Fracture Risk With Lacosamide vs Levetiracetam Monotherapy in Adults With Epilepsy

Patients with epilepsy exhibit substantially elevated fracture risk. However, comparative skeletal safety data for newer antiseizure medications (ASMs) remain limited. The aim of this study was to compare fracture risk between lacosamide and levetiracetam monotherapy in adults with epilepsy.

This retrospective cohort study used the TriNetX Global Collaborative Network. Adults with epilepsy initiating lacosamide or levetiracetam monotherapy were identified, excluding those receiving concomitant ASMs. Propensity score matching (1:1) balanced cohorts on demographics, comorbidities, and medications. The primary outcome was composite fracture (hip, cervical vertebra, and forearm). Cox regression estimated hazard ratios (HR) over 5-year follow-up. A sensitivity analysis requiring ≥6 prescription fills and excluding additional newer generation ASMs was performed.

After matching, 20,888 patients remained per cohort with balanced covariates. Composite fracture occurred in 574 (2.86%) lacosamide-treated vs 418 (2.09%) levetiracetam-treated patients (HR 1.27; 95% CI 1.11-1.44; p < 0.001). Elevated risk was observed for forearm fracture (HR 1.33; p = 0.01), major osteoporotic fracture (HR 1.21; p < 0.001), and incident osteoporosis (HR 1.18; p < 0.001). Sensitivity analysis with stricter monotherapy and longer exposure preserved the direction of effect.

Lacosamide monotherapy was associated with significantly higher fracture risk compared with levetiracetam. These findings should inform ASM selection in patients with elevated skeletal fragility. Limitations include residual confounding and the retrospective design that precludes causal inferences.

This study provides Class III evidence that among adults with epilepsy receiving monotherapy, lacosamide is associated with a higher 5-year risk of fracture than levetiracetam.