No. of trials (n) 

Corrected odds ratio of falling No. of trials 

(n) 

Corrected odratio of falling

BischoffFerrari 

2004 

145 

Effect of vitamin D on falls in older persons. Follow-up 3 to 14 mos. 

Vit. D3, 400-800 IU/day  or active vitamin D (calcitriol or alpha calcidiol  ± Ca 800-1200/day 

3 (613) 

0.83 (95% CI 0.65,1.06) 2 (259) 

0.65 (95% C0.40,1.00) 
Appendix F: Evidence Tables

F 84 

Evidence Table 3r. Systematic reviews on calcium for prevention of bone loss (upper panel) and vitamin D for prevention of falmeasures (continued) 

Author, 

year Outcome 

Interventtion 

FX Site 

Daily Vitamin D dose 

Trials (n) 

Weighted RR2

(95% CI) 

Heterogeneity p-value Pooled Risk Difference 

Hip 400-800 

IU 

5 

(9294) 

0.88 (0.69, 1.13) 0.09 

Hip 700-800 

IU 

3 

(5572) 

0.74 (0.61, 0.88) 0.74 

Hip 400 IU 2 

(3722) 

1.15 (0.88,1.50) 0.68 

2% (95% CI, 1%-4%) p<0.001 (for treatment 2-5 y) 

Any nonvert. 

400-800 

IU 

7 

(9820) 

0.83 (0.70, 0.98) 0.07 

Any nonvert. 

700-800 

IU 

5 

(6098) 

0.77 (0.68, 0.87) 0.41 

BischoffFerrari 

200540

Effect of vitamin D in prevention of hip and nonvertebral fractures in older persons. Follow-up. 1.5 to 5 yrs 

Vit. D3

400-800 IU/day ± calcium, 500-1200 mg/d 

Any nonvert. 

400 IU 2 

(3722) 

1.03 (0.86, 1.24) 0.36 

4% (95% CI, 2%-5%) p=0.02 (for treatment 1-5 y) 
Appendix F: Evidence Tables

F 85 

Evidence Table 3r. Systematic review on vitamin D ± calcium for prevention of fractures in elderly people: efficacy measures (c

Fracture Risk

Hip Vertebral Non

Author, 

year

Intervention

# Trials (n) 

Weighted RR2

(95% CI) 

Heterogeneity p-value 

# Trials (n) 

Weighted RR2

(95% CI) 

Heterogeneity p-value 

# Trials (n) 

WeigRR2

(95% 

Vit. D vs placebo or control 

7 (18668) 

1.17 (0.98, 1.41) p=0.09 

0.67 4 

(5698) 

1.13 (0.50, 2.55) p=0.8 

0.08 8 (18903) 0.99 

1.09

Vit. D vs Ca 

2 (2739) 

1.08 (0.72, 1.51) p=0.7 

0.21 3 

(2997) 

2.76 (1.27-6.00) p=0.01 

0.72 3 

(2997) 

1.02 1.22p=0.

Vit. D + Ca vs placebo or control 

7 (10376) 

0.81 (0.68, 0.96) p=0.02 

0.66 2 (2708) 0.34 (0.01, 

8.34) p=0.50 

N/A 7 (10376) 0.87 

0.97 

Avenell, 

2005143

Vit. D + Ca vs Ca 

3 (6866) 

0.81 (0.60, 1.10) p=0.20 

0.50 2 

(2681) 

0.14 (0.01-2.77) p=0.2 

N/A 4 

(3061) 

0.96 1.16p=0.

