Effect of testosterone replacement therapy on fracture risk in hypogonadal men: A systematic review and meta-analysis...

Testosterone replacement therapy is the treatment of choice in men with hypogonadism. Although its beneficial effect on bone mineral density is well established, the evidence regarding its impact on fracture risk remains inconclusive. The purpose of this study was to systematically review and meta-analyze the highest-quality available evidence regarding the effect of TRT on fracture risk in hypogonadal men.

A systematic literature search was conducted in PubMed, Scopus and Cochrane databases from inception through 30 September 2025. Only randomized controlled trials were eligible for inclusion. Outcomes were summarized as relative risk (RR), with a 95% confidence interval (CI). The I² index was used in order to quantify heterogeneity.

The initial search yielded 1145 results after removal of duplicates; seven papers underwent full-text assessment. Finally, two studies were included in the qualitative and quantitative analysis (n = 2711). TRT was associated with increased risk of clinical fractures compared with placebo (RR 1.55, 95% CI 1.21-1.97, p < 0.0001, I² 0%). However, no difference between groups was observed when the analysis was restricted to major osteoporotic fractures (hip, spine, wrist, and arm) (RR 0.62, 95% CI 0.12-3.35, p = 0.58, I² 63%). This was also the case for vertebral (RR 0.87, 95% CI 0.29-2.58, p = 0.80, I² 9%) and hip fractures (RR 1.02, 95% CI 0.33-3.09, p = 0.98, I² 0%), when analyzed separately.

TRT is associated with an increased incidence of predominantly non-major fractures, while the risk of major osteoporotic fractures, including hip and vertebral fractures, was not increased.