Testosterone may not decrease fracture risk in hypogonadism
A substudy of an industry-funded randomized trial in men with hypogonadism found that 3.50% of those assigned to testosterone and 2.46% assigned to placebo had a clinical fracture after 3.19 years of follow-up.
Testosterone treatment does not appear to affect fracture risk in men with hypogonadism, a recent analysis found.
The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial was a phase 4 trial funded by a pharmaceutical consortium led by AbbVie that examined whether testosterone treatment increased major cardiovascular events in middle-aged and older men with hypogonadism. Men were eligible for the trial if they were 45 to 80 years old, had preexisting cardiovascular disease or were at high risk, had at least one symptom of hypogonadism, and had two morning fasting plasma testosterone levels of less than 300 ng/dL in samples obtained at least 48 hours apart.
During enrollment, from May 23, 2018, to Feb. 1, 2022, patients were randomly assigned to apply a transdermal 1.62% testosterone gel or a placebo gel daily. They were asked at every in-person or telephone visit whether they had had a fracture since their previous visit, and if they said yes, their medical records were reviewed and adjudicated. Clinical fractures were defined as clinical spine or nonspine fractures documented by imaging or surgery and confirmed by adjudication, except for fractures of the sternum, fingers, toes, facial bones, and skull. The goal of the study was to assess whether testosterone treatment reduced the risk of clinical fractures. Results were published Jan. 18 by the New England Journal of Medicine.
The full analysis population of the TRAVERSE trial had 5,204 participants, 2,601 in the testosterone group and 2,603 in the placebo group. Median serum testosterone concentration increased in the testosterone group from 227 ng/dL (interquartile range, 189 to 258 ng/dL) at baseline to 368 ng/dL (interquartile range, 266 to 519 ng/dL) at six months and continued to exceed baseline levels over three years. The placebo group had no substantial change in median serum testosterone concentration.
After 3.19 years of follow-up, 91 patients in the testosterone group and 64 in the placebo group had had a confirmed clinical fracture (3.50% vs. 2.46%; hazard ratio, 1.43 [95% CI, 1.04 to 1.97]). Cumulative incidence of clinical fracture at year 3 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. Testosterone was also consistently associated with higher incidence of fractures of all types versus placebo, including non-high-impact clinical fractures, all clinical fractures including those previously excluded, and clinical fractures in patients not taking osteoporosis medications.
The authors noted that their results were unexpected, since most previous studies have shown a beneficial effect of testosterone on measures of bone structure and quality. Among other limitations, adherence to the study medication was suboptimal, information about falls was assessed only in patients who reported fractures, and bone density and structure were not assessed, they said. The researchers concluded that testosterone treatment did not reduce incidence of clinical fractures compared with placebo in middle-aged and older men with hypogonadism and that fracture incidence was numerically higher in the testosterone group.
An accompanying editorial agreed that the study results were surprising and speculated that the differences between groups may have been due in part to behavioral changes. They also addressed the trial's limitations, pointing out that most patients had obesity and diabetes and may not have had hypogonadism, and said the findings do not apply to men whose hypogonadism is due to identifiable disease of the hypothalamic pituitary-testicular axis, since they require testosterone for normal function.
“However, a potential increase in fracture risk should be considered in the decision making about testosterone therapy for men with low serum testosterone concentrations due to aging or obesity,” the editorialists wrote. “Finally, men at high risk for fragility fracture should receive osteoporotic drug therapy with proven antifracture benefit independent of any consideration of testosterone therapy.” They called for additional randomized controlled trials evaluating the effects of exogenous testosterone on fractures.