1Weighted mean difference (WMD) in BMD (treated group – control group) using percentile change from baseline 2Aggregate estimate (Relative Risk (RR), 95% confidence interval (CI)) of risk of event with vs without supplement 

Abbreviations: BMD, bone mineral density; FX, fracture; pmp, postmenopausal; IU, international unit; Vert., vertebral; NA, not applicable 
F 86 

Evidence Table 3s. Randomized controlled trials on the efficacy of calcium and/or vitamin D in preventing chronic disease that 

previous systematic reviews: characteristics of studies 

Author, year 

Study name Nutrient(s) 

Study period 

Total sample size enrolled 

Mean/ median follow-up time 

Mean participant age 

Women, n (%) 

Jackson, 

2006146

WHI Calcium/ 

Vitamin D 

1993-1998 36,282 7 62.4 36,282 (100) 

WactawskiWende, 

2006152

WHI Calcium/ 

Vitamin D 

1993-1998 36,282 7 62.4 36,282 (100) 

Meier, 

2004147

 Calcium/ 

Vitamin D 

NS 55 Planned 2 

years 

56.2 29 (52.7) 

Hunter, 

2000148

 Calcium/ 

Vitamin D 

NS 158 Planned 2 

years 

58.7 158 (100) 

Storm, 

1998149

 Calcium NS 60 Planned 2 

years 

71 60 (100) 
Appendix F: Evidence Tables 

F 87 

Evidence Table 3t. Randomized controlled trials on the efficacy of calcium and/or vitamin D in preventing chronic disease that previous systematic reviews: characteristics of the intervention. 

Author, year Intervention Chemical form Dose/Frequency of use Timing of use 

Placebo Calcium Calcium Carbonate 500 mg 

Jackson, 2006146

Vitamin D Vitamin D3 200 IU 

2 x/day 

Placebo Calcium Calcium Carbonate 500 mg 

WactawskiWende, 2006152

Vitamin D Vitamin D3 200 IU 

2 x/day 

No treatment Calcium NS 500 mg 

Meier, 2004147

Vitamin D Cholecalciferol 500 IU 

1 x/day 

Hunter, 2000 Placebo 

148

Vitamin D Cholecalciferol 800 IU 

1 x/day 

Storm, 1998 Placebo 149

Calcium Calcium Carbonate 500 mg 

2x/day 
Appendix F: Evidence Tables 

F 88 

Evidence Table 3u. Randomized controlled trials on the efficacy of calcium and/or vitamin D in preventing chronic disease that 

previous systematic reviews: results 

Author, 

year 

Study supplement 

Total Number in study (active/ placebo) 

Main results 

Total number of disease events (active/ placebo) 

Hazard Ratio 

Mean % change in BMD 

Unadjusted estimates (95% CI) P-val

Jackson, 

2006146

Calcium/ Vitamin D 

18,176/ 18106 

Hip Fracture 175/199 0.88 0.72-1.08 

Wactawski

-Wende, 

2006152

Calcium/ Vitamin D 

18,176/ 18106 

Invasive Colorectal Cancer 

168/154 1.08 0.86-1.34 

Meier, 

2004147

Calcium/ Vitamin D 

30/25 Change in 

lumbar and hip BMD (Pretreatment vs post treatment) 

 Lumbar spine of 

treatment group: +0.8%; femoral neck of treatment group: +0.1%; No significant change in controls 

 Lumb

of treagroupFemoof treagroup

Hunter, 

2000148

Calcium/ Vitamin D 

79/79 Intrapair 

difference (treatment vs. control) change in Spine and Femoral neck BMD 

 Difference in Spine 

BMD: -0.001; Difference in Femur neck BMD: +0.003 

SD difference in spine – 0.046; SD difference in Femur neck – 0.033 

>.05 

Storm 

1998149

Calcium/ Vitamin D 

NR/NR Change in 

BMD over 2 years 

 Treatment FN BMD 

change +3%; Placebo FN BMD change –0.3%; Treatment GT BMD no sig diff change; Placebo –3%; Treatment Lumbar BMD change +3.7%; Placebo Lumbar BMD change no sig diff change 

 FN di

p=.1; differep=.05spine differep<.01 
Appendix F: Evidence Tables 

F 89 

Evidence Table 4a. Characteristics of the interventions in studies of the safety of vitamin A and/or beta-carotene supplements Author, year 

