Evaluation of bone fracture risk among men with prostate cancer treated with androgen receptor pathway inhibitor-containing therapies: a systematic review and meta-analysis

Androgen receptor pathway inhibitors (ARPIs) are widely used across multiple prostate cancer disease states, but fracture outcomes are inconsistently reported across randomized trials. We aimed to quantify the risks of all-grade and grade ≥ 3 trial-reported fracture-related adverse events (AEs) associated with ARPI-containing therapies. PubMed/MEDLINE, Web of Science Core Collection, and Cochrane CENTRAL were searched from inception to August 20, 2026. Phase III randomized controlled trials evaluating abiraterone, enzalutamide, apalutamide, or darolutamide were eligible irrespective of fracture reporting. Trials with extractable arm-specific fracture data were included in the quantitative synthesis. Risk ratios (RRs) were pooled using random-effects models with restricted maximum likelihood estimation and Hartung–Knapp adjustment. Exploratory subgroup analyses and additional sensitivity and rare-event analyses were performed. Of 8,657 records identified, 22 phase III randomized trials met the eligibility criteria. Thirteen trials involving 13,712 participants contributed all-grade fracture-related AE data, and eight trials involving 9,254 participants contributed grade ≥ 3 data. ARPI-containing regimens were associated with higher trial-observed cumulative risks of all-grade fracture-related AEs (RR 2.13, 95% CI 1.74–2.60; I 2 = 45.8%; 95% prediction interval 1.23–3.68) and grade ≥ 3 fracture-related AEs (RR 2.64, 95% CI 1.73–4.02; I 2 = 11.8%). The corresponding pooled cumulative risk differences were + 4.93 and + 1.71 percentage points, respectively, but should be interpreted cautiously because observation periods and baseline fracture risks varied across trials. Exploratory agent-specific analyses suggested between-agent differences, whereas no interaction was observed by disease state; these findings were based on indirect comparisons and were imprecise in several subgroups. The direction of the associations remained statistically stable across sensitivity and rare-event analyses, although heterogeneity in fracture definitions and treatment exposure remained unresolved. ARPI-containing therapies were associated with higher trial-observed cumulative risks of reported all-grade and grade ≥ 3 fracture-related AEs compared with their respective randomized controls. These findings support individualized, guideline-concordant assessment and management of skeletal risk during ARPI-based therapy. Agent-specific differences should be interpreted cautiously because of indirect comparisons, heterogeneous fracture definitions, and limited data in several subgroups.