Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: results from a controlled trial (Finland) Calcium plus vitamin D supplementation and the risk of colorectal cancer. National Institutes of Health State-of-the-Science Conference Statement: Multivitamin/Mineral Supplements and Chronic Disease Prevention The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. Interaction between current vitamin D supplementation and menopausal hormone therapy use on breast cancer risk: evidence from the E3N cohort. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Dietary supplement use and mortality in a cohort of Swedish men. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL). Vitamin and Mineral Supplements: What Clinicians Need to Know. Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. B vitamin and/or ω-3 fatty acid supplementation and cancer: ancillary findings from the supplementation with folate, vitamins B6 and B12, and/or omega-3 fatty acids (SU.FOL.OM3) randomized trial. Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO) Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: a postintervention follow-up in the SU.VI.MAX Study. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Postmenopausal breast cancer risk and interactions between body mass index, menopausal hormone therapy use, and vitamin D supplementation: Evidence from the E3N cohort. Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial The modulation of prostate cancer risk with alpha-tocopherol: a pilot randomized, controlled clinical trial.
Summary of the Recommendations The U.S. Preventive Services Task Force ( USPSTF ) concludes 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 . This is a grade I recommendation . ( See Appendix Table 1 for a description of the USPSTF classification of recommendations . ) The USPSTF found poor evidence to determine whether supplementation with these vitamins reduces the risk for cardiovascular disease or cancer . ( See Appendix Table 2 for a description of the USPSTF classification of levels of evidence . ) The available evidence from r and omized trials is either inadequate or conflicting , and the influence of confounding variables on observed outcomes in observational studies can not be determined . As a result , the USPSTF could not determine the balance of benefits and harms of routine 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 USPSTF recommends against the use of beta-carotene supplements , either alone or in combination , for the prevention of cancer or cardiovascular disease . This is a grade D recommendation . The USPSTF found good evidence that -carotene supplementation provides no benefit in the prevention of cancer or cardiovascular disease in middle-aged and older adults . In two trials restricted to heavy smokers , -carotene supplementation was associated with higher incidence of lung cancer and higher all-cause mortality . The USPSTF concludes that -carotene supplements are unlikely to provide important benefits and might cause harm in some groups . Clinical Considerations The USPSTF did not review evidence regarding vitamin supplementation for patients with known or potential nutritional deficiencies , including pregnant and lactating women , children , elderly persons , and people with chronic illnesses .  Dietary supplements may be appropriate for people whose diet does not provide the recommended dietary intake of specific vitamins . Individuals may wish to consult a health care provider to discuss whether dietary supplements are appropriate . With the exception of vitamins for which there is compelling evidence of net harm ( for example , beta-carotene supplementation in smokers ) , there is little reason to discourage people from taking vitamin supplements . Patients should be reminded that taking vitamins does not replace the need to eat a healthy diet . All patients should receive information about the benefits of a diet high in fruits and vegetables , as well as information on other foods and nutrients that should be emphasized or avoided in their diet ( see the 2002 USPSTF recommendations on counseling to promote a healthy diet [ 1 ] ) . Patients who choose to take vitamins  should be encouraged to adhere to the dosages recommended in the Dietary Reference Intakes of the Institute of Medicine . Some vitamins , such as A and D , may be harmful in higher doses ; therefore , doses greatly exceeding the Recommended Dietary Allowance or Adequate Intake should be taken with care while considering whether potential harms outweigh potential benefits . Vitamins and minerals sold in the United States are classified as dietary supplements , and there is a degree of quality control over content if they have a U.S. Pharmacopeia seal ( 2 ) . Nevertheless , imprecision in the content and concentration of ingredients could pose a theoretical risk not reflected in clinical trials using calibrated compounds . The adverse effects of beta-carotene on smokers have been observed primarily in those taking large supplemental doses . There is no evidence to suggest that beta-carotene is harmful to smokers at levels occurring naturally in foods . The USPSTF did not review evidence supporting folic acid supplementation among pregnant women to reduce neural tube defects . In 1996 , the USPSTF recommended folic acid for all women who are planning , or capable of , pregnancy ( see the 1996 USPSTF chapter on screening for neural tube defects [ 3 ] ) . Clinicians and patients should discuss the possible need for vitamin supplementation when taking certain medications ( for example , folic acid supplementation for patients taking methotrexate ) . Scientific Evidence The USPSTF review s ( 4 - 6 ) focused on the quality of the evidence regarding the effect of routine supplementation with certain vitamins on primary prevention of cancer and cardiovascular disease . These review s were undertaken because of the growing epidemiologic evidence that dietary factors may play a role in the etiology of these diseases ( 7 - 9 ) . The review s focused on prospect i ve trials of vitamin supplementation and observational studies of associations between the use of specific supplements and the risk for cancer or cardiovascular disease . The value of vitamins naturally occurring in food , the use of vitamin supplements for the prevention of other conditions ( for example , neural tube defects ) , and the use of vitamin supplements for the secondary prevention of complications in patients with existing disease were outside the scope of these review s. Vitamin A No prospect i ve trials have examined the effect of vitamin A supplements alone on the risk for cancer . Observational studies provide no evidence that such supplements prevent cancer in men . In women , observational studies have reported a statistically significant inverse association between use of vitamin A supplements and risk for colon and breast cancer ( 10 , 11 ) . Despite efforts to adjust for confounding variables , the observational , nonr and om design of these studies makes it difficult to assess the extent to which the reduced cancer risk is attributable to vitamin A or to other characteristics of women who take vitamin A supplements .  