Could testosterone therapy actually increase the risk of bone fractures in men? Original paper

In this randomized controlled trial, men with hypogonadism (low testosterone) who received transdermal testosterone replacement therapy had a higher incidence of bone fractures, compared to men who received a placebo.

The effects of transdermal testosterone replacement therapy (TRT) on the incidence of bone fracture (primary outcome) in men with hypogonadism (decreased hormone production by the gonads; among men, this manifests as low testosterone).

Research on testosterone replacement therapy in this population has shown overall positive effects on biomarkers for bone health, which suggests that TRT may reduce bone fractures.

5,204 male participants (ages 45–80) with clinical hypogonadism (testosterone levels of less than 300 ng/mL in addition to one or more symptoms of hypogonadism).

Because this study was a subtrial of a larger study that tested the effect of TRT on the incidence of adverse cardiovascular events (the TRAVERSE trial),^[1] the participants also had preexisting cardiovascular disease or were at increased risk for cardiovascular disease.

In this long-term randomized controlled trial, the TRT group (2,603 participants) took a daily transdermal testosterone gel that provided 20.25 mg of testosterone, and the control group (2,601 participants) received a matching placebo. Bone fracture incidence was assessed over a median follow-up period of 3 years.

To maintain serum testosterone concentrations in the target range of 75 to 350 ng per deciliter, serum testosterone was measured at weeks 2, 4, 12, 26, 52, 78, 104 and then yearly until the end of the trial, with dosage adjustments as needed.

Bone fracture incidence was assessed by periodic in-person or telephone visits throughout the follow up period, followed by verification with medical records and documentation. Bone fracture occurrence was then verified by an independent investigator after review of the medical records. The incidence of fractures was analyzed irrespective of trial adherence, and no adjustments were made for multiple comparisons.

Over the 3-year follow-up period, there was an increased incidence in bone fractures in the TRT group (3.5% of participants) compared to the placebo control group (2.46% of participants).

Funding for the trial was provided by AbbVie, a consortium of testosterone manufacturers.

As the researchers noted in their paper, because the data were not corrected for multiple comparisons, the reported hazard ratios and 95% confidence intervals are not a substitute for statistical hypothesis testing. Therefore, the main takeaway from this study is that the authors did not observe the expected decrease in bone fracture rate during the 3-year follow up.

A further limitation of the study is that adherence rates were low, and the analyses were performed on an “intent to treat” basis (i.e., analyzing the participants in each group irrespective of adherence to the treatment schedule). More research is needed to better understand the effects of TRT on bone fracture risk.