Time-Dependent Effect of Anti-seizure Medications on Bone Metabolism in Patients with Epilepsy: A Cross-Sectional Study.

INTRODUCTION

Patients with epilepsy (PWE) face an elevated risk of osteoporosis and bone fractures. This study aims to elucidate bone metabolic alterations in PWE and identify early detection biomarkers and contributing factors.

METHODS

This cross-sectional study analyzed PWE from the Epilepsy Clinical database stratified by anti seizure medication (ASM) exposure duration. We analyzed bone turnover markers (BTMs), including 25-hydroxy vitamin D, osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), β-crosslaps (β-CTX) and β-CTX/OC ratio. The effects of epilepsy and ASMs on bone metabolism were analyzed by XGBoost model and SHapley Additive exPlanations (SHAP). Finally, we analyzed the mediation analyses assessing inflammatory pathway contributions.

RESULTS

A total of 476 PWE were included in this study. Compared to ASM-naïve PWE, those receiving > 2 years of ASM therapy exhibited a reduced β-CTX/OC ratio (p = 0.002), while P1NP levels declined only after > 10 years of treatment (p < 0.001). Longitudinal data revealed a continued annual decline in the β-CTX/OC ratio during the 2-year follow-up period. After adjusting for confounders, longer ASM exposure duration was significantly correlated with decreased P1NP, β-CTX and β-CTX/OC ratio levels (β = - 1.74, 95% CI - 2.56 to - 0.92; p < 0.001). XGBoost-SHAP analysis identified valproic acid (VPA), oxcarbazepine (OXC) and history of status epilepticus as key contributors to β-CTX/OC ratio variability. Polytherapy had a more pronounced effect than monotherapy, particularly when levetiracetam was combined with VPA or OXC. Mediation analysis demonstrated that platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio mediate epilepsy/ASM-related bone metabolic alterations.

CONCLUSION

PWE exhibit dynamic bone metabolic alterations. Following > 2 years of ASM therapy, osteoclast inhibition precedes the onset of osteoblast dysfunction. Prolonged ASM exposure eventually reduces bone formation markers, indicating progressive impairment of osteoblastic function and a concomitant decline in bone-forming capacity. Consequently, the β-CTX/OC ratio represents a pivotal early biomarker for monitoring bone health deterioration, demonstrating significant clinical utility.