No evidence from prospect i ve trials is available regarding the benefits of vitamin A alone in preventing cardiovascular disease . One good- quality cohort study found no effect of vitamin A supplementation in reducing cardiovascular disease mortality ( 12 ) . Vitamin C No primary prevention trial of the effect of vitamin C supplementation alone on cancer or cardiovascular disease has been reported . Observational studies have generally shown no statistically significant associations between use of vitamin C supplements and risk for cancer of the breast , prostate , colon , or lung ( 12 - 14 ) . The observational cohort studies examining the effects of vitamin C on cardiovascular disease have produced inconsistent results ( 12 , 15 , 16 ) . Vitamin E Only a few trials have examined the effects of vitamin E on the primary prevention of cancer or cardiovascular disease . A r and omized , controlled trial ( RCT ) involving Finnish male smokers found that vitamin E supplementation is not protective against lung cancer but may have a beneficial impact on prostate cancer ( 14 ) . Because prostate cancer was not a primary end point of the trial and the trial had other limitations , further evidence is needed to confirm this finding . Observational studies have shown no statistically significant association between use of vitamin E supplements and risk for prostate , lung , or breast cancer ( 5 ) . One study suggested that vitamin E protects against colon cancer , but the influence of confounding variables can not be fully excluded ( 17 ) . Among primary prevention trials , two good- quality trials ( 14 , 18 ) and one fair- quality trial ( 19 ) found no statistically significant benefit of vitamin E supplementation in preventing cardiovascular disease ( 20 ) . Only one of seven trials of vitamin E supplementation for secondary prevention demonstrated a statistically significant reduction in cardiac events ( 4 ) . Some prospect i ve cohort studies have suggested a significant benefit , but the results are mixed and the influence of confounding variables can not be excluded ( 4 ) . -Carotene A consistent body of evidence from clinical trials suggests that beta-carotene supplementation does not decrease the risk for lung , prostate , colon , breast , or nonmelanoma skin cancer ( 14 , 21 - 25 ) . -Carotene supplements were associated with an increased risk for lung cancer among smokers , especially heavy smokers , in two RCTs ( 14 , 25 ) . Results from four RCTs demonstrated no reduced risk for cardiovascular events or death after beta-carotene supplementation ( 14 , 21 , 22 , 26 - 28 ) . Antioxidant Vitamin Combinations Studies of the effects of antioxidant vitamin combinations to prevent cancer have yielded mixed results . A recent RCT reported no statistically significant effect of daily supplementation with a combination of antioxidants : vitamin E , vitamin C , and beta-carotene ( 29 ) . Some studies have suggested an adverse effect of antioxidant combinations on cancer , but the results may have been confounded by the inclusion of beta-carotene ( 5 ) . Some observational studies of antioxidant vitamin combinations have suggested a benefit in preventing cardiovascular disease ( 13 , 30 , 31 ) , but other studies , including well- design ed RCTs , have shown no benefit ( 29 , 32 , 33 ) . One secondary prevention trial showed an increase in all-cause mortality among women taking antioxidant supplements  ( 34 ) . Multiple Vitamin Combinations The incremental benefit of taking supplemental doses of folic acid and B vitamins has been examined by comparing the outcomes of observational studies while controlling for the total intake of antioxidant vitamin supplements ( 35 ) . In these analyses , folic acid supplementation was associated with significantly decreased risk for colon cancer , but the protective effect requires confirmation in prospect i ve trials . There is conflicting evidence regarding the use of multivitamins and the risk for cardiovascular disease . Among cohort studies , one good- quality study reported a statistically significant reduction in coronary events ( 36 ) , two good- quality studies reported no statistically significant effect on mortality ( 16 , 37 ) , and one BACKGROUND The General Population Nutrition Intervention Trial was a r and omized primary esophageal and gastric cancer prevention trial conducted from 1985 to 1991 , in which 29,584 adult participants in Linxian , China , were given daily vitamin and mineral supplements . Treatment with " factor D , " a combination of 50 microg selenium , 30 mg vitamin E , and 15 mg beta-carotene , led to decreased mortality from all causes , cancer overall , and gastric cancer . Here , we present 10-year follow-up after the end of active intervention . METHODS Participants were assessed by periodic data collection , monthly visits by village health workers , and quarterly review of the Linxian Cancer Registry . Hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) for the cumulative effects of four vitamin and mineral supplementation regimens were calculated using adjusted proportional hazards models . RESULTS Through May 31 , 2001 , 276 participants were lost to follow-up ; 9727 died , including 3242 from cancer ( 1515 from esophageal cancer and 1199 from gastric cancer ) . Participants who received factor D had lower overall mortality ( HR = 0.95 , 95 % CI = 0.91 to 0.99 ; P = .009 ; reduction in cumulative mortality from 33.62 % to 32.19 % ) and gastric cancer mortality ( HR = 0.89 , 95 % CI = 0.79 to 1.00 ; P = .043 ; reduction in cumulative gastric cancer mortality from 4.28 % to 3.84 % ) than subjects who did not receive factor D. Reductions were mostly attributable to benefits to subjects younger than 55 years . Esophageal cancer deaths between those who did and did not receive factor D were not different overall ; however , decreased 17 % among participants younger than 55 ( HR = 0.83 , 95 % CI = 0.71 to 0.98 ; P = .025 ) but increased 14 % among those aged 55 years or older ( HR = 1.14 , 95 % CI = 1.00 to 1.30 ; P = .047 ) [ corrected ] . Vitamin A and zinc supplementation was associated with increased total and stroke mortality ; vitamin C and molybdenum supplementation , with decreased stroke mortality . CONCLUSION The beneficial effects of selenium , vitamin E , and beta-carotene on mortality were still evident up to 10 years after the cessation of supplementation and were consistently greater in younger participants . Late effects of other supplementation regimens were also observed BACKGROUND Some epidemiological investigations suggest that higher intake or biochemical status of vitamin E and beta-carotene might be associated with reduced risk of colorectal cancer . METHODS We tested the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of colorectal cancer in the Alpha-Tocopherol , Beta-Carotene Cancer Prevention ( ATBC ) Study , a double-blind , placebo-controlled trial among 29,133 50 - 69-year-old male cigarette smokers . Participants were r and omly assigned to receive alpha-tocopherol ( 50 mg ) , beta-carotene ( 20 mg ) , both agents , or a placebo daily for 5 - 8 years . Incident colorectal cancers ( n = 135 ) were identified through the nationwide cancer registry , and 99 % were histologically confirmed . Intervention effects were evaluated using survival analysis and proportional hazards models . RESULTS Colorectal cancer incidence was somewhat lower in the alpha-tocopherol arm compared to the no alpha-tocopherol arm , but this finding was not statistically significant ( relative risk ( RR ) = 0.78 , 95 % confidence interval ( CI ) 0.55 - 1.09 ; log-rank test p = 0.15 ) . Beta-carotene had no effect on colorectal cancer incidence ( RR = 1.05 , 95 % CI 0.75 - 1.47 ; log-rank test p = 0.78 ) . There was no interaction between the two substances . CONCLUSION Our study found no evidence of a beneficial or harmful effect for beta-carotene in colorectal cancer in older male smokers , but does provide suggestive evidence that vitamin E supplementation may have had a modest preventive effect . The latter finding is in accord with previous research linking higher vitamin E status to reduced colorectal cancer risk BACKGROUND Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials . However , r and omized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking . METHODS We conducted a r and omized , double-blind , placebo-controlled trial involving 36,282 postmenopausal women from 40 Women 's Health Initiative centers : 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [ corrected ] twice daily ( 1000 mg of elemental calcium and 400 IU of vitamin D3 ) and 18,106 received a matching placebo for an average of 7.0 years . The incidence of pathologically confirmed colorectal cancer was the design ated secondary outcome . Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study . RESULTS The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo ( 168 and 154 cases ; hazard ratio , 1.08 ; 95 percent confidence interval , 0.86 to 1.34 ; P=0.51 ) , and the tumor characteristics were similar in the two groups . The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups . There were no significant treatment interactions with baseline characteristics . CONCLUSIONS Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer  among postmenopausal women . The long latency associated with the development of colorectal cancer , along with the seven-year duration of the trial , may have contributed to this null finding . Ongoing follow-up will assess the longer-term effect of this intervention . ( Clinical Trials.gov number , NCT00000611 . ) National Institutes of Health ( NIH ) consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1 ) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality ( AHRQ ) , 2 ) presentations by investigators working in areas relevant to the conference questions during a 2-day public session , 3 ) questions and statements from conference attendees during open discussion periods that are part of the public session , and 4 ) closed deliberations by the panel during the remainder of the second day and the morning of the third . This statement is an independent report of the panel and is not a policy statement of the NIH or the federal government . The statement reflects the panel 's assessment of medical knowledge available at the time the statement was written . Thus , it provides a snapshot in time of the state of knowledge on the conference topic . When reading the statement , keep in mind that new knowledge is inevitably accumulating through medical research . At least half of American adults take a dietary supplement , the majority of which are multivitamin/multimineral ( MVM ) supplements . As more and more Americans seek strategies for maintaining good health and preventing disease , and as the marketplace offers an increasing number of products to fulfill that desire , it is important that consumers have the best possible information to make their choices . Assessing the available scientific evidence on the benefits of MVM supplement use for chronic disease prevention , identifying the gaps in the evidence , and recommending an appropriate research agenda to meet the shortfalls are subjects considered in this report . The word vitamine was coined in 1912 , as an abbreviated term meant to capture the notion of important factors in the diet , or vital amines . This was preceded more than 150 years earlier by British navy physician James Lind 's discoveryin the first recorded controlled trialthat citrus juice , a good source of what was found 2 centuries later to be vitamin C , could prevent scurvy in sailors . In 1913 , the first vitamin was isolated : thiamin , the deficiency of which caused beriberi . Thirteen vitamins and 15 essential minerals have now been identified as important to human nutrition . Large-scale fortification of diets began in the United States with the addition of iodine to table salt in 1924 to prevent goiter , followed by the addition of vitamin D to milk in 1933 to prevent rickets and the addition of thiamin , riboflavin , niacin , and iron to flour in 1941 . Multivitamin/multimineral products providing more than vitamins A and D became available in pharmacies and grocery stores in the mid-1930s . In the early 1940s , the first MVM tablet was introduced . Although clinical deficiency of vitamins or minerals , other than iron , is now uncommon in the United States , growth in supplement use has accelerated rapidly with marketing spurred by cl aims some based on scientific studies that chronic conditions could be prevented or treated by supplement use . Annual sales of supplements to Americans are now reported at about $ 23 billion , a substantial share of which is spent on vitamins and minerals . Because of such widespread use of MVM , increasing public and medical confusion over apparently contradictory results from studies , and reports of possible adverse effects from overuse in certain circumstances , the Office of Dietary Supplements and the Office of Medical Applications of Research of the NIH convened a State-of-the-Science Conference on Multivitamin/Mineral Supplements and Chronic Disease Prevention , held on 1517 May 2006 , in Bethesda , Maryl and . The goal of the conference was to assess the evidence available on MVM use and outcomes for chronic disease prevention in the generally healthy population of adults and to make recommendations for future research . The conference focused on vitamins and minerals and did not deal with botanicals , hormones , or other supplements . It also did not address the treatment of vitamin or mineral deficiencies . Except for considerations of safety , the conference also did not review issues of primary relevance to pregnant women or children . Specifically , the conference explored the following key questions : 1 ) What are the current patterns and prevalence of the public 's use of MVM supplements ? 2 ) What is known about the dietary nutrient intake of MVM users versus nonusers ? 3 ) What is the efficacy of single vitamin/mineral supplement use in chronic disease prevention ? 4 ) What is the efficacy of MVM  in chronic disease prevention in the general population of adults ? 5 ) What is known about the safety of MVM  for the generally healthy population ? and 6 ) What are the major knowledge gaps and research opportunities regarding MVM use ? During the first 2 days of the conference , experts presented information on each of the key questions . After weighing the scientific evidence , including the data presented by the speakers and a formal evidence report commissioned through AHRQ , an independent panel prepared and presented a draft of this state-of-the-science statement addressing the conference questions . The evidence report prepared for the conference is available at www.ahrq.gov/clinic/tp/multivittp.htm . For the purpose of this statement , the term MVM refers to any supplement containing 3 or more vitamins and minerals but no herbs , hormones , or drugs , with each component at a dose less than the tolerable upper level determined by the Food and Nutrition Boardthe maximum daily intake likely to pose no risk for adverse health effects . Our review also included studies of the relationship of single-nutrient supplements and 2-nutrient supplements to certain disease outcomes . The term primary prevention refers to preventing the development of disease in a person who does not have the disease in question . The chronic conditions assessed include cancer ; age-related sensory loss ; and cardiovascular , endocrine , neurologic , musculoskeletal , gastroenterologic , renal , and pulmonary diseases . A word is warranted about the nature of the evidence base considered by the panel . The range of vitamins and minerals of possible interest was so broad that the conference planning committee chose to focus the evidence report on nutrients for which the potential for impact had been most strongly suggested and on conditions for which supplements were thought to have the most potential influence . The planning committee also limited the scope of the evidence report to consideration of r and omized , controlled trials ( RCTs ) , which are generally