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: 10545712
• 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/10545712
• 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; Measures; Mediating; Military Personnel; N-terminal; Oral; Osteogenesis; Osteoporosis; PTH gene; Parathyroid Hormone Receptor; Participant; Pharmaceutical Preparations; Phase; Prevalence; Procollagen; Quality of life; Randomized; Randomized, Controlled Trials; Recommendation; Research; Risk; Serum; Serum Markers; Signal Transduction; Strenuous Exercise; Stress Fractures; 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; pharmacologic; prevent; release of sequestered calcium ion into cytoplasm; 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.

锻炼对于建立和保持骨量和力量是必不可少的，但我们最近的研究提高了 目前对骨骼健康的运动建议可能不合适。我们有很强的 单次剧烈运动对骨骼有急性分解代谢作用的证据(即增加 再吸收)，持续几个小时。这是通过运动过程中血清钙(Ca)的下降来调节的， 刺激甲状旁腺激素(PTH)的分泌。然后，甲状旁腺激素激活骨吸收，以动员钙 从骨骼中，推测是为了防止血清钙的下降发展到有害的水平。这一级联 在运动过程中，通过以下两种方法中的一种，可以最大限度地减少血清钙的下降，从而显著减轻运动的影响 静脉或口服补钙。相对于运动，补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，重复的药理学 用PTH类似物(Teriparatide，abaloparatide)刺激PTH受体对骨骼有合成代谢作用， 这表明反复运动诱导的甲状旁腺素的增加可能会对骨骼产生慢性合成代谢的影响，在 除了急性分解代谢的影响，这可能只有在反复运动后才会明显。如果这是 这种情况下，运动前补钙抑制甲状旁腺素反应可能是不合适的。在这 背景，概念验证阶段将包括由跑步机运动组成的短期运动干预 最大心率的70%~80%，每天60min，每周4天，共4周。骨的血清标志物 在第一次、第八次和第十六次锻炼前、中和之后24小时内测量形成和吸收情况。 旨在解决两个问题的会议：1)一次运动对骨骼的急性分解代谢反应 持续进行重复运动(即运动训练)？2)运动训练也进行吗 产生合成代谢的甲状旁腺素介导的骨反应，类似于甲状旁腺素类似疗法的合成代谢反应？ 如果问题1和2的答案是是(持续分解代谢信号)和否(缺乏合成代谢信号)，则这 将支持随机对照试验(RCT)的需要，该试验将评估在此之前是否服用钙 减少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能力。RCT 将是一项为期36周的监督运动干预，参与者随机接受补充治疗 每次运动前约60分钟，柠檬酸盐加维生素D3(Ca+D3)或单独服用维生素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 对运动的适应，以及2)这是否通过减弱运动中骨吸收的增加而发生 在锻炼之后。首要目标是改进目前不准确的建议 锻炼身体以改善和保持骨骼健康。这项研究对退伍军人具有很高的相关性，他们在 与非退伍军人相比，髋部骨折的风险增加。此外，因为男性的骨质疏松症 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 这项研究的影响也超出了退伍军人的范围。这可能会降低与运动相关的骨骼风险 现役军人和运动员的损伤(即应力性骨折)和改善 普通人口。