FAERS-based pharmacovigilance and network toxicology analysis of esomeprazole-associated osteoporosis

Osteoporosis (OP) is a progressive skeletal disorder often exacerbated by pharmacological agents. Proton pump inhibitors (PPIs), particularly esomeprazole, have been epidemiologically linked to OP, but the underlying mechanisms remain unclear.

This study mined over 55 million adverse event (AE) records from the FDA Adverse Event Reporting System (FAERS) between 2004 and 2024 to identify drug-related OP signals. Four statistical algorithms (ROR, PRR, BCPNN, EBGM) were applied for signal detection. Logistic regression was used to assess independent risk factors. Esomeprazole, the most frequently reported PPI, was further investigated using a network toxicology framework. Drug-target predictions, differential gene expression analysis, protein-protein interaction network construction, molecular docking and molecular dynamics (MD) simulations were conducted to explore potential molecular hypotheses.

A total of 52 drugs showed potential OP-related reporting signals. Among PPI-associated OP-related reports, esomeprazole accounted for the largest proportion and was the only PPI with positive signals across all four algorithms. Logistic regression showed that esomeprazole, age, sex, and low body weight were associated with OP-related adverse event reporting. Time-to-onset analysis showed a median latency of 3.5 years. Network toxicology analysis identified 26 overlapping candidate genes between predicted esomeprazole targets and OP-related DEGs. GO and KEGG analyses highlighted bone-related pathways, including MAPK, Notch, and PI3K/AKT signaling. Protein-protein interaction network analysis identified CXCR4, AKT1, and CASP3 as candidate hub genes. Molecular docking and 100-ns MD simulations supported the binding plausibility and conformational stability of the predicted esomeprazole-target complexes.

This pharmacovigilance and computational toxicology study suggests a notable association between esomeprazole and PPI-associated OP-related adverse event reporting. The identified targets and pathways, including CXCR4, AKT1, and CASP3, provide exploratory mechanistic clues and hypothesis-generating evidence. These findings may support individualized bone health risk assessment in long-term PPI users and provide a basis for future validation studies.