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# Effectiveness and Safety of Vitamin D in Relation to Bone                Health

*Evidence Reports/Technology Assessments, No. 158*

Investigators: Ann Cranney, MD, MSc, Tanya Horsley, PhD, Siobhan O'Donnell, MSc, Hope Weiler, PhD, Lorri Puil, MD, PhD, Daylily Ooi, MD, Stephanie Atkinson, PhD, Leanne Ward, MD, David Moher, PhD, David Hanley, MD, Manchun Fang, MSc, Fatemeh Yazdi, MSc, Chantelle Garritty, BSc, Margaret Sampson, MLIS, Nick Barrowman, PhD, Alex Tsertsvadze, MD, MSc, and Vasil Mamaladze, MD, PhD.

Agency for Healthcare Research and Quality (US)2007 Aug

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## Structured Abstract

#### Objectives:

To review and synthesize the literature in the following areas: the association                    of specific circulating 25(OH)D concentrations with bone health outcomes in                    children, women of reproductive age, postmenopausal women and elderly men; the                    effect of dietary intakes (foods fortified with vitamin D and/or vitamin D                    supplementation) and sun exposure on serum 25(OH)D; the effect of vitamin D on                    bone mineral density (BMD) and fracture or fall risk; and the identification of                    potential harms of vitamin D above current reference intakes.

#### Data Sources:

MEDLINE® (1966-June Week 3 2006); Embase (2002-2006 Week 25); CINAHL (1982-June                    Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990-February                    2005); and the Cochrane Central Register of Controlled Trials (2nd Quarter                    2006).

#### Review Methods:

Two independent reviewers completed a multi-level process of screening the                    literature to identify eligible studies (title and abstract, followed by full                    text review, and categorization of study design per key question). To minimize                    bias, study design was limited to randomized controlled trials (RCTs) wherever                    possible. Study criteria for question one were broadened to include                    observational studies due to a paucity of available RCTs, and question four was                    restricted to systematic reviews to limit scope. Data were abstracted in                    duplicate and study quality assessed. Differences in opinion were resolved                    through consensus or adjudication. If clinically relevant and statistically                    feasible, meta-analyses of RCTs on vitamin D supplementation and bone health                    outcomes were conducted, with exploration of heterogeneity. When meta-analysis                    was not feasible, a qualitative systematic review of eligible studies was                    conducted.

#### Results:

167 studies met our eligibility criteria (112 RCTs, 19 prospective cohorts, 30                    case-controls and six before-after studies). The largest body of evidence on                    vitamin D status and bone health was in older adults with a lack of studies in                    premenopausal women and infants, children and adolescents. The quality of RCTs                    was highest in the vitamin D efficacy trials for prevention of falls and/or                    fractures in older adults. There was fair evidence of an association between low                    circulating 25(OH)D concentrations and established rickets. However, the                    specific 25(OH)D concentrations associated with rickets is uncertain, given the                    lack of studies in populations with dietary calcium intakes similar to North                    American diets and the different methods used to determine 25(OH)D                    concentrations. There was inconsistent evidence of an association of circulating                    25(OH)D with bone mineral content in infants, and fair evidence that serum                    25(OH)D is inversely associated with serum PTH. In adolescents, there was fair                    evidence for an association between 25(OH)D levels and changes in BMD. There                    were very few studies in pregnant and lactating women, and insufficient evidence                    for an association between serum 25(OH)D and changes in BMD during lactation,                    and fair evidence of an inverse correlation with PTH. In older adults, there was                    fair evidence that serum 25(OH)D is inversely associated with falls, fair                    evidence for a positive association with BMD, and inconsistent evidence for an                    association with fractures. The imprecision of 25(OH)D assays may have                    contributed to the variable thresholds of 25(OH)D below which the risk of                    fractures, falls or bone loss was increased.

There was good evidence that intakes from vitamin D-fortified foods (11 RCTs)                    consistently increased serum 25(OH)D in both young and older adults.

Eight randomized trials of ultraviolet (UV)-B radiation (artificial and solar                    exposure) were small and heterogeneous with respect to determination of the                    exact UV-B dose and 25(OH)D assay but there was a positive effect on serum                    25(OH)D concentrations. It was not possible to determine how 25(OH)D levels                    varied by ethnicity, sunscreen use or latitude.

