Fracture Risk Bumped With Testosterone Therapy in Hypogonadal Men

Testosterone treatment didn’t offer protection against fractures in men with hypogonadism, a TRAVERSE subtrial indicated.

Compared with placebo, men who were on a testosterone gel actually had a significantly higher risk for fracture (HR 1.43, 95% CI 1.04-1.97), found Peter Snyder, MD, of the University of Pennsylvania in Philadelphia, and colleagues.

During the median 3.19-year follow-up, 91 men on testosterone experienced a clinical fracture compared with 64 men on placebo, excluding fractures of the sternum, fingers, toes, facial bones, and skull (3.50% vs 2.46%), the group wrote in the New England Journal of Medicine.

The researchers were quite surprised to find this, Snyder told MedPage Today, referencing how prior studies have demonstrated that testosterone increases bone structure and therefore might reduce the risk of fracture, in theory.

Testosterone-treated men had a numerically higher rate of all types of fractures compared with placebo, including:

• Non-high-impact clinical fractures: 2.88% of testosterone group vs 2.19% of placebo
• Clinical fractures in those not on osteoporosis medication: 3.40% vs 2.43%
• Major osteoporotic fractures (hip, wrist, humerus, and clinical spine): 1.38% vs 1.15%
• Hip fractures: 0.27% vs 0.23%
• Clinical vertebral fractures: 0.54% vs 0.42%

In both groups, most of the fractures endured were associated with trauma, mostly commonly with falls. The most common fracture sites were ribs, wrist, and ankle. “These sites are of clinical significance because fractures at these sites are associated with low bone mineral density and with previous fractures and are therefore considered osteoporotic fractures,” the researchers pointed out, adding that these fractures are also tied with increased risk for future fractures and death.

It’s “unlikely” that this increased risk for osteoporosis fracture was a direct result of testosterone affecting bone structure and strength, argued accompanying editorial authors Mathis Grossmann, MD, PhD, of the University of Melbourne in Australia, and Bradley Anawalt, MD, of the University of Washington School of Medicine in Seattle. Instead, they think this more likely stemmed from a behavioral change from the testosterone bumping up engagement in physical activities.

Topline TRAVERSE findings, presented at the ENDO 2023 conference, found testosterone was noninferior to placebo for the occurrence of major adverse cardiac events in men with established or at high risk for cardiovascular disease. However, testosterone was linked with a higher rate of a few other risks compared with placebo including atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%), and pulmonary embolism (0.9% vs 0.5%).

“Finding that testosterone treatment of men with late-onset hypogonadism increases fracture risk, together with the previously reported increased risk of atrial fibrillation and blood clots, outweighs the benefits of this treatment on improving sexual function and, to a lesser degree, walking and mood,” said Snyder.

All in all, testosterone treatment of late-onset hypogonadism is simply not worth the risks, he warned other clinicians.

Another recent analysis from the trial found testosterone-treated men didn’t have an increased risk for adverse prostate events. However, testosterone replacement therapy was linked with a significant increase in prostate-specific antigen (PSA) values compared with placebo as early as 3 months and persisted to 12 months.

Men ages 45 to 80 (median age 63) were included in the TRAVERSE trial if they had preexisting or high risk of cardiovascular disease, at least one symptom 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. Those with a serum testosterone concentration of less than 100 ng/dL (3.5 nmol/L) or with conditions that might be worsened by testosterone treatment, like prostate cancer, were excluded. Average baseline BMI was 35.

The full-analysis population included 5,204 participants: 2,601 on testosterone and 2,603 on placebo. Testosterone-treated patients used a transdermal 1.62% testosterone gel with a goal of maintaining a serum testosterone concentration of 350 to 750 ng/dL and a hematocrit under 54%.

The median serum testosterone concentration in the testosterone group increased from 227 ng/dL at baseline to 368 ng/dL by month 6 and remained higher than baseline through year 3.

Some limitations of the study included that physical activity and risk-taking weren’t assessed, nor were bone density and structure. Editorialists Grossmann and Anawalt said future studies must include measurements of behavior and physical function affecting fracture risk.

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