Researchers from the Perelman School of Medicine at the University of Pennsylvania and colleagues wrote that trials with a sufficiently large sample and a sufficiently long duration were necessary to determine the effect of testosterone on the incidence of fractures.
In response, they conducted a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, specifically examining the risk of clinical fracture in a time-to-event analysis. The results were published in the New England Journal of Medicine.
The study included eligible men aged 45 to 80 years with preexisting, or high risk, of cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng/dL (10.4 nmol/L) in fasting plasma samples obtained at least 48 hours apart. For the trial, participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, the study team obtained their medical records and adjudicated the information.
The full-analysis population included 5,204 participants (2,601 in the testosterone group and 2,603 in the placebo group). The authors reported that after a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% CI, 1.04-1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture endpoints.
“Among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo,” the study concluded. “The fracture incidence was numerically higher among men who received testosterone than among those who received placebo.”
The results were somewhat unexpected because testosterone treatment in men who have hypogonadism due to pituitary or testicular disease has been reported to improve many measures of their bone structure and quality, according to the report.
In addition, severe hypogonadism has been associated with an increased risk of clinical fractures among men with prostate cancer. “Men with prostate cancer in whom severe hypogonadism develops after treatment with ‘superactive’ agonists of gonadotropin-releasing hormone have been observed to be more likely to sustain a fracture than men with prostate cancer who have not received this treatment,” according to the study team.
The current subtrial was of the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial, which was a phase IV trial designed primarily to determine whether testosterone treatment in middle-aged and older men with hypogonadism would increase the incidence of major adverse cardiovascular events. It also offered the opportunity to determine whether testosterone treatment would reduce the risk of clinical fractures.
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