Control arm (duration of use) INTERVENTION ARMS 

Nutrient/supplement chemical form(s) Dose/Frequency of use Timing of 

Omenn,1994 

153 Placebo (10 years or until endpoint) Vitamin A; beta-carotene Retinol in pilot phase (1985-1988) then retinyl 

palmitate in Vanguard (1988-1996) 

25000 IU; 30 mg; 15 mg in asbestos pilot; 30 mg in one arm of smoker pilot; 30 mg in Vanguard cohort (1988-1996) 

1x per day 

Omenn,1996 

93 Placebo (10 years) Active Treatment (vitamin A; beta-carotene) Retinyl palmitate ; beta- carotene 25000 IU; 30 mg 1x per day 

Sibulesky, 

1999 77 Trace nutrients All-rac-alpha tocopherol; Retinyl palmitate; 3 IU (2.2 tocopherol equivalent); 75 IU (23 

retinol equivalent) 

1x per day 

Cartmel,1999

185 Placebo (3.8 years) Retinol; vitamin E; vitamin A Retinol; all-rac-alpha tocopherol; retinol 

palmitate 

7576 retinol equivalents; 3 IU (2.2 tocopherol equivalent); 4500 RE (15,000 IU) 

NS 

Goodman, 

1993 92 Placebo (3 years) Retinol; beta-carotene Retinol; beta-carotene 25000 IU; 30 mg 1x per day 

Xuan,1991 78 Vitamin A; beta-carotene; 

vitamin E; selenium 

Retinol; beta-carotene; dalpha-tocopherol; selenium yeast 

25,000 IU; 30 mg 1x per day 

Ragavan, 

1982 186 Vitamin A NS Up to 75,000 IU NS 

Stauber,1991

187 Vitamin A NS 0-47,000 IU NS (suppl

dietary int

Lee,199996 Placebo (2.1 years) Beta-carotene Beta-carotene 50 mg Every othe

Green,199984 Placebo (4.5 years) Beta-carotene Beta-carotene 30 mg 1x per day 

meals) 

Hennekens, 

1996 95

 Beta-carotene Beta-carotene 50 mg Every othe

Omenn,1993 

91 Placebo (3 years) Vitamin A/Beta-Carotene Retinol; beta-carotene 25000 IU; 15 mg 1x per day 

Micozzi,1988 

188 Placebo (constant and low total carotenoid content (0.5-

1.6 mg/d for 3000 kcal intake level)), (6 weeks) 

Vitamin A Retinol; beta-carotene 30 mg; 12 mg 1x per day 

meals) 
Appendix F: Evidence Tables 

F 90 

Evidence Table 4b. Results of studies with information on clinical adverse effects of vitamin A supplements in the prevention oAuthor, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type 

Statistical significance (p-value) Commen

Omenn,1994 

153

Beta carotene and/or retinol 

hypertriglyceridemia NA NA NA P<0.05 Actual d

were very 

Omenn,1996 

93

Beta carotene and/or retinol

NR NR NR NR NR 

Liver enzymes NA NA NS Symptoms (joint or bone pain, headaches, hairloss, erythema or scaly skin, unusually dry skin, desquamation, exfoliation, or eruption, red rash, unusually brittle or soft nails, lip fissures or chapping, nausea, diarrhea) 

3 13 Within ea

those withhad similathose with

Sibulesky, 

1999 77

Vitamin A 

Blood cell counts, chemistries, urine studies 

NR NR 

NR 

 Standard 

chemistriebetween g

Alopecia 7 3 Conjunctivitis 2 2 Epistaxis 2 1 Cheilitis 10 10 Dry skin 21 9 Exanthema 10 9 Peeling palms 3 0 Skin infection 0 0 Headaches 19 31 Fatigue 11 12 Stiffness 3 5 Dysuria 2 0 Menstrual changes 0 0 Nausea or vomiting 2 0 WBC abnormality 92 122 Liver enzymes abnormality 134 186 Cholesterol 65 97 Hemoglobin 267 298 

