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

摘要 在美国，骨质疏松性骨折和维生素D缺乏症的发病率很高，尤其是 老年人虽然维生素D补充剂被广泛用于改善骨骼健康，但有证据表明， 缺乏单独补充维生素D来减少骨折。血清25-羟维生素D [25（OH）D] 水平被认为是评估维生素D状态的最佳分析物，目前还没有就最佳水平达成共识。 骨循环总25（OH）D浓度。而像许多激素一样，维生素D的循环必然会 蛋白质，游离25（OH）D（FVD）或生物可利用的25（OH）D水平对骨折风险的相对重要性不是 知道的技术的新进展使得直接测量生物活性FVD水平成为可能。 最近关于FVD和/或生物可利用25（OH）D是否更强的观察性研究结果 与钙稳态和骨密度（BMD）相关的总25（OH）D水平是 前后矛盾此外，没有来自大型随机对照试验的数据， 25（OH）D和/或FVD与总25（OH）D水平或维生素D相关途径中的基因变异改变效应 补充维生素D对骨折和骨密度变化的影响。为了填补知识空白，我们提出了一个 大型、NIH申办、随机、对照维生素D和OmegA-3 TriaL（VITAL）的辅助研究 测试补充维生素D3（胆钙化醇，2000 IU/d）和/或ω-3脂肪酸（鱼 在25，874名美国男性（年龄≥50岁）中， 女性（年龄≥55岁），包括5，107名非裔美国人。拟议的辅助研究将最终确定 是否补充，高剂量，维生素D3单独减少总的，非脊椎和髋部骨折的发生率， 在全国范围内25，874名VITAL参与者中，将骨折的裁定扩展到整个5年的治疗。的 拟议的研究还将严格测试生物可利用的25（OH）D和/或FVD的浓度是否 与BMD变化和骨折事件的相关性比与总25（OH）D水平的相关性更强; 这些维生素D生物标志物和维生素D相关途径中的遗传变异改变了补充维生素D的效果。 维生素D对BMD和骨折风险的影响。我们会就每一项建议目标，评估成效是否因下列因素而有所不同： 性别，（B）种族/民族，和（c）BMI。关键的VITAL资源将在不增加成本的情况下得到利用， 拟议的研究包括：血液样本和BMD测量（基线和随访时），广泛 25（OH）D水平随时间变化的数据（治疗组与安慰剂组），钙指标 稳态、临床风险因素信息和提取的DNA。这是一个独特的和成本- 有效的机会，以产生重要的积极或有益的负面结果的影响，补充 维生素D3单独对骨折风险的影响，同时也阐明了维生素D生物标志物和 骨骼中维生素D相关途径的遗传变异。拟议的辅助研究的结果 对美国男性和女性的重大临床和公共卫生影响的潜力。

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 vitamin D biomarkers and genetic variations in vitamin D-related pathways on bone. Findings from the proposed ancillary study have the potential for major clinical as well as public health impact for both men and women in the U.S.