Association study of aromatase inhibitors and adverse events related to osteoporosis: based on pharmacovigilance data

The association between long-term aromatase inhibitor (AI) use and osteoporosis remains controversial. Clarifying this relationship is critical for optimizing the safety of breast cancer survivors. This study collected publicly available data from Q1 2005 through Q1 2025 in the FAERS database. Three types of AIs were included in the study, and adverse events were restricted to the " Primary Suspect". The narrow definition of "osteoporosis/osteopenia" in the MedDRA Standard query (SMQ) was used for case screening. Additionally, to investigate adverse outcomes related to osteoporosis, we used vertebral compression fractures-the most typical fracture type in osteoporosis-to explore potential severe outcomes that may occur following drug administration. Disproportionality analysis utilized reporting odds ratio (ROR), PRR, IC, and EBGM. Positive signals were defined only when meeting criteria for all four algorithms. Subgroup and Weibull distribution analyses were performed to assess onset time. A total of 19,590 AIs related adverse event reports were extracted during the monitoring period, of which 665 were osteoporosis-related events, and the patients were mainly women aged 65 years and older. At the system-organ class (SOC) level, musculoskeletal system showed a strongest positive signal. At the SMQ level, anastrozole and letrozole showed significant positive signals associated with osteoporosis. In contrast, exemestane did not reach statistical significance. Similarly, positive disproportionality analysis signals for vertebral compression fracture as an adverse event were identified for anastrozole and letrozole, whereas negative signals were observed for exemestane. TTO analysis showed that exemestane-induced osteoporosis events followed an early failure-type curve with the median time to onset of about 245 days. Analysis reveals distinct bone safety profiles. Anastrozole and letrozole demonstrated significant associations with osteoporosis, whereas exemestane did not, suggesting a superior safety profile. These findings offer reference for clinicians regarding individualized drug selection for patients at high skeletal risk.