Cartmel,1999

185

Retinol 

Platelet count 7 7 

NR Not 

significant at 1, 13, 25, 37, 46 or 61 months 
Appendix F: Evidence Tables 

F 91 

Evidence Table 4b. Results of studies with information on clinical adverse effects of vitamin A and/or beta-carotene supplemenchronic diseases (continued) Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type 

Statistical significance (p-value) Commen

Yellowing of skin 1 0 Skin redness/dryness 14 19 Nosebleeds 4 0 Weight loss/appetite 5 6 Headaches 11 9 Anxiety/depression 21 15 Fatigue 13 13 Bone pain 14 13 Nausea/vomiting 1 0 Bowel movements 8 9 SGOT 0 2 

Goodman, 

1993 92

Retinol; betacarotene 

Alkaline phosphatase 0 1 

NR 

Hypercalcemia Muscle atrophy Total body alopecia Erosive dermatitis 

Xuan,1991 78 Vitamin A 

Psychiatric disturbances 

1 NA NA Case stud

Ragavan, 

1982 186 Vitamin A Liver function as measured by aspartate aminotransferase (AST) 

activity 

NA NA NA Retinyl es

the variabassociatioAST was (r=0.47). 

Stauber,1991

187 Vitamin A Liver function as measured by aspartate aminotransferase (AST) 

activity 

NA NA NA 0.0002 Retinyl es

the variab(Spearmar=0.34). 

Lee,199996 Betacarotene Yellowing of the skin 2131 1944 0.5 (0.24-1.03) 

Green,199984 Betacarotene Symptoms (not specified) 65 64 NR NS 

Hennekens, Skin yellowing 1745 1535 

1996 95

Betacarotene Minor gastrointestinal symptoms 

(e.g., belching) 

275 124 

NR 
Appendix F: Evidence Tables 

F 92 

Evidence Table 4b. Results of studies with information on clinical adverse effects of vitamin A and/or beta-carotene supplemenchronic diseases (continued) Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type 

Statistical significance (p-value) Commen

Increased alkaline phosphatase 1 1 Threshold level adverse symptoms 154 142 Text repo

overall ratsymptoms habits. 

Omenn,1993 

91

Vitamin A/Betacarotene 

Change in bowel habits NR NR 

NR 

 Text repo

different bdirection aspecified. 

Micozzi,1988 

189

Betacarotene Carotenodermia 5 1 NR Caroteno

physical eyellowing degrees breading. 

NR = Not reported; NS = Not significant; NA = Not applicable 
Appendix F: Evidence Tables 

F 93 

Evidence Table 4c. Results of studies with information on lipid profiles associated with the use of vitamin A and/or beta-caroteAuthor, year Nutrient 

Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Change in active group (indicate mean (95% CI)), mean (SD), mean (SE), median or other measurements 

Change in inactive group (indicate mean (95% CI)), mean (SD), mean (SE), median or other measurements 

Statistical significance (p-value) 

Omenn,1994 

153

Retinol; betacarotene 

Increased triglyceride levels 

NA NA Mean: 0 mg/dL after 

72 months 

Mean: -25 mg/dL after 72 months 

p<0.01 

Triacylglycerol Mean (95% CI): 

baseline: 1.42 mmol/L (1.35-1.48); 49 months: 1.77 mmol/L (1.69-1.85) 

Mean (95% CI): baseline: 1.38 mmol/L (1.32-1.45); 49 months: 1.59 mmol/L (1.52-1.66) 

HDL Mean (95% CI): 

baseline: 1.26 mmol/L (1.22-1.29); 49 months: 1.16 mmol/L (1.13-1.19) 

Mean (95% CI): baseline: 1.24 mmol/L (1.21-1.28); 49 months 1.17 mmol/L (1.14-1.20) 

