Enhancing Skeletal Adaptation to Exercise by Attenuating the Acute Disruption of Calcium Homeostasis During Exercise

运动对于建立和保持骨量和力量是必不可少的，但我们最近的工作提高了 目前对骨骼健康的锻炼建议可能不合适。我们有强大 有证据表明单次剧烈运动在骨中具有急性分解代谢作用（即，增加 再吸收）持续几个小时。这是由运动期间血清钙（Ca）的降低介导的， 其刺激甲状旁腺激素（PTH）分泌。然后PTH激活骨吸收以动员Ca 从骨骼中提取，大概是为了防止血清钙的下降发展到有害的水平。该级联 的事件可以显着减弱，最大限度地减少血清钙在运动过程中，通过以下任一 静脉内或口服Ca施用。钙补充相对于运动的时间可能很重要， 因为它必须在运动时被肠道吸收。有趣的是，重复的药理学 用PTH类似物（特立哌酮，阿巴帕酮）刺激PTH受体对骨具有合成代谢作用， 这表明，反复运动引起的PTH增加可能具有慢性合成代谢骨骼效应， 除了急性分解代谢作用，这可能是明显的，只有经过反复锻炼会议。如果这是 在这种情况下，通过运动前补充钙来抑制PTH反应可能不合适。在这 在这种情况下，概念验证阶段将包括一个短期的运动干预，包括跑步机运动， 最大心率的70%至80%，每天60分钟，每周4天，持续4周。骨血清标志物 将在第1、8和16次运动之前、期间和之后24小时测量形成和再吸收 讨论两个问题：1）骨骼对一次运动的急性分解代谢反应 随着重复的锻炼持续发生（即，运动训练）？2)运动训练也 产生合成代谢PTH介导的骨反应，类似于PTH类似物治疗的合成代谢反应？ 如果对问题1和2的回答是“是”（持续分解代谢信号）和“否”（缺乏合成代谢信号）， 将支持随机对照试验（RCT）的必要性，该试验将评估是否在 减弱急性分解代谢反应的运动改善了骨骼对运动训练的适应。的RCT 将是一个36周的监督运动干预，参与者随机服用补充钙 柠檬酸盐加维生素D3（Ca+D3）或单独的维生素D3（D3;对照）。 主要目的是确定1）运动前服用钙是否能提高骨密度（BMD） 适应运动，以及2）这是否通过减弱运动期间骨吸收的增加而发生， 在运动后。总体目标是改进目前不精确的建议， 运动，以改善和保持骨骼健康。这项研究对退伍军人具有高度相关性，他们在 与非退伍军人相比，髋部骨折的风险增加。此外，由于男性骨质疏松症是 认识不足，诊断不足，治疗不足，为男性退伍军人提供有效的非- 降低骨折风险的药物治疗选择可能有助于缩小这一治疗差距。的潜在 这项研究的影响也超出了退伍军人。它可以降低运动相关性骨质疏松的风险 损伤（即，应力性骨折），并改善 一般人口。

Exercise is essential for building and maintaining bone mass and strength, but our recent work has raised the possibility that current exercise recommendations for bone health may not be appropriate. We have strong evidence that a single bout of vigorous exercise has an acute catabolic effect in bone (i.e., increased resorption) that lasts several hours. This is mediated by a decrease in serum calcium (Ca) during exercise, which stimulates parathyroid hormone (PTH) secretion. PTH then activates bone resorption to mobilize Ca from bone, presumably to prevent the decrease in serum Ca from progressing to a harmful level. This cascade of events can be markedly attenuated by minimizing the decline in serum Ca during exercise via either intravenous or oral Ca administration. The timing of Ca supplementation relative to exercise is likely important, because it must be available for gut absorption during exercise. Interestingly, repeated pharmacologic stimulation of the PTH receptor with PTH analogs (teriparatide, abaloparatide) has anabolic effects on bone, suggesting that repeated exercise-induced increases in PTH could have a chronic anabolic skeletal effect, in addition to the acute catabolic effect, which may be apparent only after repeated exercise sessions. If this is the case, suppressing the PTH response with pre-exercise Ca supplementation may not be appropriate. In this context, the proof-of-concept phase will include a short exercise intervention consisting of treadmill exercise at 70% to 80% of maximal heart rate, 60 minutes per day, 4 days per week, for 4 weeks. Serum markers of bone formation and resorption will be measured before, during, and for 24 hours after the 1st, 8th, and 16th exercise sessions to address two questions: 1) Does the acute catabolic response of bone to a single bout of exercise continue to occur with repeated exercise sessions (i.e., exercise training)? 2) Does exercise training also generate an anabolic PTH-mediated bone response, similar to the anabolic response to PTH analog therapy? If the answers to questions 1 and 2 are YES (persistent catabolic signal) and NO (lack of anabolic signal), this will support the need for the randomized controlled trial (RCT), which will evaluate whether taking Ca before exercise to attenuate the acute catabolic response improves skeletal adaptations to exercise training. The RCT will be a 36-week supervised exercise intervention, with participants randomized to take supplemental Ca citrate plus vitamin D3 (Ca+D3) or vitamin D3 alone (D3; control) about 60 minutes before each exercise. Primary aims are to determine 1) whether taking Ca before exercise enhances bone mineral density (BMD) adaptations to exercise, and 2) whether this occurs by attenuating the increase in bone resorption during and after exercise sessions. The overarching goal is to improve the currently imprecise recommendations for exercise to improve and maintain bone health. This research is of high relevance to Veterans, who are at increased risk of hip fracture when compared with non-Veterans. Further, because osteoporosis in men is under-recognized, under-diagnosed, and under-treated, providing male Veterans with an effective non- pharmacologic therapeutic option to reduce fracture risk may help close this treatment gap. The potential impact of this research also extends beyond Veterans. It could lead to reduced risk of exercise-related bone injury (i.e., stress fractures) in active duty military personnel and athletes and to improved bone health in the general population.