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

睾酮联合治疗和运动对髋部骨折后轴骨和肌肉的机制影响

• 批准号: 10455404
• 负责人: Marian T. Hannan
• 金额: $ 38.79万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-07 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455404
• 关键词: Activins; Address; Aging; Ancillary Study; Androgen Receptor; Androgens; Area; Binding; Biological; Biological Assay; Bone Density; Clinical; Collection; Control Groups; Developed Countries; Dialysis procedure; Dose; Elderly; Enrollment; Equilibrium; Estradiol; Europe; Evaluation; Exercise; Female; Finite Element Analysis; Follistatin; Fracture; Funding; Future; GDF8 gene; Glycoproteins; Goals; Gonadal Steroid Hormones; Hip Fractures; Hormonal; Hormones; Hospitals; Image; Intervention; Knowledge; Measures; Monitor; Muscle; Outcome; Parents; Participant; Pathway interactions; Placebos; Population; Premature Mortality; Prevention; Public Health; Randomized, Controlled Trials; Recovery; Recovery of Function; Regimen; Rehabilitation therapy; Resources; Serum; Skeleton; Societies; Speed; Spinal; Stanolone; Surrogate Markers; Testosterone; Therapeutic Intervention; Time; Transforming Growth Factor beta; Vertebral column; Woman; Women' s Group; X-Ray Computed Tomography; bone; bone strength; cortical bone; density; disability; exercise intervention; exercise regimen; improved; improved mobility; member; new therapeutic target; novel; older women; osteoporosis with pathological fracture; post intervention; prevent; programs; public health relevance; randomized trial; recruit; resistance exercise; response; skeletal; socioeconomics; spine bone structure; substantia spongiosa

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.

项目摘要/摘要 骨质疏松性骨折具有重大的公共卫生影响，需要更好的方法来最大化 髋部骨折的功能恢复。这项辅助研究将基于资助的父母锻炼试验 从髋部骨折恢复的3组女性中的睾丸激素：对照，运动 +安慰剂（EX + PL）或 运动+睾丸激素（EX+ T）。父母研究的目标是研究合成代谢激素的使用 超出运动干预措施，增强功能恢复。这项研究的目的是调查 老年女性骨骼和肌肉的低剂量透皮睾丸激素的合成代谢反应 通过增加体积骨矿物质密度的机械评估，从髋部骨折中恢复 雄激素途径中的面积和密度以及睾丸激素和下游代谢产物的度量 以及卵泡蛋白/激活素途径。中心假设是运动和睾丸激素会增加 骨骼强度，肌肉区域和肌肉密度比EX+PL或对照组更大程度； 同样，这些变化的幅度将与特定性类固醇变化的幅度有关 浓度以及卵泡素的增加，睾丸激素与雄激素的结合上调 受体。这是一个独特的，时间敏感的机会，作为其他成像和精华素的启动 需要收集来解决我们的目标。 我们的研究目的将比较三组患有髋部骨折的女性（对照，Ex+PL和Ex+T）， 重要的QCT衍生骨和肌肉结局的6个月变化（体积小梁和皮质 骨矿物质密度，体积积分骨矿物质密度和椎骨强度使用有限元 分析脊柱，脊髓肌区域和肌肉密度）。最重要的是，该研究将 还确定睾丸激素，游离睾丸激素的6个月变化的相对贡献， 二氢睾丸激素（DHT），Follistatin和雌二醇伴随骨骼和肌肉结局的变化。 与EX+PL或对照组相比，假设具有睾丸激素方案的运动可以产生 骨骼和肌肉结局的改善明显更大。此外，6个月的变化是 假设与游离睾丸激素的增加直接相关，循环的综合水平 睾丸激素 + DHT，卵泡蛋白的增加，但随着雌二醇的变化而增加。 该项目将坚强地增强家长研究的科学内容和价值，利用资源来 提高对骨骼和肌肉反应荷尔蒙和运动涉及的途径的理解 干预后骨折。该项目的结果可能会确定治疗的新颖目标 干预措施，预防断裂并提供了髋部骨折临床结果的有用的替代标记。