Cartmel, 

1999185

Retinol 

LDL 

NA NA 

Mean (95% CI): baseline: 3.55 mmol/L (3.47-3.63); 49 months: 3.61 mmol/L (3.53-3.70) 

Mean (95% CI): baseline: 3.55 mmol/L (3.47-3.63); 49 months: 3.49 mmol/L (3.42-3.57) 

NA = Not applicable; NR = Not Reported; LDL = low-density lipoprotein; HDL = high-density lipoprotein; SD = Standard Deviation; SE = Standard 
Appendix F: Evidence Tables 

F 94 

Evidence Table 4d. Assessment of the likelihood that reported adverse effect were caused by use of a vitamin A and or beta-ca

Author, year Nutrient Adverse effect 

Temporal relationship 

Doseresponse relationship 

Adverse effects disappeared after discontinuation of supplementation 

Evidence of supplement use 

Lac

Omenn,1994 

153

Beta carotene and/or retinol 

hypertriglyceridemia Yes NR NR NR N

Omenn,1996 

93

Beta carotene and/or retinol

NR NA NA NA NA N

Sibulesky, 

1999 77

Vitamin A Liver enzymes Yes NR NR Yes N

Alopecia Conjunctivitis Epistaxis Cheilitis Dry skin Exanthema Peeling palms Skin infection Headaches Fatigue Stiffness Dysuria Menstrual changes Nausea or vomiting White blood cell count abnormality Liver enzymes abnormality Hemoglobin 

Cartmel, 

1999185

Retinol 

Platelet count 

Yes NR NR NR N
Appendix F: Evidence Tables 

F 95 

Evidence Table 4d. Assessment of the likelihood that reported adverse effect were caused by use of a vitamin A and or beta-ca(continued) 

Author, year Nutrient Adverse effect 

Temporal relationship 

Doseresponse relationship 

Adverse effects disappeared after discontinuation of supplementation 

Evidence of supplement use 

Lac

Yellowing of skin Skin redness/dryness Nosebleeds Weight loss/appetite Headaches Anxiety/depression Fatigue Bone pain Nausea/vomiting Bowel movements Serum glutamic oxaloacetic transaminase 

Goodman, 

1993 92

Retinol; betacarotene 

Alkaline phosphotase 

Yes No NR Yes N

Muscle cramps Diarrhea Poor appetite Runny nose Joint pain Chapping of lips/face Yellowing of skin Broken nails Hair loss Tingling in limbs Headache 

Xuan,1991 78 Vitamin A, 

betacarotene, Vitamin E, selenium 

Lethargy 

Yes NR NR Yes N

Hypercalcemia Muscle atrophy Total body alopecia Erosive dermatitis Psychiatric disturbances 

Ragavan, 

1982 186

Vitamin A 

Thyroid function 

 Yes Y

Stauber, 

1991187 Vitamin A Liver function as measured by aspartate aminotransferase activity Yes NR Yes No N
Appendix F: Evidence Tables 

F 96 

Evidence Table 4d. Assessment of the likelihood that reported adverse effect were caused by use of a vitamin A and or beta-ca(continued) 

Author, year Nutrient Adverse effect 

Temporal relationship 

Doseresponse relationship 

Adverse effects disappeared after discontinuation of supplementation 

Evidence of supplement use 

Lac

Lee,199996 Betacarotene Yellowing of the skin Yes NR NR Yes N

Green,1999 

84

Betacarotene Symptoms (not specified) NR NR NR NR N

Hennekens, Skin yellowing 

1996 95

Betacarotene Minor GI symptoms (e.g. belching) NR NR NR Yes N

Omenn,1993 

91

Vitamin A/betacarotene 

Increased alkaline phosphate Yes NR NR Yes N

Micozzi,1988 

188

Betacarotene Carotenodermia Yes Yes Yes Yes N

NR = Not reported 
Appendix F: Evidence Tables 

F 97 

Evidence Table 4e. Characteristics of the interventions in studies of the safety of vitamin E supplements Author, year 

