# VITamin D OmegA-3 TriaL (VITAL): Fractures, Vitamin D and Genetic Markers

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $527,533

## Abstract

ABSTRACT
There are high prevalences of osteoporotic fractures and vitamin D deficiency in the U.S., especially among
older adults. Although vitamin D supplements are widely used to improve bone health, evidence for a role of
supplemental vitamin D alone in reducing fractures is lacking. While the serum 25-hydroxyvitamin D [25(OH)D]
level is considered the best analyte to assess vitamin D status, currently there is no consensus on the optimal
circulating total 25(OH)D concentration for bone. While, like many hormones, vitamin D circulates bound to
proteins, the relative importance of free 25(OH)D (FVD) or bioavailable 25(OH)D levels on fracture risk is not
known. New advances in technology make it possible to directly measure the biologically active, FVD level.
Results from recent observational studies on whether FVD and/or bioavailable 25(OH)D are more strongly
associated than total 25(OH)D levels with calcium homeostasis and bone mineral density (BMD) are
inconsistent. In addition, there are no data from large, randomized controlled trials on whether bioavailable
25(OH)D and/or FVD vs. total 25(OH)D levels or gene variations in vitamin D-related pathways modify effects
of supplemental vitamin D on fractures and changes in BMD. To fill gaps in knowledge, we propose an
ancillary study to the large, NIH-sponsored, randomized, controlled VITamin D and OmegA-3 TriaL (VITAL)
that is testing effects of supplemental vitamin D3 (cholecalciferol, 2000 IU/d), and/or omega-3 fatty acids (fish
oil, 1 g/d) in the primary prevention of cancer and cardiovascular disease in 25,874 U.S. men (aged ≥50) and
women (aged ≥55), including 5,107 African Americans. The proposed ancillary study will definitively determine
whether supplemental, high-dose, vitamin D3 alone reduces incident total, non-vertebral and hip fractures by
extending adjudication of fractures to the full 5 years of treatment in 25,874 VITAL participants nationwide. The
proposed studies will also rigorously test whether concentrations of bioavailable 25(OH)D and/or FVD are
more strongly associated with changes in BMD and incident fractures than total 25(OH)D levels; and whether
these vitamin D biomarkers and genetic variants in vitamin D-related pathways modify effects of supplemental
vitamin D on BMD and fracture risk. For each of the proposed aims, we will assess whether results vary by (a)
sex, (b) race/ethnicity, and (c) BMI. Key VITAL resources will be leveraged at no additional cost to the
proposed studies including: blood samples and BMD measurements (at baseline and follow-up), extensive
data on changes in 25(OH)D levels over time (in the treatment vs. placebo arms), measures of calcium
homeostasis, information on clinical risk factors, and extracted DNA. This proposal provides a unique and cost-
efficient opportunity to generate important positive or informative negative results about effects of supplemental
vitamin D3 alone on fracture risk, while also elucidating the relative importance of ...

## Key facts

- **NIH application ID:** 10174746
- **Project number:** 5R01AR070854-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MERYL Susan LEBOFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $527,533
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174746

## Citation

> US National Institutes of Health, RePORTER application 10174746, VITamin D OmegA-3 TriaL (VITAL): Fractures, Vitamin D and Genetic Markers (5R01AR070854-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10174746. Licensed CC0.

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