Trial of vitamin D supplementation and neuromuscular functioin in older adults

描述（由申请人提供）：科学界对最佳健康所需的维生素D量存在分歧。2011年，医学研究所（IOM）得出结论，尽管科学证据支持维生素D对骨骼健康的作用，但由于缺乏随机试验，缺乏对非骨骼健康结果（如神经肌肉功能）的有力证据。IOM委员会还得出结论，25-羟基维生素D （25[OH]D）浓度为20 ng/mL （50 nmol/L）对骨骼和整体健康是足够的。这一结论引发了争议，因为大量观察性研究发现，25(OH)D浓度为30 ng/mL （75 nmol/L）对非骨骼健康结果有益。这一争议的解决非常重要，因为近2000万老年人（或美国老年人口的一半）的25(OH)D浓度在20至30 ng/mL之间。越来越多的证据表明，维生素D对减少跌倒的作用是通过改善神经肌肉功能来调节的。观察性研究表明，25(OH)D浓度与肌肉力量和与跌倒风险相关的身体机能指标（如步态、平衡）之间存在关联。然而，先前的维生素D补充试验对肌肉力量和身体表现变化的结果一直模棱两可。此外，维生素D对神经肌肉功能影响的潜在机制尚不清楚。我们建议：1)确定将25（OH)D浓度增加至e30 ng/mL是否会改善25(OH)D初始浓度为20-<30 ng/mL~的老年人的神经肌肉功能；2）研究维生素D补充可能增强肌肉生理和性能的潜在机制。为了实现这些目标，我们将在200名25（OH)D浓度为20-<30 ng/mL的老年（70-89岁）男性和女性中进行一项为期12个月的随机安慰剂对照试验，以确定补充维生素D3对以下方面的影响：1）老年人跌倒的既定危险因素神经肌肉功能的改变（目的1）；2)在40名随机选择的参与者中，4个月以上潜在生理机制的变化（目的2）。参与者将被随机分配到2000 IU/d维生素D3加600 mg/d钙或安慰剂加钙组。将在基线、4个月和12个月时评估下肢肌肉力量和力量、身体表现和姿势摇摆，并每月评估跌倒情况（目的1）。将在基线和4个月时对股外侧肌进行肌肉活检，以评估肌纤维类型、收缩性和去神经，以及卫星细胞的数量和分化阶段（目的2）。确定25(OH)D浓度增加至e30 ng/mL是否会改善作为跌倒危险因素的神经肌肉缺陷，以及将维生素D和神经肌肉功能联系起来的相关潜在生理机制，将为老年人神经肌肉相关结局的维生素D补充建议提供重要数据。

DESCRIPTION (provided by applicant): The scientific community disagrees on the amount of vitamin D required for optimal health. In 2011, the Institute of Medicine (IOM) concluded that while scientific evidence supports a role of vitamin D for bone health, compelling evidence was lacking for non-bone health outcomes such as neuromuscular function due to the paucity of randomized trials. The IOM committee also concluded that 25-hydroxyvitamin D (25[OH]D) concentrations e20 ng/mL (50 nmol/L) were sufficient for bone and overall health. This conclusion has sparked controversy as a large volume of observational research has found that 25(OH)D concentrations e30 ng/mL (75 nmol/L) are beneficial for non-bone health outcomes. The resolution of this controversy is important since almost 20 million older adults (or one-half of the older U.S. adult population) have 25(OH)D concentrations between 20 and 30 ng/mL. There is growing evidence that vitamin D's effect on reducing falls is mediated by improvements in neuromuscular function. Observational studies show associations between 25(OH)D concentrations and muscle strength and physical performance measures associated with fall risk (e.g., gait, balance). Results from previous vitamin D supplementation trials on changes in muscle strength and physical performance have been equivocal, however. Moreover, the underlying mechanisms for vitamin D's effect on neuromuscular function are lacking. We propose to: 1) determine whether increasing 25(OH)D concentrations to e30 ng/mL will improve neuromuscular function in older adults with initial 25(OH)D concentrations of 20-<30 ng/mL~ and 2) examine potential underlying mechanisms by which vitamin D supplementation may enhance muscle physiology and performance. To achieve these goals we will conduct a 12-month, double-blind randomized placebo controlled trial in 200 older (70-89 yrs) men and women with 25(OH)D concentrations of 20-<30 ng/mL to determine the effect of vitamin D3 supplementation on 1) change in neuromuscular functions that are established risk-factors for falls in older adults (Aim 1)~ and 2) changes in the underlying physiological mechanisms over 4 months in a subset of 40 randomly selected participants (Aim 2). Participants will be randomized to 2000 IU/d vitamin D3 plus 600 mg/d calcium or placebo plus calcium. Lower extremity muscle power and strength, physical performance, and postural sway will be assessed at baseline, 4 months and 12 months and falls assessed monthly (Aim 1). Muscle biopsies of the vastus lateralis will be taken at baseline and 4 months to assess muscle fiber type, contractility, and denervation, and number and differentiation stage of satellite cell (Aim 2). Determining whether increasing 25(OH)D concentrations to e30 ng/mL will improve neuromuscular deficits that are risk factors for falls and the associated underlying physiological mechanisms linking vitamin D and neuromuscular function will provide important data to inform vitamin D supplementation recommendations for neuromuscular-related outcomes in older adults.