Seventy-four trials examined the effect of vitamin D3 or D2                    on 25(OH)D concentrations. Most trials used vitamin D3, and the                    majority enrolled older adults. In three trials, there was a greater response of                    serum 25(OH)D concentrations to vitamin D3 compared to vitamin                        D2, which may have been due to more rapid clearance of vitamin                        D2 in addition to other mechanisms. Meta-analysis of 16 trials of                    vitamin D3 was consistent with a dose-response effect on serum                    25(OH)D when comparing daily doses of < 400 IU to doses ≥ 400 IU. An                    exploratory analysis of the heterogeneity demonstrated a significant positive                    association comparable to an increase of 1 – 2 nmol/L in serum 25(OH)D for every                    100 additional units of vitamin D although heterogeneity remained after                    adjusting for dose.

Vitamin D3 in combination with calcium results in small increases in                    BMD compared to placebo in older adults although quantitative synthesis was                    limited due to variable treatment durations and BMD sites. The evidence for                    fracture reduction with vitamin D supplementation was inconsistent across 15                    trials. The combined results of trials using vitamin D3 (700 – 800 IU                    daily) with calcium (500 – 1,200 mg) was consistent with a benefit on fractures                    although in a subgroup analysis by setting, benefit was primarily in elderly                    institutionalized women (fair evidence from two trials). There was inconsistent                    evidence across 14 RCTs of a benefit on fall risk. However, a subgroup analysis                    showed a benefit of vitamin D in postmenopausal women, and in trials that used                    vitamin D3 plus calcium. In addition, there was a reduction in fall                    risk with vitamin D when six trials that adequately ascertained falls were                    combined. Limitations of the fall and fracture trials included poor compliance                    with vitamin D supplementation, incomplete assessment of vitamin D status and                    large losses to follow-up.

We did not find any systematic reviews that addressed the question on the level                    of sunlight exposure that is sufficient to maintain serum 25(OH)D concentrations                    but minimizes risk of melanoma and non-melanoma skin cancer.

There is little evidence from existing trials that vitamin D above current                    reference intakes is harmful. In most trials, reports of hypercalcemia and                    hypercalciuria were not associated with clinically relevant events. The Women's                    Health Initiative study did report a small increase in kidney stones in                    postmenopausal women aged 50 to 79 years whose daily vitamin D3                    intake was 400 IU (the reference intake for 50 to 70 years, and below the                    reference intake for > 70 years) combined with 1000 mg calcium. The                    increase in renal stones corresponded to 5.7 events per 10,000 person-years of                    exposure. The women in this trial had higher calcium intakes than is seen in                    most post-menopausal women.

#### Conclusions:

The results highlight the need for additional high quality studies in infants,                    children, premenopausal women, and diverse racial or ethnic groups.

There was fair evidence from studies of an association between circulating                    25(OH)D concentrations with some bone health outcomes (established rickets, PTH,                    falls, BMD). However, the evidence for an association was inconsistent for other                    outcomes (e.g., BMC in infants and fractures in adults). It was difficult to                    define specific thresholds of circulating 25(OH)D for optimal bone health due to                    the imprecision of different 25(OH)D assays. Standard reference preparations are                    needed so that serum 25(OH)D can be accurately and reliably measured, and                    validated.

In most trials, the effects of vitamin D and calcium could not be separated.                    Vitamin D3 (>700 IU/day) with calcium supplementation compared                    to placebo has a small beneficial effect on BMD, and reduces the risk of                    fractures and falls although benefit may be confined to specific subgroups.

Vitamin D intake above current dietary reference intakes was not reported to be                    associated with an increased risk of adverse events. However, most trials of                    higher doses of vitamin D were not adequately designed to assess long-term                    harms.

