The Mechanistic Effects of Combined Testosterone Therapy and Exercise on Axial Bone and Muscle Post-Hip Fracture

项目摘要/摘要 骨质疏松性骨折对公众健康有重大影响，需要更好的方法来最大限度地 髋部骨折后的功能恢复。这项辅助研究将建立在一项由父母资助的锻炼试验的基础上 髋部骨折后康复的3组女性：对照组、运动安慰剂(Ex Pl)或 运动性睾丸素(ExT)。父母的研究目标是调查一种合成代谢激素的使用 在运动干预之外促进功能恢复。这项研究的目的是调查 小剂量透皮睾酮对老年女性骨骼和肌肉的合成代谢反应 通过添加体积骨密度、肌肉的力学评估来恢复髋部骨折 雄激素途径中睾酮及其下游代谢物的面积和密度及其测量 卵泡抑素/激活素途径。中心假设是运动和睾丸素会增加 骨骼力量、肌肉面积和肌肉密度均大于ExPl组和对照组； 此外，这些变化的大小将与特定性激素的变化大小有关 浓度和卵泡抑素也增加，卵泡抑素由与雄激素结合的睾酮上调 受体。这是一个独特的、时间敏感的机会，因为启动了额外的成像和血清 为了达到我们的目标，需要收集资金。 我们的研究目的是比较三组最近髋部骨折的女性(对照组、Ex Pl和Ex T)， 重要的QCT衍生骨和肌肉结果的6个月变化(体积、骨小梁和皮质骨 骨密度、体积积分骨密度和椎体强度的有限元分析 分析脊柱，以及脊柱旁肌肉面积和肌肉密度)。最重要的是，这项研究将 还要确定6个月内睾酮、游离睾酮、 双氢睾酮(DHT)、卵泡抑素和雌二醇对骨骼和肌肉结果的伴随变化。 与ExPl或对照组相比，假设使用睾丸素方案的运动产生 在骨骼和肌肉结果方面有显著的改善。此外，6个月的变化是 假设与游离睾丸素的增加直接相关，循环中的结合水平 睾酮DHT，卵泡抑素增加，但不随雌二醇变化。 该项目将有力地提高家长研究的科学内容和价值，利用资源来 提高对骨骼和肌肉对荷尔蒙和运动反应的认识 干预措施髋部骨折后。这个项目的结果可能会确定治疗的新靶点。 干预，预防骨折，并为髋部骨折的临床结果提供有用的替代指标。

Project Summary/Abstract Osteoporotic fractures have substantial public health impact and better approaches are needed to maximize the functional recovery from hip fracture. This ancillary study will build upon a funded parent trial of exercise and testosterone in 3 groups of women recovering from hip fracture: controls, exercise + placebo (Ex+Pl), or exercise+ testosterone (Ex+T). The parent study goal is to investigate the use of an anabolic hormone to enhance functional recovery beyond exercise interventions. The objective of this study is to investigate the anabolic responses of low-dose transdermal testosterone on the skeleton and muscle in older women recovering from hip fracture, by adding mechanistic assessment of volumetric bone mineral density, muscle area and density as well as measures of testosterone and downstream metabolites in the androgen pathway and the follistatin/activin pathway. The central hypothesis is that exercise and testosterone will increase skeletal strength, muscle area and muscle density to a greater extent than either Ex+Pl or a Control group; also that the magnitude of these changes will be related to the magnitude of change in specific sex steroid concentrations and also increases in follistatin, which is up-regulated by testosterone binding to the androgen receptor. This is a unique, time-sensitive opportunity, as initiation of the additional imaging and serum collection is required to address our aims. Our study aims will compare in three groups of women with recent hip fracture (controls, Ex+Pl, and Ex+T), the 6-month changes in important QCT derived bone and muscle outcomes (volumetric trabecular and cortical bone mineral density, volumetric integral bone mineral density, and vertebral strength using finite element analysis of the spine, as well as paraspinal muscle area and muscle density). Most importantly, the study will also determine the relative contributions of 6-month changes in testosterone, free testosterone, dihydrotestosterone (DHT), follistatin, and estradiol to concomitant changes in the bone and muscle outcomes. Compared to Ex+Pl or to a control group, an Exercise with Testosterone regimen is hypothesized to produce significantly greater improvements in the bone and muscle outcomes. Further, the 6-month changes are hypothesized to be directly associated with increases in free testosterone, the combined levels of circulating testosterone + DHT, and increases in follistatin, but not with changes in estradiol. This project will robustly enhance the scientific content and value of the parent study, leveraging resources to improve understanding of the pathways involved in bone and muscle responses to hormonal and exercise interventions post-hip fracture. Outcomes from this project are likely to identify novel targets for therapeutic interventions, fracture prevention and provide useful surrogate markers of clinical outcomes of hip fracture.