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

维生素 D OmegA-3 TriaL (VITAL)：骨折、维生素 D 和遗传标记

• 批准号: 9902329
• 负责人: MERYL Susan LEBOFF
• 金额: $ 58.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902329
• 关键词: 25-hydroxyvitamin D; Affect; African American; Albumins; Ancillary Study; Antibodies; Benefits and Risks; Binding Proteins; Bioavailable; Biological; Biological Assay; Biological Markers; Blood specimen; Body mass index; Bone Density; Bone Diseases; Calcium; Candidate Disease Gene; Cardiovascular Diseases; Cholecalciferol; Clinical; Conflict (Psychology); Consensus; Consent; Cross-Sectional Studies; DNA; Data; Dose; Elderly; Ethnic Origin; Ethnic group; Femoral Fractures; Fish Oils; Fracture; Funding; Genes; Genetic Markers; Genetic Variation; Genetic study; Genotype; Goals; Guidelines; High Prevalence; Hip Fractures; Homeostasis; Hormones; Institute of Medicine (U.S.); Knowledge; Malignant Neoplasms; Measurement; Measures; Medical Records; Metabolism; Observational Study; Omega-3 Fatty Acids; Osteoporosis; Outcome; Parents; Participant; Pathway interactions; Placebos; Population; Prevention; Prevention trial; Primary Cancer Prevention; Primary Prevention; Proteins; Public Health; Questionnaires; Race; Randomized; Randomized Controlled Trials; Reporting; Resources; Risk; Risk Factors; Role; Sampling; Serum; Supplementation; Technology; Testing; Time; Uncertain Risk; United States National Institutes of Health; Variant; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin D-Binding Protein; Woman; absorption; adjudication; aged; arm; biomarker performance; bone; bone health; clinical risk; cohort; cost; cost efficient; delta opioid receptor; design; follow-up; fracture risk; genetic variant; high risk; improved; interest; men; osteoporosis with pathological fracture; prevent; radiological imaging; receptor function; sex; systematic review; treatment duration; whole genome

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.

抽象的 在美国，骨质疏松性裂缝和维生素D缺乏症的患病率很高，尤其是在 老年人。尽管维生素D补充剂被广泛用于改善骨骼健康，但证据表明 缺乏减少骨折的补充维生素D。而血清25-羟基维生素D [25（OH）D] 水平被认为是评估维生素D状态的最佳分析物，目前尚无关于最佳的共识 骨循环总计25（OH）D浓度。而像许多激素一样，维生素D圆圈与 蛋白质，免费25（OH）D（FVD）或生物利用25（OH）D水平的相对重要性不是骨折风险 已知。技术的新进步使得可以直接测量生物活跃的FVD水平。 最近关于FVD和/或生物可利用25（OH）D的观察性研究的结果更强烈 与钙稳态和骨矿物质密度（BMD）相关的总计25（OH）D水平是 不一致。此外，没有关于生物利用的大型随机对照试验的数据 25（OH）d和/或FVD与总计25（OH）D水平或维生素D相关途径的基因变异修改效果 裂缝上的补充维生素D和BMD的变化。为了填补知识的空白，我们提出了一个 对大型，NIH赞助的，随机，受控的维生素D和Omega-3试验的辅助研究 这是补充维生素D3（胆石质，2000 IU/d）和/或omega-3脂肪酸（FISH）的测试作用（FISH 石油，1 g/d）在25,874名男性（≥50岁）和 妇女（≥55岁），包括5,107名非裔美国人。拟议的辅助研究将确定确定 是否补充，高剂量，维生素D3是否会减少事件的总数，非静脉和髋部骨折 在全国25,874名重要参与者中，将骨折的调整扩展到整整5年的治疗。这 拟议的研究还将严格测试生物利用的浓度25（OH）D和/或FVD是否是 与总计25（OH）D水平相比，与BMD和入射骨折的变化更加密切相关；是否 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的影响 BMD和断裂风险的维生素D。对于每个提议的目标，我们将评估结果是否因（a）而变化 性别，（b）种族/种族和（c）BMI。关键的重要资源将不得不以无需额外的费用 拟议的研究包括：血液样本和BMD测量（基线和随访），广泛 随着时间的流逝（在治疗臂与安慰剂臂）的25（OH）D水平变化的数据，钙的度量 稳态，有关临床危险因素的信息和提取的DNA。该建议提供了独特而成本 - 有效的机会，产生有关补充影响的重要积极或信息的负面结果 仅维生素D3就骨折风险，同时还阐明了维生素D生物标志物和 骨头上维生素D相关途径的遗传变异。拟议的辅助研究的发现具有 对美国男性和女性的主要临床和公共卫生影响的潜力