considered the gold st and ard for evidence -based decision making . These are studies in which participants are allocated by chance alone to receive or not to receive 1 of 2 or more clinical interventions . For example , while folate supplementation was initially shown to decrease the risk for neural tube defects in animal studies , outcome data in nonhuman models were not considered sufficient evidence on which to base policy recommendations . At the next level of evidence , observational studies in humans suggested efficacy of folate supplementation to prevent such defects . However , these were criticized because they were not r and omized and were potentially subject to bias . Not until these findings were confirmed by RCTs in humans was public policy implemented , including fortification of cereal grains with folate . An observational study is one in which the exposure or treatment of interest is not assigned to the participant by the investigator . Such studies suggested that -carotene intake might protect against the development of some types of cancer . However , RCTs of -carotene supplementation not only showed no benefit , they also found an increased risk for lung cancer in persons who smoked cigarettes or who were exposed to asbestos . These examples illustrate both the risk of relying only on observational studies and the advantage of RCTs in identifying both benefits and risks of MVM supplementation . Limiting the focus of our statement to RCTs has some inherent limitations , given the potential of other types of studies to provide important insights . Observational studies , for example , are particularly useful for generating hypotheses , defining adverse effects , and documenting long-term treatment consequences . They are often essential precursors to the well-conducted RCTs important for policy formation . Our principal recommendations focus on the compelling research activities that must be supported to better inform the decisions that millions of Americans are making each day to use or not to use MVM supplements to prevent chronic disease . At the same time , mindful of the constraints of the available evidence base , we have also taken care not to make premature recommendations about whether generally healthy Americans should or should not take MVM supplements . Because of the need for more reliable information on MVMs , we have made strong recommendations for research and for increased U.S. Food and Drug Administration ( FDA ) oversight of the MVM industry . 1 . What Are the Current Patterns and Prevalence of the Public 's Use of MVM Supplements ? More than half of American adults take dietary supplements in the belief that they will make them feel better , give them greater energy , improve their health , and prevent and treat disease . The use of supplements has been steadily increasing , and growth appears likely to continue . Currently , users spend more than $ 23 billion per year on supplements , and among this supplement-using population , MVM is the major category of supplements , used by about one third of Americans . Uncertainty remains in estimating prevalence of use because of problems defining these products ; increasing complexity in the formulation of supplements , including more non-MVM components and specialized formulas ; and varying frequency of use . It appears that use is higher BACKGROUND Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables , as well as high serum levels of vitamin E ( alpha-tocopherol ) and beta carotene , are associated with a reduced risk of lung cancer .  METHODS We performed a r and omized , double-blind , placebo-controlled primary -prevention trial to determine whether daily supplementation with alpha-tocopherol , beta carotene , or both would reduce the incidence of lung cancer and other cancers .  A total of 29,133 male smokers 50 to 69 years of age from southwestern Finl and were r and omly assigned to one of four regimens : alpha-tocopherol ( 50 mg per day ) alone , beta carotene ( 20 mg per day ) alone , both alpha-tocopherol and beta carotene , or placebo . Follow-up continued for five to eight years . RESULTS Among the 876 new cases of lung cancer diagnosed during the trial , no reduction in incidence was observed among the men who received alpha-tocopherol ( change in incidence as compared with those who did not , -2 percent ; 95 percent confidence interval , -14 to 12 percent ) . Unexpectedly , we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not ( change in incidence , 18 percent ; 95 percent confidence interval , 3 to 36 percent ) . We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer . Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not . Beta carotene had little or no effect on the incidence of cancer other than lung cancer . Alpha-tocopherol had no apparent effect on total mortality , although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not . Total mortality was 8 percent higher ( 95 percent confidence interval , 1 to 16 percent ) among the participants who received beta carotene than among those who did not , primarily because there were more deaths from lung cancer and ischemic heart disease . CONCLUSIONS We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene . In fact , this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects BACKGROUND Experimental studies suggest protective effects of vitamin D on breast carcinogenesis , particularly on estrogen receptor-positive tumors . Epidemiologic data are less conclusive . OBJECTIVE Our objective was to investigate the association between postmenopausal breast cancer risk and current or past vitamin D supplementation overall and according to the use of menopausal hormone therapy ( MHT ) . DESIGN Between 1995 and 2008 , 2482 invasive breast cancer cases were diagnosed among 57,403 postmenopausal women from the E3N prospect i ve cohort during 581,085 person-years .  Vitamin D supplementation was assessed from biennially self-administered question naires sent in 1995 , 2000 , 2002 , and 2005 and from medico-administrative data on drug reimbursements since 2004 . Multivariable HRs for primary invasive breast cancer and 95 % CIs were estimated by using Cox models . RESULTS A decreased postmenopausal breast cancer risk was associated with current ( HR : 0.82 ; 95 % CI : 0.69 , 0.97 ) but not past ( HR : 1.10 ; 95 % CI : 0.92 , 1.31 ) vitamin D supplementation ( P-homogeneity = 0.02 ) . The association with current vitamin D supplementation  differed according to MHT use : ever users ( HR : 0.74 ; 95 % CI : 0.60 , 0.90 ) and never users ( HR : 1.13 ; 95 % CI : 0.89 , 1.56 ) ; P-homogeneity = 0.02 . CONCLUSIONS In this observational study , current vitamin D supplementation , mostly taken daily and combined with calcium , was associated with a decreased postmenopausal breast cancer risk in MHT users . These findings should be confirmed before considering vitamin D supplementation to partly balance the MHT-associated increased breast cancer risk BACKGROUND Cases of enhanced anticoagulant effect in response to high-dose vitamin E supplementation have been reported among patients taking oral anticoagulants .  