Evaluation of bone safety and antiseizure medications: a multi-source pharmacovigilance and Mendelian randomization analysis.

The association between antiseizure medications (ASMs) and bone disorders remains inadequately investigated despite growing concern about drug-induced bone adverse events (AEs). We analyzed data from the FDA Adverse Event Reporting System (FAERS) database (Q1 2004-Q2 2025), identifying 7688 reports of bone health-related AEs listing ASMs as primary suspect drugs. Disproportionality analysis was performed using the reporting odds ratio (ROR) for signal detection. Subsequently, network pharmacology was applied to explore underlying biological pathways. Finally, two-sample Mendelian randomization (MR) was conducted to estimate potential causal associations between ASM-related gene targets and bone health outcomes. Disproportionality analysis revealed significant associations between ASMs and several bone health-related AEs, including increased blood alkaline phosphatase, ankle fracture, vitamin D deficiency, craniofacial fracture, cervical vertebral fracture, and skull fracture. Significant associations of bone health were identified for traditional enzyme-inducing ASMs, including carbamazepine, phenytoin, and phenobarbital, and newer agents, including perampanel, brivaracetam, lacosamide, and zonisamide. Pathway analysis predicted calcium and MAPK signaling. MR revealed genetically predicted effects of CAT, TNFRSF9, and USP48 on osteoporosis and of MGP, MFN2, PLOD1, and TNFRSF9 on ankle fracture. By integrating real-world pharmacovigilance with genetic insights, this study characterizes the associations between both conventional and newer ASMs and adverse bone health outcomes, mechanistically implicating the role of Calcium and MAPK signaling pathways. Furthermore, we identified several key regulatory genes.