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

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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.