Although a vitamin E-vitamin K interaction was proposed to underlie this effect , it has not been systematic ally investigated in adults with normal baseline coagulation status . OBJECTIVE The objective was to study the effect of 12 wk of supplementation with 1000 IU RRR-alpha-tocopherol/d on biochemical measures of vitamin K status in men and women not taking oral anticoagulants . DESIGN  Vitamin K status , which was assessed with the use of plasma phylloquinone concentrations , the degree of under-gamma-carboxylation of prothrombin ( proteins induced by vitamin K absence-factor II , PIVKA-II ) , and the percentage of undercarboxylated osteocalcin ( ucOC ) , was determined in 38 men and women with rheumatoid arthritis ( study A ) and in 32 healthy men ( study B ) participating in 2 independent , 12-wk r and omized clinical trials of vitamin E supplementation ( 1000 IU/d ) . RESULTS Mean ( + /- SD ) PIVKA-II increased from 1.7 + /- 1.7 to 11.9 + /- 16.1 ng/mL ( P < 0.001 ) in study A and from 1.8 + /- 0.6 to 5.3 + /- 3.9 ng/mL ( P < 0.001 ) in study B in response to 12 wk of vitamin E supplementation . An increase in PIVKA-II is indicative of poor vitamin K status . In contrast , the other measures of vitamin K status ( ie , plasma phylloquinone concentration and percentage of ucOC ) did not change significantly in response to the supplementation . CONCLUSIONS High-dose vitamin E supplementation increased PIVKA-II in adults not receiving oral anticoagulant therapy . The clinical significance of these changes warrants further investigation , but high doses of vitamin E may antagonize vitamin K. Whether such an interaction is potentially beneficial or harmful remains to be determined The use of dietary supplements has increased substantially in most industrialized countries . The aim of this study was to prospect ively examine the association between use of dietary supplements and  all-cause mortality , cancer mortality and CVD mortality in men . We used the population -based prospect i ve cohort of 38 994 men from central Sweden , 45 - 79 years of age , with no cancer or CVD at baseline and who completed a self-administered FFQ including questions on dietary supplement use and life-style factors in 1997 . During average 7.7 years of follow-up , 3403 deaths were ascertained ; among them , 771 due to cancer and 930 due to CVD ( during 5.9 years of follow-up ) . In multivariate adjusted models including all men there was no association observed between use of any dietary supplement or of multivitamins , vitamin C , vitamin E or fish oil specifically and all-cause mortality , cancer or CVD mortality . Among current smokers , regular use of any supplement was associated with statistically significant increased risk of cancer mortality : relative risk ( RR ) 1.46 ( 95 % CI 1.06 , 1.99 ) . Among men reporting an inadequate diet at baseline ( assessed by Recommended Food Score ) , there was a statistically significant inverse association between use of any dietary supplement and CVD mortality ( RR 0.72 ; 95 % CI 0.57 , 0.91 ) , no associations were observed among men with adequate diets . In conclusion , we can not exclude that the use of dietary supplements is harmful for smokers . On the other h and , among men with an insufficient diet , the use of supplements might be beneficial in reducing CVD mortality BACKGROUND A number of vitamins and minerals have been shown to influence carcinogenesis in experimental animals . In humans , epidemiologic evidence suggests that intake of fruits and vegetables may reduce risk of esophageal and other cancers . Vitamins and minerals in these foods may contribute to the reduced cancer risk . The people of Linxian , China , have persistently low intake of multiple nutrients and exhibit one of the world 's highest rates of esophageal/gastric cardia cancer , with an exceptionally high risk of esophageal dysplasia . PURPOSE To determine whether supplementation with multiple vitamins and minerals may reduce esophageal/gastric cardia cancer among persons with esophageal dysplasia , we conducted a 6-year prospect i ve intervention trial in Linxian . METHODS Mortality and cancer incidence were ascertained from May 1985 through May 1991 for 3318 persons with cytologic evidence of esophageal dysplasia who were r and omly assigned to receive , throughout that period , daily supplementation with 14 vitamins and 12 minerals or placebo . Doses were typically two to three times U.S. Recommended Daily Allowances . Compliance was assessed by counting unused pills monthly for all trial participants and by assaying nutrient levels in blood collected from sample s of individuals r and omly selected without replacement every 3 months throughout the trial . Cancers were identified through routine surveillance and by special cytology and endoscopy screenings after 2 1/2 years and 6 years . RESULTS A total of 324 deaths occurred during the 6-year intervention period ; 167 occurred in the control ( placebo ) group and 157 occurred in the  supplement  group . Cancer was the leading cause of death ( 54 % of all deaths ) ; 18 % were due to cerebrovascular diseases and 29 % to other causes . Cumulative esophageal/gastric cardia death rates were 8 % lower ( relative risk [ RR ] = 0.92 ; 95 % confidence interval [ CI ] = 0.67 - 1.28 ) among individuals receiving supplements rather than placebo , a nonsignificant ( P > .10 ) difference . Risk of total mortality was 7 % lower ( RR = 0.93 ; 95 % CI = 0.75 - 1.16 ; P > .10 ) , total cancer 4 % lower ( RR = 0.96 ; 95 % CI = 0.71 - 1.29 ; P > .10 ) , cerebrovascular disease 38 % lower ( RR = 0.62 ; 95 % CI = 0.37 - 1.06 ; P = .08 ) , and other diseases 12 % higher ( RR = 1.12 ; 95 % CI = 0.74 - 1.69 ; P > .10 ) among the treated group . Cumulative cancer incidence rates were nearly the same in the two groups . CONCLUSIONS No substantial short-term beneficial effect on incidence or mortality for this type of cancer occurred following daily supplementation with multiple vitamins and minerals among adults with precancerous lesions of the esophagus . IMPLICATION S Although no statistically significant short-term benefits were observed , longer follow-up should be more informative about the effectiveness of this 6-year supplementation on cancer and other diseases among individuals with esophageal dysplasia Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease ( CVD ) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention . The VITamin D and Omega-A 3 TriaL ( VITAL ) is an ongoing nationwide , r and omized , double-blind , placebo-controlled clinical trial design ed to fill this knowledge gap . The study population consists of 25,874 U.S. adults without cancer or CVD at baseline , who were selected only on age ( men aged ≥50 and women aged ≥55 ) , with an oversampling of African Americans ( n=5,107 ) . In a 2 × 2 factorial design , participants were r and omized to one of four supplement groups : [ 1 ] active vitamin D3 ( cholecalciferol ; 2000 IU/d ) and active marine omega-3 fatty acids ( Omacor ® fish oil , eicosapentaenoic acid [ EPA ] and docosahexaenoic acid [ DHA ] , 1g/d ) ; [ 2 ] active vitamin D and omega-3 placebo ; [ 3 ] vitamin D placebo and active marine omega-3 fatty acids ; or [ 4 ] vitamin D placebo and omega-3 placebo . The mean length of the r and omized treatment period will be 5 years . The r and omization was successful , as evidence d by similar distributions of baseline demographic , health , and behavioral characteristics across treatment groups . The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed . VITAL is expected to provide important information on the benefit-risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD Dietary supplementation is approximately a $ 30 billion industry in the United States , with more than 90 000 products on the market . In recent national surveys , 52 % of US adults reported use of at least 1 supplement product , and 10%reporteduseofatleast4suchproducts.1 Vitamins and minerals are among the most popular supplements and are taken by 48 % and 39 % of adults , respectively , typically to maintain health and prevent disease . Despite this enthusiasm , most r and omized clinical trials of vitamin and mineral supplements have not demonstrated clear benefits for primary or secondary prevention of chronic diseases not related to nutritional deficiency . Indeed , some trials suggest that micronutrient supplementation in amounts that exceed the recommended dietary