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: 9948580
• 负责人: Marian T. Hannan
• 金额: $ 40.25万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9948580
• 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; 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; Lead; 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; Skeletal Muscle; Skeleton; Societies; Speed; Spinal; Stanolone; Stepparent; 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.

项目概要/摘要 骨质疏松性骨折对公共健康有重大影响，需要更好的方法来最大限度地发挥作用 髋部骨折的功能恢复。这项辅助研究将建立在一项资助的家长运动试验的基础上 3 组从髋部骨折中恢复的女性的睾酮水平：对照组、运动 + 安慰剂 (Ex+Pl) 或 运动+睾酮（Ex+T）。家长研究的目标是调查合成代谢激素的用途 增强运动干预之外的功能恢复。本研究的目的是调查 低剂量透皮睾酮对老年女性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、肌肉的机械评估 面积和密度以及雄激素途径中睾酮和下游代谢物的测量 和卵泡抑素/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比 Ex+Pl 组或对照组更大； 此外，这些变化的幅度将与特定性类固醇的变化幅度相关 浓度以及卵泡抑素的增加，卵泡抑素通过睾酮与雄激素的结合而上调 受体。这是一个独特的、时间敏感的机会，因为额外的成像和血清的启动 需要收集来实现我们的目标。 我们的研究目的是比较三组最近发生髋部骨折的女性（对照组、Ex+Pl 和 Ex+T）， 重要的 QCT 衍生骨骼和肌肉结果（体积小梁和皮质）的 6 个月变化 使用有限元计算骨矿物质密度、体积积分骨矿物质密度和椎骨强度 脊柱分析，以及椎旁肌肉面积和肌肉密度）。最重要的是，该研究将 还确定 6 个月睾酮、游离睾酮变化的相对贡献， 二氢睾酮 (DHT)、卵泡抑素和雌二醇会伴随骨骼和肌肉结果的变化。 与 Ex+Pl 或对照组相比，假设睾酮运动方案可产生 骨骼和肌肉结果显着改善。此外，6个月的变化是 假设与游离睾酮的增加直接相关，循环中睾酮的综合水平 睾酮 + DHT，并且卵泡抑素增加，但雌二醇没有变化。 该项目将大力提高母研究的科学内容和价值，利用资源 增进对骨骼和肌肉对激素和运动反应的途径的了解 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标 干预措施、骨折预防并提供髋部骨折临床结果的有用替代标志。