There is a high prevalence of inadequate vitamin D levels in the United States. Despite enthusiasm for the use of vitamin D for bone health, there are limited data on the effects of high-dose vitamin D supplements vs. placebo on bone health and body composition outcomes. Previous data support a positive relationship between 25-hydroxyvitamin D [25(OH) D] levels and bone mineral density (BMD). However, results from clinical trials that test vitamin D supplementation alone on areal BMD (aBMD) are sparse and inconsistent, and it is not known whether vitamin D can prevent or reverse the structural deterioration characteristic of osteoporosis. Recent advances in bone imaging make it possible to assess volumetric BMD (vBMD), structure, and micro- architecture non-invasively with high-resolution peripheral computed tomography (HR-pQCT). In addition, observational studies show an inverse relationship between 25(OH) D levels and body mass index (BMI). Since vitamin D is stored in fat, new dual X-ray absorptiometry (DXA) measures of adiposity can advance understanding of this relationship and determine whether or not supplemental vitamin D has effects on body composition. We propose an ancillary study to the NIH-sponsored, Vitamin D and OmegA-3 Trial (VITAL) (U01 CA138962), an ongoing, randomized, double-blind, placebo-controlled trial of vitamin D3 (cholecalciferol, 2000 IU/d) and/or marine omega-3 fatty acids (1 gm/d) in 20,000 men and women, to test the effects of vitamin D3 on BMD, geometry, architecture, and body composition. In a sub-cohort of 600 participants recruited from the NIH-sponsored Clinical and Translational Science Center (CTSC) in Boston, we seek to test the following hypotheses, with measures at baseline and year 2:
Aim 1 : High-dose vitamin D3 will (a) produce small increases in aBMD at the spine, hip, forearm and total body, as assessed by DXA and (b) improve balance of bone remodeling through decreases in bone turnover;
Aim 2 : High-dose vitamin D3 will improve: vBMD and bone structure and architecture at the distal radius and tibia, as assessed by HR-pQCT and bone strength estimates;
Aim 3 : High-dose vitamin D3 will result in lower (a) total body fat and fat mass index (FMI-fat mass/height2) and/or b) regional fat measures, as assessed by DXA. For each Aim, we will determine whether effects vary with (a) baseline 25(OH) D levels, (b) gender, (c) race/skin pigmentation, and (d) BMI or FMI. We will also define how the 25(OH) D levels corresponding to high-dose vitamin D supplementation affects these bone health and body composition outcomes. In order to complete pre-randomization testing in this sub-cohort, it is critical that this ancillary study be undertaken during the CTSC baseline visits, which begin December, 2011 and extend to early 2013. The proposed studies will provide positive or informative negative results about effects of vitamin D3 alone on bone health and body composition, and enhance understanding of the skeletal mechanisms through which vitamin D may affect fracture outcomes evaluated in a separate study (AR060574). Findings from this proposal will fill gaps in knowledge and inform clinical and public health recommendations.

Public Health Relevance

The purported health benefits of vitamin D are receiving wide attention in the medical literature and the popular press. While some data support a benefit of vitamin D on fracture reduction, there is no information on the effects of high-dose vitamin D on bone structure and architecture and the effects of adiposity on these relationships. Findings from these clinical studies including advanced imaging techniques will elucidate the role of vitamin D on bone mass, architecture and body composition in men and women enrolled in the VITAL study.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Neurological, Aging and Musculoskeletal Epidemiology Study Section (NAME)
Program Officer
Lester, Gayle E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Goldman, A L; Donlon, C M; Cook, N R et al. (2018) VITamin D and OmegA-3 TriaL (VITAL) bone health ancillary study: clinical factors associated with trabecular bone score in women and men. Osteoporos Int 29:2505-2515
Donlon, Catherine M; LeBoff, Meryl S; Chou, Sharon H et al. (2018) Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL): Effects on Bone Structure and Architecture. Contemp Clin Trials 67:56-67
Haas, Andrea V; LeBoff, Meryl S (2018) Osteoanabolic Agents for Osteoporosis. J Endocr Soc 2:922-932
Quraishi, Sadeq A; Camargo Jr, Carlos A; Manson, JoAnn E (2016) Low vitamin D status in Europe: moving from evidence to sound public health policies. Am J Clin Nutr 103:957-8
Crandall, Carolyn J; LaMonte, Michael J; Snively, Beverly M et al. (2016) Physical Functioning Among Women Aged 80 Years and Older With Previous Fracture. J Gerontol A Biol Sci Med Sci 71 Suppl 1:S31-41
Bassuk, Shari S; Manson, JoAnn E; Lee, I-Min et al. (2016) Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL). Contemp Clin Trials 47:235-43
Pradhan, Aruna D; Manson, JoAnn E (2016) Update on the Vitamin D and OmegA-3 trial (VITAL). J Steroid Biochem Mol Biol 155:252-6
Weaver, C M; Alexander, D D; Boushey, C J et al. (2016) Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int 27:367-76
Crandall, Carolyn J; Hovey, Kathleen M; Cauley, Jane A et al. (2015) Wrist Fracture and Risk of Subsequent Fracture: Findings from the Women's Health Initiative Study. J Bone Miner Res 30:2086-95
LeBoff, Meryl S; Yue, Amy Y; Copeland, Trisha et al. (2015) VITAL-Bone Health: rationale and design of two ancillary studies evaluating the effects of vitamin D and/or omega-3 fatty acid supplements on incident fractures and bone health outcomes in the VITamin D and OmegA-3 TriaL (VITAL). Contemp Clin Trials 41:259-68

Showing the most recent 10 out of 16 publications