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Fracture occurrences were numerically higher among men who received testosterone than placebo across a subtrial of the phase 4 TRAVERSE trial.
A subtrial of the phase 4 TRAVERSE trial revealed testosterone treatment was not associated with a reduction in the incidence of clinical fractures, compared with placebo, among middle-aged and older men with hypogonadism.1
The findings showed the 3-year cumulative incidence of all clinical fractures was nearly 4% among those treated with testosterone, compared with 2.8% in the placebo group. Further data revealed the fracture incidence was also numerically greater in the testosterone group for all other fracture endpoints.
“We did not expect these results, because most previous studies showed that testosterone improved many measures of bone structure and quality,” wrote the investigative team, led by Peter J. Snyder, MD, Perelman School of Medicine, University of Pennsylvania.
The TRAVERSE phase 4 trial, designed to address whether testosterone treatment would increase the incidence of major adverse cardiovascular events in middle-aged and older men, provided an opportunity to address whether testosterone treatment would reduce the risk of clinical fractures.2 The planned Fracture subtrial assessed the effect of testosterone on the risk of incident clinical fractures in all participants in TRAVERSE.
Testosterone treatment among men with hypogonadism, due to pituitary or testicular disease, or aging, has been reported to improve several bone density and quality measures.3 However, severe hypogonadism has been linked to an increased risk of clinical fractures among men with prostate cancer. Thus, a trial with a sufficiently large sample and long duration could benefit the understanding of the effect of testosterone therapy on fracture incidence.1
Eligible participants in the TRAVERSE subtrial were aged 45 to 80 years with clinical hypogonadism, defined by 2 morning testosterone concentrations of ≤300 ng per deciliter in fasting plasma samples obtained ≥48 hours apart, and showed evidence of preexisting, or an increased risk of, cardiovascular disease (CVD). Participants were randomly assigned in a 1:1 ratio to receive either a once-daily transdermal 1.62% testosterone gel or a matching placebo gel.
For the analysis, participants were asked during an in-person or telephone visit if they had a fracture since the previous visit. Reports on the nature of the injury and the location of the fracture were collected, and investigators asked permission to collect source documents, such as radiology reports. The primary fracture endpoint in the time-to-event analysis was the first clinical fracture – fractures were defined as a clinical spine or non-spine fracture, while fractures of the sternum, fingers, toes, facial bones, and skull were excluded from the analysis.
Enrollment occurred from May 2018 to February 2022. The full-analysis population consisted of 5204 participants, including 2601 patients in the testosterone group and 2603 in the placebo group. Participants experienced a median follow-up of 3.19 years and exhibited adherence of approximately 90% across both trial groups.
Median testosterone levels in the testosterone cohort increased from 227 ng per deciliter at baseline to 368 ng per deciliter at month 6 and sustained a higher level than baseline through year 3. On the other hand, the placebo cohort did not experience a substantial change in the median serum testosterone cohort.
Snyder and colleagues noted a clinical fracture occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio [HR], 1.43; 95% CI, 1.04 - 1.97). At year 3, the cumulative incidence of clinical fractures was 3.8% (95% CI, 3.0 to 4.6) in the testosterone group and 2.8% (95% CI, 2.1 to 3.5) in the placebo group.
Further safety analyses revealed testosterone was not associated with a higher risk of major adverse cardiovascular events, but treatment was associated with an increased risk of atrial fibrillation, pulmonary embolism, and acute kidney injury.
“The fact that testosterone was associated with increased fracture risk among middle-aged and older men with hypogonadism should be considered in the context of potential benefits and other risks of testosterone treatment in these men,” investigators wrote.