Contrary to the known benefits of testosterone on bone health in the treatment of older men with hypogonadism, a new study reported a surprisingly increased, not decreased, incidence of fracture with the treatment compared with placebo, with the most common fracture sites being those associated with low bone mineral density (BMD).
“We did not expect these results because most previous studies showed that testosterone improved many measures of bone structure and quality,” reported the authors in the study, published in the New England Journal of Medicine.
“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,” they wrote.
With its large enrollment and long duration, “this is a very important study,” Bradley D. Anawalt, MD, who was not involved in the research, told Medscape Medical News.
“It is the first study with a large enough number of men taking testosterone for more than a year to determine whether raising serum testosterone from low blood concentrations into the normal range will affect the risk of fractures,” said Anawalt, of the Department of Medicine, University of Washington School of Medicine, Seattle, Washington, who coauthored an editorial published with the study.
Subtrial Involved Hypogonadal Men at Cardiovascular Risk
With testosterone’s well-known role in increasing BMD and achieving peak bone mass, a benefit of its treatment in preventing fracture in men with low testosterone has seemed feasible; however, long-term studies on the issue have been lacking.
To investigate, first author Peter J. Snyder, MD, of the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and colleagues conducted a subtrial of the landmark, double-blind, randomized, TRAVERSE trial, which was designed to evaluate the risk for major adverse cardiovascular events (MACE) among older men with a high risk for cardiovascular events and hypogonadism who were treated with testosterone.
While the study showed no increased risk for MACE vs placebo, testosterone treatment was linked to an increased risk for atrial fibrillation, pulmonary embolism, and acute kidney injury.
The new subtrial looking at the fracture risk evaluated data on the study’s 5204 participants at 316 sites in the United States, who had a median age of 64 and hypogonadism. The participants were randomized to receive either transdermal 1.62% testosterone gel (n=2601) or matching placebo gel (n=2603).
For the study, hypogonadism was defined as having two morning testosterone concentrations of less than 300 ng/dL (10.4 nmol/L) in fasting plasma samples obtained at least 48 hours apart, along with one or more symptoms of hypogonadism.
The participants were generally obese, with a mean body mass index of 35; approximately, 70% had diabetes, and fewer than 1% were receiving osteoporosis medication.
Characteristics between the treatment and placebo groups were similar in factors including age, race, the use of medications to treat osteoporosis, serum testosterone and estradiol concentrations, and the authors’ note.
After a median follow-up of 3.19 years, 3.50% (91 participants) of those in the testosterone treatment group experienced a clinical fracture compared with 2.46% (64 participants) of those in the placebo group, after excluding fractures of the sternum, fingers, toes, facial bones, and skull (hazard ratio [HR], 1.43).
Those in the testosterone treatment group also had higher rates than those in the placebo group of non–high-impact clinical fractures (HR, 1.32); all clinical fractures, including those that were excluded (HR, 1.52); and clinical fractures among participants not taking osteoporosis medication (HR, 1.41).
Of note, the most common sites of fractures were the ribs, wrist, and ankle, suggesting the possibility of testosterone having a negative effect on bone structure.
“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 authors reported.
“More important, they are associated with an increased risk of future fractures and increased mortality,” they added.
With the findings unexpected, the trial was not designed to assess mechanisms that might explain an increase in fractures, such as changes in bone density and structure.
Of note, the change in serum testosterone concentrations in the testosterone treatment group over the course of the study was lower than that has been reported in some other studies, increasing from a median of 227 ng/dL at baseline to 368 ng/dL at month 6 and remaining higher for the study’s duration; however, a lower increase would not explain an increase in fractures, the authors said.
Testosterone-Related Behavioral Changes Explain Increased Fracture Risk?
In their editorial, Anawalt and coauthor Mathis Grossmann, MD, PhD, of the Department of Medicine (Austin Health), University of Melbourne, Melbourne, Australia, noted that with relatively rapid increases in fracture observed after testosterone treatment in the trial, the possibility of the results reflecting treatment on bone strength and structure is unlikely.
Instead, testosterone’s behavioral effects may have put patients at a higher risk for fracture.
“Testosterone might have affected behaviors such as engaging in physical activities associated with fracture risk,” they speculated.
In the previous Testosterone Trials, which Snyder, first author of the current study, was also involved as an investigator, men with low testosterone concentrations treated with testosterone were indeed more likely to report increased energy vs placebo, Anawalt told Medscape Medical News.
“These men also walked faster and farther in time-walking trials,” he noted. “It is possible that the effect of increased energy that seems to occur early after initiation of testosterone would increase the risk of fall or trauma compared to placebo.”
“It is also possible that testosterone might increase risk-taking behavior that would increase the risk of traumatic fracture,” he added.
Snyder told Medscape Medical News he “agreed that increased physical activity or even risky behavior could explain the increased risk of fractures.”
“But because we did not evaluate for those possibilities, these remain speculations,” he said.
The study’s high rates of obesity and diabetes, which can suppress sex hormone–binding globulin, are a caveat, and the authors added that “many participants might have had low serum total testosterone concentrations but normal free testosterone concentrations, ie, pseudo-hypogonadism.”
“[The fact] that the men were obese does make the testosterone values at the baseline not quite as low as they appear,” Snyder explained. “But these men were probably moderately hypogonadal.”
The take-home message should be that “the increased risk of fracture [with testosterone treatment], in addition to the increased risks of atrial fibrillation and pulmonary embolism outweigh the benefits of improved sexual function and small improvements in walking and mood,” Snyder said.
“I therefore recommend against treating age-related hypogonadism for most men.”
The study received support from AbbVie, Acerus Pharmaceuticals, Endo Pharmaceuticals, and Upsher-Smith Laboratories. Anawalt had no disclosures to report.
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