allowance (RDA)—eg , high doses of beta carotene , folic acid , vitamin E , or selenium — may have harmful effects , including increased mortality , cancer , and hemorrhagic stroke.2 In this Viewpoint , we provide information to help clinicians address frequently asked questions about micronutrient supplements from patients , as well as promote appropriate use and curb inappropriate use of such supplements among generally healthy individuals . Importantly , clinicians should counsel their patients that such supplementation is not a substitute for a healthful and balanced diet and , in most cases , provides little if any benefit beyond that conferred by such a diet . Clinicians should also highlight the many advantages of obtaining vitamins and minerals from food instead of from supplements . Micronutrients in food are typically better absorbed by the body and are associated with fewer potential adverse effects.2,3 A healthful diet provides an array of nutritionally important substances in biologically optimal ratios as opposed to isolated compounds in highly concentrated form . Indeed , research shows that positive health outcomes are more strongly related to dietary patterns and specific food types than to individual micronutrient or nutrient intakes.3 Although routine micronutrient supplementation is not recommended for the general population , targeted supplementation may be warranted in high-risk groups for whom nutritional requirements may not be met through diet alone , including people at certain life stages and those with specific risk factors ( discussed in the next 3 sections and in the Box ) RATIONALE Lung cancer is the leading cause of cancer-related mortality in the United States . Although supplements are used by half the population , limited information is available about their specific effect on lung cancer risk . OBJECTIVES To explore the association of supplemental multivitamins , vitamin C , vitamin E , and folate with incident lung cancer . METHODS Prospect i ve cohort of 77,721 men and women aged 50 - 76 years from Washington State in the VITAL ( VITamins And Lifestyle ) study . Cases were identified through the Seattle-Puget Sound SEER ( Surveillance , Epidemiology , and End Results ) cancer registry . MEASUREMENTS AND MAIN RESULTS Hazard ratios ( HRs ) for incident lung cancer according to 10-year average daily use of supplemental multivitamins , vitamin C , vitamin E , and folate . A total of 521 cases of lung cancer were identified . Adjusting for smoking , age , and sex , there was no inverse association with any supplement . Supplemental vitamin E was associated with a small increased risk of lung cancer ( HR , 1.05 for every 100-mg/d increase in dose ; 95 % confidence interval [ CI ] , 1.00 - 1.09 ; P = 0.033 ) . This risk of supplemental vitamin E was largely confined to current smokers ( HR , 1.11 for every 100-mg/d increase ; 95 % CI , 1.03 - 1.19 ; P < 0.01 ) and was greatest for non-small cell lung cancer ( HR , 1.07 for every 100-mg/d increase ; 95 % CI , 1.02 - 1.12 ; P = 0.004 ) . CONCLUSIONS Supplemental multivitamins , vitamin C , vitamin E , and folate were not associated with a decreased risk of lung cancer .  Supplemental vitamin E was associated with a small increased risk . Patients should be counseled against using these supplements to prevent lung cancer BACKGROUND To advance knowledge about the cancer-chemopreventive potential of individual nutrients , we investigated the effects of B vitamin and /or ω-3 fatty acid supplements on cancer outcomes among survivors of cardiovascular disease . METHODS This was an ancillary study of the Supplementation With Folate , Vitamins B(6 ) and B(12 ) and /or Omega-3 Fatty Acids ( SU.FOL.OM3 ) secondary prevention trial ( 2003 - 2009 ) . In all , 2501 individuals aged 45 to 80 years were r and omized in a 2 × 2 factorial design to one of the following 4 daily supplementation groups : ( 1 ) 5-methyltetrahydrofolate ( 0.56 mg ) , pyridoxine hydrochloride ( vitamin B(6 ) ; 3 mg ) and cyanocobalamin ( vitamin B(12 ) ; 0.02 mg ) ; ( 2 ) eicosapentaenoic and docosahexaenoic acid ( 600 mg ) in a 2:1 ratio ; ( 3 ) B vitamins and ω-3 fatty acids ; or ( 4 ) placebo .  Overall and sex-specific hazard ratios ( HRs ) and 95 % CIs regarding the cancer outcomes were estimated with Cox proportional hazards models . RESULTS After 5 years of supplementation , incident cancer was vali date d in 7.0 % of the sample ( 145 events in men and 29 in women ) , and death from cancer occurred in 2.3 % of the sample . There was no association between cancer outcomes and supplementation with B vitamins ( HR , 1.15 [ 95 % CI , 0.85 - 1.55 ] ) and /or ω-3 fatty acids ( HR , 1.17 [ 95 % CI , 0.87 - 1.58 ] ) . There was a statistically significant interaction of treatment by sex , with no effect of treatment on cancer risk among men and increased cancer risk among women for ω-3 fatty acid supplementation ( HR , 3.02 [ 95 % CI , 1.33 - 6.89 ] ) . CONCLUSION We found no beneficial effects of supplementation with relatively low doses of B vitamins and /or ω-3 fatty acids on cancer outcomes in individuals with prior cardiovascular disease . Trial Registration is rct n.org Identifier : IS RCT N41926726 Introduction Optimal vitamin D status promotes skeletal health and is recommended with specific treatment in individuals at high risk for fragility fractures . A growing body of literature has provided indirect and some direct evidence for possible extraskeletal vitamin D-related effects . Purpose and Methods Members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis have review ed the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases , providing recommendations and guidelines for future studies in this field . Results and conclusions Robust mechanistic evidence is available from in vitro studies and in vivo animal studies , usually employing cholecalciferol , calcidiol or calcitriol in pharmacologic rather than physiologic doses . Although many cross-sectional and prospect i ve association studies in humans have shown that low 25-hydroxyvitamin D levels ( i.e. , < 50 nmol/L ) are consistently associated with chronic diseases , further strengthened by a dose-response relationship , several meta-analyses of clinical trials have shown contradictory results . Overall , large r and omized controlled trials with sufficient doses of vitamin D are missing , and available small to moderate-size trials often included people with baseline levels of serum 25-hydroxyvitamin D levels  > 50 nmol/L , did not simultaneously assess multiple outcomes , and did not report overall safety ( e.g. , falls ) . Thus , no recommendations can be made to date for the use of vitamin D supplementation in general , parental compounds , or non-hypercalcemic vitamin D analogs in the prevention and treatment of extra-skeletal chronic diseases . Moreover , attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health can not be recommended based on current evidence , since safety has yet to be confirmed . Finally , the promising findings from mechanistic studies , large cohort studies , and small clinical trials obtained for autoimmune diseases ( including type 1 diabetes , multiple sclerosis , and systemic lupus erythematosus ) , cardiovascular disorders , and overall reduction in mortality require further confirmation The Supplementation in Vitamins and Mineral Antioxidants Study was a double-blind , placebo-controlled , r and omized trial , in which 12,741 French adults ( 7,713 women aged 35 - 60 years and 5,028 men aged 45 - 60 years ) received a combination of ascorbic acid ( 120 mg ) , vitamin E ( 30 mg ) , beta-carotene ( 6 mg ) , selenium ( 100 microg ) and zinc ( 20 mg ) , or placebo daily for a median follow-up time of 7.5 years [ October 1994 to September 2002 ] . Antioxidant