Global Pharmacovigilance Study of Bone Fractures with Androgen Receptor Pathway Inhibitors in Prostate Cancer

Background Androgen receptor pathway inhibitors (ARPIs) improve the survival of men with various states of advanced prostate cancer, but complications, including bone fractures, have been associated with treatment. Although rates of SREs are reported in ARPI registration trials, real-world data describing SRE rates during treatment with ARPIs is lacking. Methods We conducted a global pharmacovigilance study using VigiBase, the World Health Organization’s international database of adverse drug reaction reports. All reports involving abiraterone, enzalutamide, apalutamide, or darolutamide in adult men from 2011 to September 2024 were included. Fractures were defined using standardized MedDRA terms, and disproportionality analyses quantified reporting odds ratios (RORs) with 95% confidence intervals and Bayesian shrinkage estimates (EB05). Two prespecified sensitivity analyses were performed, redefining the reference group as men on androgen deprivation therapy (ADT) alone and stratifying results by age groups. Results Among 282,143 VigiBase reports involving ARPIs, 1,140 (0.4%) included fractures. In primary analysis, ARPI therapy demonstrated a pharmacovigilance signal for increased SRE reporting (ROR 1.87, 95% CI 1.77–1.98; EB05 1.77). Signals were consistent for abiraterone, enzalutamide, and apalutamide, but not for darolutamide. Using ADT as reference, ARPIs remained associated with higher reporting of fractures (ROR 1.43, 95% CI 1.29–1.58; EB05 1.08). Age-stratified analyses demonstrated signals across all categories, with numerically larger disproportionality estimates among older men. Conclusions In this global pharmacovigilance analysis, ARPIs were consistently associated with increased reporting of fractures, including when compared with ADT alone. This highlights the potentially additive skeletal toxicity of treatment intensification, and underscore the importance of bone health monitoring and preventive strategies, particularly among older patients.