Vitamin D and Omega-3 Fatty Acids(VITAL Trial): Effects on Fractures

描述（由申请人提供）：骨质疏松性骨折是与低维生素D水平相关的主要公共卫生问题。先前的数据强烈表明，每天服用700国际单位的维生素D可以减少骨折和跌倒。基础和小型临床试验表明，omega-3脂肪酸也可能对骨骼有益，但对骨折的影响尚不清楚。在普通人群（即未选择疾病风险的人群）中，缺乏每日高剂量维生素D和/或omega-3脂肪酸的大型一级预防试验。我们提出了一项VITAL研究的辅助研究，一项大型、随机、双盲、安慰剂对照的维生素D（以维生素D3[胆骨化醇]的形式）和/或海洋omega-3脂肪酸（二十碳五烯酸[EPA] +二十二碳六烯酸[DHA]）补充剂的试验，以提高知识和测试维生素D3 （2000 IU/ D）和/或鱼油（EPA+DHA, 1g/ D）对骨折、骨质流失、跌倒和虚弱的初级预防作用。越来越多的人热衷于补充维生素D来支持骨骼健康，并使用可能也对骨骼有影响的鱼油，这强调了及时启动这项辅助研究的迫切需要，并与新资助的VITAL母研究（U01CA 138962）相结合。拟议的辅助研究将包括来自美国国立卫生研究院（nih）赞助的5年VITAL母试验的2万名女性和男性（分别为65岁和60岁），以及来自波士顿、芝加哥、休斯顿和旧金山临床和转化科学中心（CTSCs）的700名参与者的亚队列，以严格检验这些假设：主要目的：在VITAL队列中，维生素D3和/或EPA+DHA是否会减少a)全骨折和b)髋部或非椎体骨折的发生率？次要目的：在CTSC亚队列中，维生素D3和/或EPA+DHA是否会减少脊柱、髋关节和全身的骨质流失，正如基线和第2年的双x线吸收测量所评估的那样，其效果是否会随着(a)基线和随访的这些营养素的血液水平、(b)性别、(c)种族/皮肤色素沉着和(d)体重指数而变化？第三目标：在VITAL队列中，维生素D3和/或EPA+DHA补充剂是否会a)根据年度问卷评估降低跌倒的风险，b)根据基于问卷的虚弱指数确定降低虚弱？基线和后续血液采集将按月进行季节匹配，以防止维生素D水平的季节性偏差。为了完成CTSC试验点参与者的预随机化测量，至关重要的是，这项辅助研究必须与母体VITAL试验安慰剂“预选赛”同时进行，以获得基线和随访测量，该试验计划于2010年中期开始。这项时间敏感的辅助研究将严格测试这些营养补充剂在改善骨骼健康方面的作用，并将在维生素D和omega-3脂肪酸对骨折、骨密度、跌倒和虚弱的影响方面提供积极或信息无效的结果。我们期望这项辅助研究的结果将为临床实践提供信息，说明高剂量维生素D和/或鱼油是否能减轻与年龄相关的骨折增加的负担，这将带来广泛的公共卫生益处。

DESCRIPTION (provided by applicant): Osteoporotic fractures are major public health problems that have been associated with low vitamin D levels. Previous data strongly suggest that doses of vitamin D = 700 IU/day reduce fractures and possibly falls. Basic and small clinical trials suggest that omega-3 fatty acids may also have beneficial skeletal effects, but effects on fractures are not known. Large primary prevention trials with high daily doses of vitamin D and/or omega-3 fatty acids in general populations (i.e., unselected for disease risk) are lacking. We propose an ancillary study to the VITAL study, a large, randomized, double-blind, placebo-controlled trial of vitamin D (in the form of vitamin D3 [cholecalciferol]) and/or marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements, to advance knowledge and test the effects of vitamin D3 (2000 IU/d) and/or fish oil (EPA+DHA, 1g/d) for primary prevention of fractures, bone loss, falls, and frailty. Growing enthusiasm for supplemental vitamin D to support bone health, and use of fish oil, which may also have skeletal effects, underscores the urgent need for a timely initiation of this ancillary study in conjunction with the newly funded VITAL parent study (U01CA 138962). The proposed ancillary study will include 20,000 women and men (>age 65 and 60, respectively) from the 5-year, NIH-sponsored, parent VITAL trial and a sub-cohort from that trial of 700 participants from Clinical and Translational Science Centers (CTSCs) in Boston, Chicago, Houston, and San Francisco to critically test these hypotheses: Primary Aims: In the VITAL cohort, will vitamin D3 and/or EPA+DHA reduce incident a) total fractures and b) hip or non-vertebral fractures? Secondary Aims: In the CTSC sub-cohort, will vitamin D3 and/or EPA+DHA reduce bone loss of the spine, hip, and total body, as assessed by Dual X-ray Absorptiometry at baseline and year 2 and do effects vary with (a) baseline and follow up blood levels of these nutrients, (b) gender, (c) race/skin pigmentation, and (d) body mass index? Tertiary Aims: In the VITAL cohort, will Vitamin D3 and/or EPA+DHA supplementation a) reduce the risk of falls as assessed by annual questionnaires and b) reduce frailty as determined by the questionnaire- based frailty index? Baseline and follow-up blood collections will be matched for season by month to prevent seasonal bias for vitamin D levels. In order to complete pre-randomization measurements among participants in the CTSC sites, it is essential that this ancillary study be undertaken in parallel to the parent VITAL trial placebo "run-in" to get baseline and follow-up measurements, which is scheduled to begin in mid-2010. This time-sensitive ancillary study will rigorously test the role of these nutritional supplements in improving skeletal health and will provide positive or informative null results on the effects of vitamin D and omega-3 fatty acids on fractures, bone density, falls, and frailty. We expect that findings from this ancillary study will inform clinical practice on whether high daily dose vitamin D and/or fish oil reduces the burden of age-related increases in fractures, which would result in widespread public health benefits. PUBLIC HEALTH RELEVANCE: Osteoporotic fractures and low vitamin D levels are major public health concerns. Several lines of evidence suggest that supplemental vitamin D may reduce the risk of fractures, bone loss, and falls, but the effects of high-dose vitamin D on these endpoints are lacking. We propose to conduct a time-sensitive, ancillary study to the large, randomized, controlled clinical trial - the VITamin D and OmegA-3 TriaL (VITAL) - to evaluate the role of high dose vitamin D and/or omega-3 fatty acids in the primary prevention of fractures, bone loss, falls, and also frailty; findings from this proposed ancillary study will advance science and inform clinical practice on the role(s) of vitamin D and/or omega-3 fatty acid supplements in bone health and fracture prevention.