Meta-analysis shows testosterone replacement therapy increases clinical fracture risk in hypogonadal men compared to placebo

$Meta-analysis shows testosterone replacement therapy increases clinical fracture risk in…$

Photo by Trust "Tru" Katsande / Unsplash

Maturitas Published June 5, 2026 Medically reviewed June 5, 2026 Study authors: Anagnostis Panagiotis, Divaris Efstathios, Zidrou Maria, Kassi Evanthia, Tournis Symeon PubMed ↗ DOI ↗ By Dr. Lars van Dijk, PhD · Surgical, Procedural & Diagnostic

Key Takeaway

Testosterone replacement therapy is associated with a significantly increased risk of clinical fractures in hypogonadal men based on this meta-analysis.

This systematic review and meta-analysis evaluated the impact of testosterone replacement therapy on fracture risk among men with hypogonadism. The analysis pooled data from randomized controlled trials involving a total of 2,711 participants to assess safety and efficacy regarding bone health outcomes.

The primary analysis revealed a concerning increase in the risk of clinical fractures for patients receiving testosterone compared to those on placebo. The relative risk was 1.55, with a 95% confidence interval ranging from 1.21 to 1.97, indicating a statistically significant elevation in fracture incidence. This finding suggests a potential safety concern that clinicians must weigh against the benefits of treatment.

However, when examining specific fracture types, the results were more nuanced. There was no significant difference observed for major osteoporotic fractures, vertebral fractures, or hip fractures. The confidence intervals for these subtypes were wide, often crossing the null value, which implies uncertainty in the estimates for these specific outcomes. Despite the lack of significance in these subgroups, the overall clinical fracture signal remains the most critical takeaway.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedJun 2026

PMID42066666

View Original Abstract ↓

OBJECTIVE: 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. STUDY DESIGN: 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 I index was used in order to quantify heterogeneity. RESULTS: 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, I 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, I 63%). This was also the case for vertebral (RR 0.87, 95% CI 0.29-2.58, p = 0.80, I 9%) and hip fractures (RR 1.02, 95% CI 0.33-3.09, p = 0.98, I 0%), when analyzed separately. CONCLUSION: 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.