Disproportionality analysis of musculoskeletal and connective tissue disorders associated with aromatase inhibitors: A real-world pharmacovigilance study.

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Background: Aromatase inhibitors (AIs) are a cornerstone of endocrine therapy for hormone receptor-positive breast cancer and are well known to induce musculoskeletal symptoms under profound estrogen deprivation. Although arthralgia and bone pain are well recognized, the broader spectrum of musculoskeletal adverse events has not been systematically evaluated in large scale pharmacovigilance data. Methods: We analyzed the U.S. FDA Adverse Event Reporting System database from 2004 to 2023, restricted to reports with a breast cancer indication to minimize confounding by off-label use. Analyses were performed within the MedDRA System Organ Class (SOC) “Musculoskeletal and connective tissue disorders”. The dataset comprised 549,824 adverse event reports corresponding to 154,633 unique cases, including 7,028 AI-exposed cases. Case/non-case disproportionality analyses were conducted at both the SOC and the Preferred Term (PT) levels within this SOC. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) were calculated. A signal was defined as three or more AI exposed cases with a lower bound of the 95% CI of the ROR exceeding 1. Significant PTs were ranked by AI exposed case counts, and the top 10 were presented. Results: At the SOC level, 1,742 AI exposed cases were identified, showed significant disproportionality (ROR 1.82, 95% CI 1.72-1.92) (Table). At the PT level, 55 musculoskeletal PTs met the predefined signal criteria, with the top 10 presented in the Table. Among established musculoskeletal toxicities, “Arthralgia” was the most frequently reported PT (n=725; ROR 4.46, 95% CI 4.10-4.84), followed by “Bone pain”, “Pain in extremity”, “Myalgia”, and “Back pain”. Additional significant signals broadening the musculoskeletal spectrum included “Musculoskeletal stiffness”, “Musculoskeletal pain”, “Arthritis”, and “Trigger finger”. Conclusions: In this large post-marketing real-world pharmacovigilance analysis of reports with a breast cancer indication, AIs demonstrated significant and clinically relevant disproportionality across a broad spectrum of musculoskeletal adverse events. These findings support proactive musculoskeletal monitoring in AI treated patients and warrant further investigation.

Disproportionality analysis results for AI-related adverse drug reactions.