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

通过减轻运动过程中钙稳态的急性破坏来增强骨骼对运动的适应

• 批准号: 10251565
• 负责人: Wendy M Kohrt
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10251565
• 关键词: Acute; Address; Attenuated; Blood; Bone Density; Bone Injury; Bone Resorption; C-telopeptide; Calcium; Cholecalciferol; Chronic; Citrates; Collagen Type I; Cyclophosphamide; Diagnosis; Educational Intervention; Event; Exercise; Female; Forteo; General Population; Goals; Guidelines; Heart Rate; Hip Fractures; Homeostasis; Hormone secretion; Hour; Human Resources; Intravenous; Lead; Measures; Mediating; Military Personnel; N-terminal; Oral; Osteogenesis; Osteoporosis; PTH gene; Parathyroid Hormone Receptor; Participant; Pharmaceutical Preparations; Pharmacology; Phase; Prevalence; Procollagen; Quality of life; Randomized; Randomized Controlled Trials; Recommendation; Research; Risk; Serum; Serum Markers; Signal Transduction; Strenuous Exercise; Stress Fractures; Supervision; Therapeutic; Time; Training; Veterans; Weight-Bearing state; Work; absorption; active duty; analog; attenuation; bone; bone health; bone mass; bone strength; calcium supplementation; exercise intervention; exercise prescription; exercise training; fracture risk; high risk; hormone analog; improved; male; men; nutrition; prevent; response; skeletal; treadmill

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.

锻炼对于建立和维持骨量和力量至关重要，但我们最近的工作提高了 当前针对骨骼健康的运动建议可能不合适。我们有强大的 有证据表明，单次剧烈运动会对骨骼产生急性分解代谢作用（即增加 吸收）持续几个小时。这是由运动期间血清钙 (Ca) 降低介导的， 它刺激甲状旁腺激素（PTH）的分泌。然后 PTH 激活骨吸收以动员 Ca 来自骨骼，大概是为了防止血清钙的减少发展到有害水平。这个级联 通过最大限度地减少运动期间血清钙的下降，可以显着减弱事件的发生 静脉或口服钙给药。相对于运动补充钙的时机可能很重要， 因为它必须在运动过程中可供肠道吸收。有趣的是，重复药理学 用 PTH 类似物（特立帕肽、abaloparatide）刺激 PTH 受体对骨骼具有合成代谢作用， 表明反复运动引起的 PTH 增加可能会产生慢性合成代谢骨骼效应， 除了急性分解代谢效应外，这种效应只有在反复运动后才会显现出来。如果这是 在这种情况下，通过运动前补充钙来抑制 PTH 反应可能并不合适。在这个 在这种情况下，概念验证阶段将包括短期锻炼干预，包括跑步机锻炼 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 次、第 8 次和第 16 次运动之前、期间和之后 24 小时测量形成和吸收 会议旨在解决两个问题：1）骨骼的急性分解代谢反应是否会对单次运动产生影响 重复运动（即运动训练）后是否继续发生？ 2）也进行运动训练吗 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？ 如果问题 1 和 2 的答案为“是”（持续分解代谢信号）和“否”（缺乏合成代谢信号），则此 将支持随机对照试验（RCT）的需要，该试验将评估之前是否服用钙 减轻急性分解代谢反应的运动可以改善骨骼对运动训练的适应。随机对照试验 将是一项为期 36 周的监督运动干预，参与者随机服用补充钙 每次运动前约 60 分钟服用柠檬酸盐加维生素 D3 (Ca+D3) 或单独维生素 D3（D3；对照）。 主要目的是确定 1) 运动前服用钙是否可以提高骨矿物质密度 (BMD) 对运动的适应，以及 2) 这是否是通过减弱运动期间骨吸收的增加而发生的 锻炼后。总体目标是改进目前不精确的建议 锻炼以改善和保持骨骼健康。这项研究与退伍军人高度相关，他们处于 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 认识不足、诊断不足和治疗不足，为男性退伍军人提供了有效的非 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。潜力 这项研究的影响不仅限于退伍军人。它可能会降低运动相关骨骼的风险 减少现役军人和运动员的损伤（即应力性骨折），并改善骨骼健康 一般人群。