supplementation decreased total cancer incidence and total mortality in men . Postintervention follow-up assessment of total cancer incidence , ischemic cardiovascular disease incidence and total mortality was carried out for 5 years [ September 1 , 2002 , to September 1 , 2007 ] . No late effect of antioxidant supplementation  was revealed 5 years after ending the intervention neither on ischemic cardiovascular disease incidence and mortality in both genders nor on cancer incidence in women . Regarding duration of intervention effects in men , the reduced risk of total cancer incidence and total mortality was no longer evident after the 5-year postintervention follow-up . During the postsupplementation period , the relative risk ( RR ) for total cancer incidence ( n = 126 ) was 0.98 ( 95 % confidence interval [ CI ] , 0.75 - 1.27 ) among antioxidant recipients compared to nonrecipients . For total mortality ( n = 90 ) , the RR was 0.98 ( 95 % CI , 0.75 - 1.26 ) for men receiving antioxidants compared to nonrecipients . In conclusion , beneficial effects of antioxidant supplementation in men disappeared during postintervention follow-up The Alpha-Tocopherol Beta-Carotene ( ATBC ) Cancer Prevention Study was a placebo-controlled , r and omized intervention trial testing the hypothesis that beta-carotene and alpha-tocopherol ( vitamin E ) supplements prevent lung and other cancers . The study is predicated on a substantial body of evidence supporting a role in cancer prevention for these micronutrients . Based on the 2 x 2 factorial study design , 29,133 eligible male cigarette smokers aged 50 - 69 y were r and omly assigned to receive beta-carotene ( 20 mg ) , alpha-tocopherol ( 50 mg ) , beta-carotene and alpha-tocopherol , or placebo daily for 5 - 8 y. Capsule compliance was high ( median = 99 % ) . beta-Carotene treatment did not result in a decrease in cancer at any of the major sites but rather in an increase at several sites , most notably lung , prostate , and stomach ( number of cases 474 compared with 402 , 138 compared with 112 , and 70 compared with 56 , respectively ) . The vitamin E group had fewer incident cancers of the prostate and colorectum compared with the group not receiving vitamin E ( number of cases 99 compared with 151 and 68 compared with 81 , respectively ) , but more cancers of the stomach ( 70 compared with 56 ) . In contrast to these intervention-based findings for beta-carotene and vitamin E supplements , we observed lower lung cancer rates in men with higher amounts of both serum and dietary beta-carotene and vitamin E at baseline Experimental studies suggest protective effects of vitamin D on breast carcinogenesis , but epidemiological evidence is not conclusive . Body mass index ( BMI ) has been shown to modulate the effect of supplementation on the vitamin D status , but its potential influence on the relationship with breast cancer risk has been little studied . We investigated a potential interaction between BMI and vitamin D supplementation  on breast cancer risk while considering an already reported interaction between vitamin D supplementation and menopausal hormone therapy ( MHT ) use . Vitamin D supplementation was prospect ively investigated in 57,403 postmenopausal women from the French E3N cohort including 2,482 incident breast cancer cases diagnosed between 1995 and 2008 .  Multivariable hazard ratios ( HR ) for primary invasive breast cancer and 95 % confidence intervals ( CI ) were estimated using Cox models . Among MHT ever users , vitamin D supplementation was associated with decreased breast cancer risk , similarly across BMI strata ( Phomogeneity = 0.83 ) . Among MHT never users , ever vitamin D supplementation was associated with increased postmenopausal breast cancer risk in women with baseline BMI < 25 kg/m(2 ) ( HR = 1.51 , 95 % CI : 1.13 , 2.02 ) , but not in women with higher BMI ( 0.98 , 95 % CI : 0.62 , 1.56 ) , Phomogeneity = 0.12 . In conclusion , our findings suggest that vitamin D supplementation may reduce the excess breast cancer risk in MHT users , but draw attention on a potential risk in postmenopausal women not exposed to high exogenous or endogenous hormones , i.e. non-overweight MHT-non users , especially in the present context of increasing vitamin D supplement use and decreasing MHT use Objective Vitamin E and selenium are promising nutrients for the prevention of prostate cancer , and both are currently being tested in a large r and omized trial for prostate cancer . However , results are not expected for at least 6 years . We aim ed to investigate the association of vitamin E and selenium supplementation with prostate cancer in the VITamins And Lifestyle ( VITAL ) study , a cohort study specifically design ed to examine supplement use and future cancer risk . Methods In a prospect i ve design , 35,242 men recruited between 2000 and 2002 from western Washington State completed a question naire , including detailed questions about vitamin E and selenium supplement intake during the past 10 years from br and -specific multivitamins and single supplements . Using linkage to the western Washington SEER cancer registry , we documented 830 new cases of prostate cancer from baseline through December 2004 . Results A 10-year average intake of supplemental vitamin E was not associated with a reduced prostate cancer risk overall [ hazard ratio ( HR ) 0.86 , 95 % confidence interval ( CI ) 0.65–1.1 for ≥400 IU/day vs. non-use , p for trend 0.36 ] ; however , risk for advanced prostate cancer ( regionally invasive or distant metastatic , n = 123 ) decreased significantly with greater intake of supplemental vitamin E ( HR 0.43 , 95 % CI 0.19–1.0 for 10-year average intake ≥400 IU/day vs. non-use , p for trend 0.03 ) . There was no association  between selenium supplementation and prostate cancer risk ( HR 0.90 , 95 % CI 0.62–1.3 for 10-year average intake > 50 μg/day vs. non-use , p for trend 0.97 ) . Conclusions In this prospect i ve cohort , long-term supplemental intake of vitamin E and selenium were not associated with prostate cancer risk overall ; however , risk of clinical ly relevant advanced disease was reduced with greater long-term vitamin E supplementation BACKGROUND Epidemiologic evidence indicates that diets high in fruits and vegetables are associated with a reduced risk of several cancers , including cancers of the esophagus and stomach . Vitamins and minerals in these foods may contribute to the reduced cancer risk . The people of Linxian County , China , have one of the world 's highest rates of esophageal/gastric cardia cancer and a persistently low intake of several micronutrients . PURPOSE We sought to determine if dietary supplementation with specific vitamins and minerals can lower mortality from or incidence of cancer as well as mortality from other diseases in Linxian . METHODS Individuals of ages 40 - 69 were recruited in 1985 from four Linxian communes . Mortality and cancer incidence  during March 1986-May 1991 were ascertained for 29,584 adults who received daily vitamin and mineral supplementation throughout this period . The subjects were r and omly assigned to intervention groups according to a one-half replicate of a 2(4 ) factorial experimental design . This design enabled testing for the effects of four combinations of nutrients : ( A ) retinol and zinc ; ( B ) riboflavin and niacin ; ( C ) vitamin C and molybdenum ; and ( D ) beta carotene , vitamin E , and selenium . Doses ranged from one to two times U.S. Recommended Daily Allowances . RESULTS A total of 2127 deaths occurred among trial participants during the intervention period .  