## Contents

                          - Expand All
                          - Collapse All

                        - Preface
                        - Acknowledgments
                        - Executive Summary
                        - 1. Introduction                           - Overview
                          - Objectives
                          - Background
                          - Summary
                        - 2. Methods                           - Key Questions Addressed in This Report
                          - Study Identification
                          - Data Abstraction
                          - Data Assessment
                        - 3. Results                           - Results of the Literature Search
                          - Question 1. Are There Specific Concentrations of Serum 25(OH)D That Are                Associated With Bone Health Outcomes in Infants, Children, Women of Reproductive                Age, Postmenopausal Women and Elderly Men?
                          - 1A. Infants and Children
                          - Question 1B. Are Specific Circulating Concentrations of 25-Hydroxvitamin D                [25(OH)D] Associated with Bone Health Outcomes in Pregnant and Lactating                Women?
                          - Question 1C. Are Specific Circulating Concentrations of 25 Hydroxyvitamin D                [25(OH)D] Associated With Bone Health Outcomes in Postmenopausal Women and Elderly                Men?
                          - Question 2. How Does Dietary Intake of Vitamin D, Sun Exposure, and/or Vitamin D                Supplementation Affect Serum 25(OH)D Concentrations?
                          - Question 2A. Does Dietary Intake from Foods Fortified with Vitamin D Affect                Concentrations of Circulating 25(OH)D?
                          - Question 2B. What is the Effect of UV Exposure on Circulating 25(OH)D                Concentrations?
                          - Question 2C. What Is the Effect of Vitamin D Supplementation on Circulating                25(OH)D?
                          - Question 3A. What is the Evidence Regarding the Effect of Supplemental Vitamin D                on Bone Density in Women of Reproductive Age and Postmenopausal Women and Elderly                Men?
                          - Question 3B. What is the Evidence Regarding the Effect of Supplemental Vitamin D                on Fractures in Women of Reproductive Age and/or Postmenopausal Women and Elderly                Men?
                          - Question 3C. What is the Evidence Regarding the Effect of Supplemental Vitamin D                on Falls in Postmenopausal Women and Elderly Men?
                          - Question 4. Is There a Level of Sunlight Exposure (Time of Year, Latitude, BMI,                the Amount of Skin Exposed) That is Sufficient to Maintain Adequate Vitamin D                Concentrations, But Does Not Increase the Risk of Non-Melanoma or Melanoma Skin                Cancer?
                          - Question 5. Does Intake of Vitamin D, Above Current Reference Intakes, Lead to                Toxicity?
                        - 4. Discussion                           - Overview
                          - Question 1A. Are there Specific Concentrations of 25(OH)D Associated with Bone Health Outcomes?
                          - Question 2A. Does Dietary Intake from Foods Fortified with Vitamin D Affect Concentrations of Circulating 25(OH)D?
                          - Question 2B. What is the Effect from UV Exposure on Circulating 25(OH)D Concentrations? Does This Vary With Different Age Groups, Ethnicity, Use of Sunscreen, Latitude and/or BMI?
                          - Question 2C. What Is the Effect of Vitamin D Supplementation on Concentrations of Circulating 25(OH)D?
                          - Question 3. What is the Evidence Regarding the Effect of Supplemental Vitamin D on Bone Density, Fractures and Falls in Postmenopausal Women and Elderly Men?
                          - Question 4. Is There a Level of Sunlight Exposure That Is Sufficient to Maintain Adequate Vitamin D Concentrations, But Does Not Increase the Risk of Skin Cancer?
                          - Question 5. Does Intake of Vitamin D, Above Current Reference Intakes, Lead to Toxicity?
                          - Strengths and Limitations of the Review
                          - Conclusions and Knowledge Gaps
                          - Research Needs and Future Directions
                        - Key Terms
                        - List of Acronyms/Abbreviations
                        - Appendixes                           - Appendix A. Search Strategies
                          - Appendix B. Screening, Data Abstraction, and Quality Assessment Forms
                          - Appendix C. Statistics Information Form
                          - Appendix D. Quality Assessment of RCTs
                          - Appendix E. Reference List - Quality Assessment of RCTs
                          - Appendix F. Additional Data Provided by Study Authors
                          - Appendix G. List of Unobtained Articles
                          - Appendix H. Additional Acknowledgments
                          - Appendix I. List of Excluded Studies at Full-Text Screening (Level 2 screening)
                          - Appendix J. List of Excluded Studies on the Basis Study Design (Level 3 screening)
                        - References and Included Studies

                          - Expand All
                          - Collapse All

Prepared for: Agency for Healthcare Research and Quality, U.S. Department                of Health and Human Services.1                 Contract No. 290-02-0021.                Prepared by: University of Ottawa                    Evidence-based Practice Center, Ottawa, Canada.

#### Suggested citation:

Cranney A, Horsley T, O'Donnell S, Weiler HA, Puil                    L, Ooi DS, Atkinson SA, Ward LM, Moher D, Hanley DA, Fang M, Yazdi F, Garritty                    C, Sampson M, Barrowman N, Tsertsvadze A, Mamaladze V. Effectiveness and Safety                    of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment                    No. 158 (Prepared by the University of Ottawa Evidence-based Practice Center                    (UO-EPC) under Contract No. 290-02-0021. AHRQ Publication No. 07-E013.                    Rockville, MD: Agency for Healthcare Research and Quality. August                    2007.

**No investigators have any affiliations or financial involvement (e.g.,                    employment, consultancies, honoraria, stock options, expert testimony, grants or                    patents received or pending, or royalties) that conflict with material presented                    in this report.**

This report is based on research conducted by the University of Ottawa Evidence-based                Practice Center (EPC) under contract to the Agency for Healthcare Research and                Quality (AHRQ), Rockville, MD (Contract No. 290-02-0021). 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.

                        - 1
                        - 
540 Gaither Road, Rockville, MD 20850. www​.ahrq.gov

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Bookshelf ID: NBK38410

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