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。以前的数据有力地表明，每天服用700IU的维生素D可以减少骨折和跌倒的可能性。基础和小型临床试验表明，omega-3脂肪酸也可能对骨骼有有益的影响，但对骨折的影响尚不清楚。缺乏在普通人群中(即未根据疾病风险进行选择)每日大剂量服用维生素D和/或omega-3脂肪酸的大型初级预防试验。我们建议对VITAL研究进行一项大型、随机、双盲、安慰剂对照的维生素D(维生素D3[胆钙醇]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])补充剂的辅助研究，以增进人们的认识，并测试维生素D3(2000IU/d)和/或鱼油(EPA+DHA，1g/d)对骨折、骨丢失、跌倒和脆弱的一级预防作用。人们对补充维生素D以支持骨骼健康的热情日益高涨，使用鱼油也可能对骨骼有影响，这突显了与新资助的重要父母研究(U01CA 138962)一起及时启动这项辅助研究的迫切需要。拟议的辅助研究将包括来自NIH赞助的为期5年的家长VITAL试验的20,000名女性和男性(年龄分别为65岁和60岁)，以及来自波士顿、芝加哥、休斯顿和旧金山的临床和翻译科学中心(CTSC)的700名参与者的子队列，以严格检验这些假设：主要目标：在VITAL队列中，维生素D3和/或EPA+DHA能否减少a)全部骨折和b)髋部或非脊椎骨折的事件？次要目标：在CTSC亚队列中，维生素D3和/或EPA+DHA是否会减少脊柱、髋部和全身的骨丢失，如在基线和第二年通过双X射线吸收测量仪评估的那样，效果是否会因(A)这些营养素的基线和随访水平、(B)性别、(C)种族/皮肤色素沉着和(D)体重指数而不同？第三个目标：在重要的队列中，维生素D3和/或EPA+DHA补充剂a)降低了年度问卷评估的跌倒风险，b)降低了基于问卷的脆弱指数确定的脆弱程度？基线和后续血液采集将按季节逐月进行匹配，以防止维生素D水平的季节性偏差。为了在CTSC站点的参与者中完成预随机化测量，这项辅助研究必须与父母VITAL试验安慰剂“磨合”并行进行，以获得基线和后续测量，计划于2010年年中开始。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，并将提供关于维生素D和omega-3脂肪酸对骨折、骨密度、跌倒和脆弱的影响的阳性或信息性无效结果。我们预计，这项辅助研究的结果将为临床实践提供参考，即每天大剂量的维生素D和/或鱼油是否可以减轻与年龄相关的骨折增加的负担，这将导致广泛的公众健康益处。 公共卫生相关性：骨质疏松性骨折和低维生素D水平是主要的公共卫生问题。一些证据表明，补充维生素D可能会降低骨折、骨丢失和跌倒的风险，但大剂量维生素D对这些终点的影响是缺乏的。我们建议对大型随机对照临床试验-维生素D和omega-3试验(VITAL)-进行一项时间敏感的辅助研究，以评估大剂量维生素D和/或omega-3脂肪酸在一级预防骨折、骨丢失、跌倒和脆弱中的作用；这项拟议的辅助研究的结果将推动科学发展，并为临床实践提供关于维生素D和/或omega-3脂肪酸补充剂在骨骼健康和骨折预防中的作用(S)。

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.