VITamin D and OmegA-3 TriaL (VITAL): Interrelationship of Vitamin D and Vitamin K on Bone

摘要 骨质疏松症是最常见的骨骼疾病；5360万美国人骨量减少，这 增加了他们发生脆性骨折的风险。除了维生素D缺乏症的高流行率外，最近 研究表明，大约60%的老年男性和40%的老年女性维生素K不足 进水口。越来越多的证据表明，维生素D和维生素之间存在重要的相互关系 骨骼上的K。维生素D增加肠道钙的吸收，刺激两种蛋白质的产生， 骨钙素和基质GLA蛋白。维生素K在激活这些蛋白质方面起着至关重要的作用，因此 骨钙素结合骨骼中的钙和基质GLA蛋白抑制软组织中的钙化，包括 肾脏。维生素D和K对这些蛋白质的最佳功能都很重要。虽然维生素D 补充剂被广泛用于改善骨骼健康，补充维生素D单独用于减少 骨折显示结果不一致。新出现的证据表明，补充D在低的情况下 维生素K状态对骨骼健康措施的影响较小。因此，低维生素K状态可能是 测试维生素D和骨骼健康的试验中的一些不一致之处，可能会导致毒性 归因于高剂量维生素D，如肾结石。此前没有一项随机对照试验 足够的能量来测试维生素K状态对骨折风险的影响或维生素K状态与 在骨骼上补充高剂量维生素D。为了填补知识空白，我们提出了一项创新的辅助研究 由美国国立卫生研究院赞助的大型维生素D和omega-3试验(VITAL)。至关重要的是测试补充剂的效果 维生素D3(胆钙化醇，2000IU/d)和/或omega-3脂肪酸(鱼油，1g/d)在一级预防中的作用 25,871名美国男性(年龄为≥50)和女性(年龄为≥55)中的癌症和心血管疾病，包括5,106人 非裔美国人。在这项竞争性的更新应用中，《至关重要：对骨骼结构的影响和 我们将通过3个敏感的生物标志物来评估低维生素K状态是否会改变 补充维生素D对骨折、骨密度和骨结构的影响 尿钙排泄增加，这是导致低骨密度和肾结石的危险因素。在这个过程的第一个周期中 Grant，我们超过了招募目标，并收集了基线和随机后2年的成像研究 骨密度、结构和建筑将在拟议的研究中使用(n=771)。此外，其他 将利用关键的重要资源，包括：16953份基线血样和6000份后续血样； 维生素D、钙、肌酐和甲状旁腺激素的测定；以及骨折和肾脏的判定 石头。这项建议提供了一个独特的机会，在最大的补充维生素D研究中澄清， 维生素D和K的相互依赖性及其在骨折、骨健康指标和尿液中的作用 钙的排泄。拟议辅助研究的结果将对解释正在进行的 维生素D试验，并为推进临床护理和公共卫生建议提供新的见解。

ABSTRACT Osteoporosis is the most common bone disease; 53.6 million Americans have a reduced bone mass, which increases their risk of fragility fractures. In addition to the high prevalence of vitamin D deficiency, recent studies show that approximately 60% of older men and 40% of older women have inadequate vitamin K intakes. Growing evidence indicates that there are important interrelationships between vitamin D and vitamin K on bone. Vitamin D increases intestinal calcium absorption and stimulates production of two proteins, osteocalcin and matrix Gla protein. Vitamin K plays an essential role in activating these proteins so that osteocalcin incorporates calcium in bone and matrix Gla protein inhibits calcification in soft tissues, including the kidney. Both vitamins D and K are important for optimal function of these proteins. Although vitamin D supplements are widely used to improve bone health, trials of supplemental vitamin D alone in reducing fractures showed inconsistent results. Emerging evidence indicates that supplemental D in the context of low vitamin K status is less effective on bone health measures. Therefore, low vitamin K status may account for some of the inconsistencies of trials testing vitamin D and bone health and may contribute to toxicities attributed to high-dose vitamin D such as kidney stones. No previous randomized controlled trials have been adequately powered to test effects of vitamin K status on fracture risk or the interaction of vitamin K status with high-dose, supplemental vitamin D on bone. To fill knowledge gaps, we propose an innovative, ancillary study to the large, NIH-sponsored, VITamin D and OmegA-3 TriaL (VITAL). VITAL 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 25,871 U.S. men (aged ≥50) and women (aged ≥55), including 5,106 African Americans. In this competitive renewal application of “VITAL: Effects on Bone Structure and Architecture,” we will determine whether low vitamin K status, assessed by 3 sensitive biomarkers, modifies effects of supplemental vitamin D on fractures, bone mineral density (BMD) and structure, and secondarily on increases in urine calcium excretion, a risk factor for low BMD and kidney stones. During the first cycle of this grant, we surpassed recruitment goals and collected baseline and 2-yr post-randomization imaging studies for bone density, structure and architecture that will be used in the proposed studies (n=771). In addition, other key VITAL resources will be leveraged including: 16,953 baseline and 6,000 follow-up blood samples; measures of vitamin D, calcium, creatinine and parathyroid hormone; and adjudicated fractures and kidney stones. This proposal provides a unique opportunity to clarify in the largest study of supplemental vitamin D, the interdependencies of vitamins D and K and their roles on fractures, bone health measures, and urine calcium excretion. Findings from the proposed ancillary study will be critical to the interpretation of on-going vitamin D trials and provide new insights to advance clinical care and public health recommendations.