Control arm (duration of use) INTERVENTION ARMS 

Nutrient/supplement chemical form(s) Dose/Frequency of use Timing of us

Lee,2005 87 Placebo (10.1 years) Vitamin E Alpha-tocopherol 600 IU every other d

McNeil,2004 

113 Vitamin E D-alpha-tocopherol 335 mg 1x per day 

de Gaetano, 

2001117 No vitamin E (3.6 months) Vitamin E Synthetic alpha tocopherol 300 mg 1x per day 

Trace nutrients All-rac-alpha tocopherol; 

Retinyl palmitate; 

3 IU (2.2 tocopherol equivalent); 75 IU (23 retinol equivalent) 

Sibulesky, 

1999 77

Treatment 2; treatment 3 D-alpha-tocopherol 1000 IU; 1500IU 

1x per day 

Xuan,1991 78 Vitamin A; beta-carotene; 

vitamin E; selenium 

Retinol; beta-carotene; dalpha-tocopherol; selenium yeast 

25000 IU; 30 mg; 50 mg; 800 IU; 400 mcg 

1x per day 

Simons,1996 

189 Placebo (soybean oil), (6 weeks) Treatment 1 (500IU/d) D-alpha-tocopherol 500 IU NS 

Tsai,1978 190 Placebo (4 weeks) Intervention - 

megavitamin E 

Dl-alpha-tocopherol acetate 

200 IU 3x per day (w

meals) 

 NS – Not specified 
Appendix F: Evidence Tables 

F 98 

Evidence Table 4f. Results of studies with information on clinical adverse effects of vitamin E supplements in the prevention o

Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects in inactive group, n (%) 

Point estimate in active group, indicate what type

Statistical significance (p-value) 

Lee,2005 87 Vitamin E Epistaxis NR NR 1.06 (1.01-1.11) 0.02 

McNeil,2004 Adverse events 351 327 

113

Vitamin E 

Major adverse event (death, disability, hospitalization) 

127 128 

NR 0.56 

Bleeding: gastrointestinal bleed; intracranial bleed; ocular bleed; epistaxis; other 

16; 11; 2; 1; 1; 14; 11; 0; 1; 1; 1 

Gastrointestinal disease other than bleed 

6 5 

de Gaetano, NA 

2001117

Vitamin E 

Other events 30 27 NR 0.003 

Liver enzymes NA NA Symptoms (joint or bone pain, headaches, hairloss, erythema or scaly skin, unusually dry skin, desquamation, exfoliation, or eruption, red rash, unusually brittle or soft nails, lip fissures or chapping, nausea, diarrhea)

3 13 

Sibulesky, 

199977

Vitamin E; vitamin A 

Blood cell counts, chemistries, urine studies 

NR NR 

Xuan,1991 78 Vitamin E, 

selenium 

Stroke 1 (vitamin E + 

selenium) 

1 (placebo) NR 

Nausea Increased bowel frequency 

Simons,1996 

189

Vitamin E 

Recurrent tenosynovitis in ankle 

1 0 NR 

Muscular weakness 13/17 (male/female) 12/14 

(male/female) 

Gastrointestinal disorder 0/6 (male/female) 0/0 (male/female) Worse work performance 4/6 (male/female) 4/4 (male/female) Worse sexuality 1/0 (male/female) 0/1 (male/female) Worse general well-being 5/10 (male/female) 5/6 (male/female) Serum cholesterol level NA NA 

Tsai,1978 190 Vitamin E 

Serum triglyceride level NA NA 

NR 

NR = Not reported; NS = Not significant; NA = Not applicable 
Appendix F: Evidence Tables 

F 99 

Evidence Table 4g. Assessment of the likelihood that reported adverse effect were caused by use of a vitamin E supplement 

