Background The management of bone metastases requires careful balancing of therapeutic efficacy against distinct safety profiles. Current understanding of differential adverse event patterns between zoledronic acid and denosumab warrants more sophisticated analytical approaches to identify clinically relevant risk biomarkers and underlying molecular mechanisms. Methods We conducted an advanced pharmacovigilance study utilizing the FDA Adverse Event Reporting System (FAERS) database (2004–2024). Our multidimensional analytical framework integrated five established signal detection algorithms (ROR, PRR, BCPNN, MGPS, and MHRA) with comprehensive temporal and demographic stratification to identify clinically relevant safety patterns. Additionally, a network pharmacology approach was employed to explore the molecular mechanisms of zoledronic acid–associated osteonecrosis, involving target prediction, protein–protein interaction (PPI) network construction, and functional enrichment analysis. Results Analysis of 8849 reports revealed distinct toxicity profiles: Denosumab demonstrated significant associations with metabolic complications including hypocalcemia (ROR: 4.32; 95% CI: 3.87–4.82) and osteonecrosis of the jaw, whereas zoledronic acid showed stronger signals for nonjaw osteonecrosis and renal impairment. Temporal analysis revealed significantly earlier onset of adverse events with denosumab (median: 178 days) compared to zoledronic acid (median: 378 days). Network pharmacology identified 271 common targets shared by bone metastasis, zoledronic acid, and osteonecrosis. Subsequent PPI network and module analysis prioritized 76 key genes, with hub genes (e.g., TP53, TNF, IL‐6, AKT1, and STAT3) enriched in inflammatory signaling, apoptosis regulation, and pathways such as PI3K–Akt and TNF signaling. Conclusion This comprehensive safety analysis demonstrates distinct risk architectures for these bone‐targeting therapies. The integration of real‐world pharmacovigilance with network pharmacology provides data‐driven insights for personalized treatment selection and reveals potential molecular mechanisms underlying zoledronic acid–associated osteonecrosis. The identification of key risk‐modifying factors, temporal patterns, and candidate molecular pathways enables the development of biomarker‐informed monitoring strategies, representing a significant advancement in pharmacovigilance methodology for optimizing safety in cancer patients with bone metastases.
Peng et al. (Thu,) studied this question.