medwireNews: Testosterone given to middle-aged and older men with hypogonadism does not appear to protect them from bone fracture and may, in fact, increase the risk, indicate the results of a subtrial involving more than 5000 US men.
After a median follow-up of 3.2 years, significantly more men treated with testosterone (n=2601) than placebo (n=2603) had experienced the primary endpoint of a clinical fracture, at 3.5% versus 2.5% (hazard ratio=1.43). The primary endpoint was defined as a clinical fracture of the spine or non-spine (excluding the sternum, fingers, toes, facial bones, and skull) that had been documented by imaging or the need for surgery and confirmed by an adjudicator.
The risk for fracture was also numerically higher, albeit not significantly, for almost all the other fracture end points that were tested, say the researchers. These included a clinical fracture occurring in any bone, non-high impact fractures, fractures occurring in men not taking osteoporosis medication, and fracture-free survival.
“We did not expect these results, because most previous studies showed that testosterone improved many measures of bone structure and quality,” observe Peter Snyder (University of Pennsylvania, Philadelphia, USA) and co-authors in The New England Journal of Medicine.
The reported data come from a planned subtrial of the phase 4 TRAVERSE study, a randomized, double-blind, placebo-controlled trial designed to assess the cardiovascular safety of testosterone replacement in men aged 40–80 years.
For inclusion, all of the men had to have one or more symptoms of hypogonadism and testosterone concentrations of less than 300 ng/dL (10.4 nmol/L) in fasting plasma samples taken in the morning on two occasions at least 48 hours apart.
“The trial participants appear to be representative of men with hypogonadism in this age range in the United States, except for an intentionally increased prevalence of cardiovascular disease,” note the researchers.
Treatment consisted of daily application of a transdermal gel to each shoulder that contained either testosterone (1.62%) or placebo. The testosterone dose was adjusted to maintain a serum concentration of 350–750 ng/dL (12.1–26.0 nmol/L) and a hematocrit of less than 54%.
Fracture risk was determined by asking the participants if they had sustained a fracture since their previous study appointment, and if so, the scan results and related documentation were checked and adjudicated.
Overall, 309 fractures occurred in 224 participants – 186 in the testosterone group and 123 in the placebo group. Most were confirmed as being a fracture (82.8% and 78.9% in each group respectively), with 4–5% adjudicated as not a fracture, 5–6% as uncertain, and 8–10% as having insufficient documentation.
Most fractures were associated with trauma, most commonly falls. The most frequent sites of fractures were the ribs, wrist, and ankle.
“These sites are of clinical significance because fractures at these sites are associated with low bone mineral density and previous fractures, and are considered osteoporotic fractures,” say the researchers. Osteoporosis was not a criterion for entry into the study, they point out, nor was it a reason for exclusion.
“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,” the researchers suggest.
While benefits may include improved mood and sexual function and increased hemoglobin levels, prior TRAVERSE findings show that testosterone may increase the of atrial fibrillation, pulmonary embolism, and acute kidney injury, albeit with increase in the likelihood of major adverse cardiovascular events,
In a related editorial, Mathis Grossmann (University of Melbourne and Austin Health, Heidelberg, Victoria, Australia) and Bradley Anawalt (University of Washington School of Medicine, Seattle, USA) comment that “[t]he findings do not apply to men with hypogonadism due to identifiable disease of the hypothalamic–pituitary–testicular axis, who need testosterone for normal function.”
They add, however, that “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.”
Moreover, “men at high risk for fragility fracture should receive osteoporotic drug therapy with proven antifracture benefit independent of any consideration of testosterone therapy,” the editorialists conclude.
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