Author, year Nutrient Adverse effect 

Temporal relationship 

Dose-response relationship 

Adverse effects disappeared after discontinuation of supplementation 

Evidence of supplement use 

Lee,2005 87 Vitamin E Epistaxis Yes NR NR NR 

McNeil,2004 Adverse events 

113

Vitamin E 

Major adverse event (death, disability, hospitalization) 

Yes NR NR Yes 

Bleeding: gi bleed; intracranial bleed; ocular bleed; epistaxis; other GI disease other than bleed 

de Gaetano, 

2001117

Vitamin E 

Other events 

Yes NR NR NR 

Liver enzymes Symptoms (joint or bone pain, headaches, hairloss, erythema or scaly skin, unusually dry skin, desquamation, exfoliation, or eruption, red rash, unusually brittle or soft nails, lip fissures or chapping, nausea, diarrhea) 

Sibulesky, 

1999 77

Vitamin A 

Blood cell counts, chemistries, urine studies 

Yes NR NR Yes 

Xuan,1991 

78

Vitamin E, selenium 

Stroke Yes NR NR Yes Nausea Increased bowel frequency 

Simons,1996 

189

Vitamin E 

Recurrent tenosynovitis in ankle 

Yes NR NR Yes 

Tsai,1978 190 Vitamin E Muscular weakness, 

gastrointestinal disorder, worse work performance, worse sexuality, worse general well-being, serum cholesterol level, serum triglyceride level 

Yes NR NR Yes 

 NR = Not reported 
Appendix F: Evidence Tables 

F 100 

Evidence Table 4h. Characteristics of the interventions in studies of the safety of other supplements Author, year 

Control arm (duration of use) INTERVENTION ARMS 

Nutrient/supplement Chemical form(s) Dose/Frequency of use Timing of us

Clark,1996 

133 Placebo (10 years) Selenium Selenium yeast 200 mcg NS 

Vitamin A Retinol 25000 IU; 30 mg Beta carotene Beta-carotene 50 mg Vitamin E D-alpha-tocopherol 800 Iu 

Xuan,1991 78

Selenium Selenium yeast 400 mcg 

1x per day 

Chelated iron (bis-glycino iron II) 

Coplin,1991 Bis-glycino iron chelate 191

Ferrous sulfate 

50 mg 1x per day (b

breakfast) 

Idjradinata, 

1994 159 Placebo (syrup), (4 month) Iron Ferrous sulfate 3 mg/kg NS 

MMWR,1993 

192

 Iron Ferrous sulfate 30-40 tablets of 325 

mg/tablet 

Accidental po

NS = Not specified 
Appendix F: Evidence Tables 

F 101 

Evidence Table 4i. Results of studies with information on clinical adverse effects of other supplements in the prevention of chr

Author, year Nutrient Adverse effect 

Adverse effects in supplement group, n (%) 

Adverse effects 

in inactive group, n (%) 

Point estimate in active group 

Statistical significance (p-value) C

Clark,1996 

133 Selenium Gastrointestinal upset 21 14 NR 

Xuan,1991 See comments See comments See comments 78 Vitamin E, selenium 

Stroke 1 (vitamin E + 

selenium) 

1 (placebo) 

NR S

s

Moderate-to-severe adverse symptoms (abdominal pain, bloating, constipation, diarrhea, nausea, vomiting, headache, fatigue) 

14 (ferrous sulfate) 8 (chelate form) T

hw

Abdominal pain 7 (ferrous) 9 (chelated) Bloating 10 (ferrous) 9 (chelated) Constipation 13 (ferrous) 13 (chelated) Diarrhea 9 (ferrous) 7 (chelated) Nausea 12 (ferrous) 9 (chelated) Vomiting 0 (ferrous) 0 (chelated) Gastrointestine 25 (ferrous) 23 (chelated) Headache 5 (ferrous) 7 (chelated) Fatigue 6 (ferrous) 6 (chelated) 

Coplin,1991 191 Iron 

Overall total 26 (ferrous) 25 (chelated) 

NR 

Idjradinata, 

1994 159 Iron Growth retardation (in wt gain, measured by kg 

every 2 weeks) 