Cancer was the leading cause of death , with 32 % of all deaths due to esophageal or stomach cancer , followed by cerebrovascular disease ( 25 % ) . Significantly ( P = .03 ) lower total mortality ( relative risk [ RR ] = 0.91 ; 95 % confidence interval [ CI ] = 0.84 - 0.99 ) occurred among those receiving supplementation with beta carotene , vitamin E , and selenium . The reduction was mainly due to lower cancer rates ( RR = 0.87 ; 95 % CI = 0.75 - 1.00 ) , especially stomach cancer ( RR = 0.79 ; 95 % CI = 0.64 - 0.99 ) , with the reduced risk beginning to arise about 1 - 2 years after the start of supplementation with these vitamins and minerals . No significant effects on mortality rates from all causes were found for supplementation with retinol and zinc , riboflavin and niacin , or vitamin C and molybdenum . Patterns of cancer incidence , on the basis of 1298 cases , generally resembled those for cancer mortality . CONCLUSIONS The findings indicate that vitamin and mineral supplementation of the diet of Linxian adults , particularly with the combination of beta carotene , vitamin E , and selenium , may effect a reduction in cancer risk in this population . IMPLICATION S The results on their own are not definitive , but the promising findings should stimulate further research to clarify the potential benefits of micronutrient supplements BACKGROUND It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer . To date , however , the published results of r and omized , placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect . We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population . METHODS The Supplementation en Vitamines et Mineraux Antioxydants ( SU.VI.MAX ) study is a r and omized , double-blind , placebo-controlled primary prevention trial . A total of 13 017 French adults ( 7876 women aged 35 - 60 years and 5141 men aged 45 - 60 years ) were included . All participants took a single daily capsule of a combination of 120 mg of ascorbic acid , 30 mg of vitamin E , 6 mg of beta carotene , 100 mug of selenium , and 20 mg of zinc , or a placebo . Median follow-up time was 7.5 years . RESULTS No major differences were detected between the groups in total cancer incidence ( 267 [ 4.1 % ] for the study group vs 295 [ 4.5 % ] for the placebo group ) , ischemic cardiovascular disease incidence ( 134 [ 2.1 % ] vs 137[2.1 % ] ) , or all-cause mortality ( 76 [ 1.2 % ] vs 98 [ 1.5 % ] ) . However , a significant interaction between sex and group effects on cancer incidence was found ( P = .004 ) . Sex-stratified analysis showed a protective effect of antioxidants in men ( relative risk , 0.69 [ 95 % confidence interval [ CI ] , 0.53 - 0.91 ] ) but not in women ( relative risk , 1.04 [ 95 % CI , 0.85 - 1.29 ] ) . A similar trend was observed for all-cause mortality ( relative risk , 0.63 [ 95 % CI , 0.42 - 0.93 ] in men vs 1.03 [ 95 % CI , 0.64 - 1.63 ] in women ; P = .11 for interaction ) . CONCLUSIONS After 7.5 years , low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women . Supplementation may be effective in men only because of their lower baseline status of certain antioxidants , especially of beta carotene Background Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women , but the long-term benefits and potential harms are unknown . This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss , bone turnover , and fractures . Methods and Findings This single-center study was design ed as a 2-y r and omized , placebo-controlled , double-blind trial , extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures . A total of 440 postmenopausal women with osteopenia were r and omized to either 5 mg of vitamin K1 or placebo daily . Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points , bone turnover markers , height , fractures , adverse effects , and health-related quality of life . This study has a power of 90 % to detect 3 % differences in BMD between the two groups . The women in this study were vitamin D replete , with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline . Over 2 y , BMD decreased by −1.28 % and −1.22 % ( p = 0.84 ) ( difference of −0.06 % ; 95 % confidence interval [ CI ] −0.67 % to 0.54 % ) at the lumbar spine and −0.69 % and −0.88 % ( p = 0.51 ) ( difference of 0.19 % ; 95 % CI −0.37 % to 0.75 % ) at the total hip in the vitamin K and placebo groups , respectively . There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period . Daily vitamin K1 supplementation  increased serum vitamin K1 levels by 10-fold , and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels ( bone formation marker ) . However , C-telopeptide levels ( bone resorption marker ) were not significantly different between the two groups . Fewer women in the vitamin K group had clinical fractures ( nine versus 20 , p = 0.04 ) and fewer had cancers ( three versus 12 , p = 0.02 ) . Vitamin K supplements  were well-tolerated over the 4-y period . There were no significant differences in adverse effects or health-related quality of life between the two groups . The study was not powered to examine fractures or cancers , and their numbers were small . Conclusions Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD , but may protect against fractures and cancers in postmenopausal women with osteopenia . More studies are needed to further examine the effect of vitamin K on fractures and cancers . Trial registration : Clinical Trials.gov ( # NCT00150969 ) and Current Controlled Trials ( # IS RCT N61708241 PURPOSE Studies suggest that vitamin E may decrease the risk of  prostate cancer .  The Prevention Research Veteran Affairs E-vitamin Nutrition Trial is a r and omized , double-blind , placebo controlled study design ed to assess the effects of vitamin E supplementation on biomarkers associated with prostate cancer risk in peripheral blood and prostate tissue . MATERIAL S AND METHODS A total of 44 patients with increased prostate specific antigen ( PSA ) and /or abnormal digital rectal examination on initial evaluation were r and omized to receive 400 IU vitamin E ( 22 ) vs placebo ( 22 ) . Serum vitamin E , PSA , dehydroepi and rosterone , testosterone and insulin-like growth factor-1 ( IGF-1 ) were measured in the 2 groups at baseline and then at 3-month intervals . Results are reported in 28 patients  ( placebo in 14 and vitamin E in 14 ) who completed the treatment as specified by the protocol . RESULTS Serum Vitamin E was significantly higher in patients on  vitamin E supplementation . alpha-Tocopherol supplementation did not affect the levels of PSA , serum and rogens ( testosterone and dehydroepi and rosterone ) or ( IGF-1 ) . CONCLUSIONS Serum alpha-tocopherol is increased by oral supplementation of vitamin E. We found that alpha-tocopherol supplementation has no effect on serum and rogens , IGF-1 or PSA . The lack of an effect of vitamin supplementation on PSA avoids any bias in the diagnosis of prostate cancer in  vitamin E treated patients . Our results suggest that a decrease in prostate cancer risk with alpha-tocopherol is likely to occur through a mechanism that is nonhormonal and independent of IGF-1
There is currently no firm evidence that vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly community-dwelling women .
Vitamin D₃ supplementation  decreased cancer mortality  and vitamin D supplementation  decreased all-cause mortality , but these estimates are at risk of type I errors due to the fact that too few participants were examined , and to risks of attrition bias originating from substantial dropout of participants .
Combined vitamin D₃ and calcium supplements  increased nephrolithiasis , whereas it remains unclear from the included trials whether vitamin D₃ , calcium , or both were responsible for this effect .
BACKGROUND The evidence on whether vitamin D supplementation is effective in decreasing cancers is contradictory .
OBJECTIVES To assess the beneficial and harmful effects of vitamin D supplementation for prevention of cancer in adults .