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

项目总结/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 髋部骨折的功能恢复。这项辅助研究将建立在一个资助的家长试验的行使 在3组髋部骨折恢复期妇女中观察睾酮水平：对照组、运动+安慰剂组（Ex+Pl），或 运动+睾酮（Ex+T）。父母研究的目标是调查使用合成代谢激素， 增强功能恢复，超越运动干预。本研究的目的是调查 低剂量经皮睾酮对老年妇女骨骼和肌肉的合成代谢反应 从髋部骨折中恢复，通过增加体积骨矿物质密度、肌肉 面积和密度以及睾酮和雄激素途径下游代谢物的测量 以及卵泡抑素/激活素途径。中心假设是运动和睾丸激素会增加 骨骼强度、肌肉面积和肌肉密度在更大程度上高于Ex+Pl或对照组; 这些变化的幅度也将与特定性类固醇的变化幅度有关 卵泡抑素的浓度也增加，这是由睾酮结合雄激素上调 受体的这是一个独特的，时间敏感的机会，因为启动额外的成像和血清 我们的目标需要收集。 我们的研究目的是比较三组近期髋部骨折的女性（对照组、Ex+Pl组和Ex+T组）， 6-重要的QCT衍生骨和肌肉结果（体积小梁和皮质骨）的月变化 骨密度、体积积分骨密度和椎体强度的有限元分析 脊柱的分析以及脊柱旁肌肉面积和肌肉密度）。最重要的是，该研究将 还确定了睾酮，游离睾酮， 二氢睾酮（DHT），卵泡抑素和雌二醇的骨和肌肉结果的伴随变化。 与Ex+Pl或对照组相比，假设运动加替吉奥方案产生 骨骼和肌肉结果的显著改善。此外，6个月的变化是 假设与游离睾酮的增加直接相关， 睾酮+双氢睾酮，并增加卵泡抑素，但不与雌二醇的变化。 该项目将有力地提高母研究的科学内容和价值，利用资源， 提高对骨骼和肌肉对激素和运动的反应所涉及的途径的理解 髋部骨折后的干预措施。该项目的结果可能会确定新的治疗靶点 干预，骨折预防，并提供有用的替代指标的临床结果髋部骨折。

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.