NR NA NA M

egp(0

MMWR,1993 

192 Iron Deaths 5 NR NR P

Adverse symptoms causing drop-out, most commonly gastrointestinal upset (nausea, gas, indigestion) 

Ca 6, minerals 3, Ca and minerals 4 

Strause,1994 Placebo 3 

193

Calcium; trace minerals; calcium and minerals; placebo 

Drop-outs due to surgery, major illness, or death 

Ca 2, minerals 1, Ca and minerals 2 

Placebo 1 

NR 

NR = Not reported; NS = Not significant; NA = Not applicable
Appendix F: Evidence Tables 

F 102 

Evidence Table 4j. Assessment of the likelihood that reported adverse effects were caused by use of any other supplement 

Author, year Nutrient Adverse effect 

Temporal relationship 

Dose-response relationship 

Adverse effects disappeared after discontinuation of supplementation 

Evidence of supplement use 

Clark,1996 

133 Selenium Gastrointestinal upset Yes NR NR Yes 

Xuan,1991 78 Vitamin E, selenium Stroke Yes NR NR Yes 

Coplin,1991 191 Iron Moderate-to-severe adverse symptoms 

(abdominal pain, bloating, constipation, diarrhea, nausea, vomiting, headache, fatigue) 

NR NR NR NR 

Idjradinata, 

1994 159 Iron Growth retardation (in wt gain, measured by 

kg every 2 weeks) 

NR NR NR Yes 

Strause, 

1994 193

Calcium; trace minerals; calcium and minerals; placebo 

Adverse symptoms, most commonly GI upset (nausea, gas, indigestion) 

NR No NR No 

NR = Not reported 
Appendix G: List of Acronyms 

G 1 

List of Acronyms

AERS Adverse Event Reporting System 

AHRQ Agency for Healthcare Research and Quality 

AMD Age-related macular degeneration 

AREDS Age-Related Eye Disease Study 

ATBC Alpha-Tocopherol Beta-Carotene Cancer Prevention 

BCC Basal cell carcinomas 

BMD Bone mineral density 

BMI Body mass index 

CARET Βeta-Carotene and Retinol Efficacy Trial 

CENTRAL The Cochrane Central Register of Controlled Trials 

CFSAN Center for Food Safety and Applied Nutrition 

CI Confidence interval 

DRI Dietary reference intake 

DSHEA Dietary Supplement Health and Education Act 

EPC Evidence-based Practice Center 

FDA Food and Drug Administration 

GRAS Generally Recognized As Safe 

HR Hazard ratio 

IPO Percentage pixel opaque 

LOAEL Lowest-observed-adverse- effect level 

LOCS II Lens Opacities Classification System 

MeSH Medical Subject Heading 

MONMD Multi-center Ophthalmic and Nutritional Eye-Related Macular Degeneration Study 

NCSP Nambour Skin Cancer Prevention Trial 

NHANES National Health and Nutrition Examination Survey 

NIH National Institutes of Health 

NOAEL No-observed-adverse-effect level 

NPC Nutritional Prevention of Cancer 

OMAR Office of Medical Applications of Research 

OR Odds ratio 

PDF Portable document format 

PHS Physician’s Health Study 

PPP Primary Prevention Project 

RDA Recommended daily allowance 

RE Retinol equivalent 

REACT Roche European American Cataract Trial 

RR Relative risk 

SAM S-adenosylmethionine 

SCC Squamous cell carcinoma 

SCP Skin Cancer Prevention Study 

SELECT Selenium and Vitamin E Cancer Prevention Trial 

SU.VI.MAX Supplementation en Vitamines et Mineraux Antioxydants 

UF Uncertainty factor 

UL Tolerable upper level intake 

VECAT Vitamin E, Cataract, and Age-Related Maculopathy Trial 

VLDL Very low density lipoprotiens 

WHI Women’s Health Initiative study 

WHS Women’s Health Study