Bone Turnover Responses to Sleep Restriction and Subsequent Sleep Recovery

项目摘要 睡眠和昼夜节律紊乱对许多生物系统产生负面影响， 可改变的低骨量和骨折的风险因素。我们是第一个报道累积睡眠 限制同时昼夜节律中断（类似于轮班工作）抑制了骨标志物 在健康男性中形成但不吸收。这些数据与在动物中进行的睡眠限制研究的数据相似 其中还观察到与对照组相比骨矿物质密度（BMD）较低。这种骨头的分离 如果睡眠和昼夜节律紊乱， 发生在青春期或成年早期骨建模和巩固期间，并可能加速骨 后期经历的损失（例如，在更年期过渡期间，当睡眠障碍常见时）。我 K23数据表明，睡眠限制和昼夜节律紊乱相结合会诱导类似的BTM 这些变化发生在暴露于睡眠和睡眠相结合的几天内， 昼夜节律紊乱睡眠时间不足，没有极端的昼夜节律紊乱，对BTM的影响， 独立于住院实验室环境和固有的身体活动，以及逆转 或通过恢复睡眠改善BTM损伤尚不清楚。本R 03的总体科学目标 应用是评估睡眠时间不足的影响，没有极端的昼夜节律中断， 男性和女性的BTM，独立于身体活动，以及恢复睡眠对稳定BTM的作用 或者补偿缩短的睡眠时间。核心假设是睡眠时间不足， 独立于相对缺乏体力活动，将损害女性和男性的骨形成标志物（P1 NP） 骨吸收标志物（CTX）没有变化，延长睡眠时间将恢复P1 NP 水平到基线。这些新的试验数据将为我的K23提供关键的扩展，以产生创新的 具有重大临床影响的假设，我可以在我的R 01测试-一个全面的调查 睡眠和昼夜节律紊乱改变人类骨骼健康的机制。具体目标是： 1.调查工作周中睡眠时间不足是否会降低骨形成的标志物 而不改变骨吸收标志物。 2.确定睡眠不足会导致骨生物标志物的变化，而不依赖于身体活动 通过比较睡眠受限参与者与对照者的BTM变化， 3.确定延长睡眠一个周末或3周是否可以改善或逆转骨骼损伤 由睡眠限制引起的新陈代谢。 这项研究将对科学和病人护理产生持续和强大的影响，因为它可以 介绍了骨质疏松症预防、评估和治疗的范式转变。

PROJECT SUMMARY Sleep and circadian disruptions negatively impact many biological systems and may represent novel, modifiable risk factors for low bone mass and fracture. We were the first to report that cumulative sleep restriction with concurrent circadian disruption (akin to rotating shift work) suppressed a marker of bone formation but not resorption in healthy men. These data parallel those from sleep restriction studies in animals where lower bone mineral density (BMD) compared to controls was also observed. This uncoupling of bone turnover markers (BTMs) in humans may limit attainment of peak bone mass if sleep and circadian disruption occur in adolescence or early adulthood during bone modeling and consolidation, and may accelerate bone loss when experienced later (e.g. during the menopausal transition, when sleep disturbance is common). My K23 data have demonstrated that combined sleep restriction and circadian disruption induce similar BTM changes in women and that these changes occur within a few days of exposure to the combined sleep and circadian disturbance. The effects of insufficient sleep duration, without extreme circadian disruption, on BTMs, independent of the inpatient laboratory environment and inherent physical inactivity, and the ability to reverse or improve BTM impairments with recovery sleep are unknown. The overall scientific objectives of this R03 application are to evaluate the effects of insufficient sleep duration, without extreme circadian disruption, on BTMs in women and men, independent of physical inactivity, and the role of recovery sleep to stabilize BTMs or compensate for the period of shortened sleep. The central hypothesis is that insufficient sleep duration, independent of relative physical inactivity, will impair a marker of bone formation (P1NP) in women and men with no change in a marker of bone resorption (CTX), and that extending sleep duration will restore P1NP levels to baseline. These novel pilot data will provide a critical extension to my K23 to generate innovative hypotheses with significant clinical impact that I can test in my R01 - a comprehensive investigation of the mechanisms by which sleep and circadian disruption alter bone health in humans. The specific aims are: 1. Investigate if insufficient sleep duration during the work week decreases a marker of bone formation without altering a bone resorption marker. 2. Establish that insufficient sleep induces changes in bone biomarkers independent of physical inactivity inherent in an inpatient lab study, by comparing BTM changes in sleep-restricted participants to controls. 3. Determine if extending sleep for a weekend or 3 weeks can improve or reverse impairments in bone metabolism induced by sleep restriction. This research will have a sustained and powerful influence on science and patient care because it can introduce a paradigm shift in osteoporosis prevention, evaluation, and treatment.