Enzyme-inducing antiepileptic drugs and fractures in people with epilepsy: A systematic review

Objective: People with epilepsy (PWE) have an increased fracture risk, independent of seizures. Antiepileptic drugs are thought to increase this risk, particularly those that induce the hepatic cytochrome P450 enzyme system. We aimed to determine whether PWE treated with enzyme-inducing antiepileptic drugs (EIAEDs) have decreased bone mineral density (BMD), or increased fracture incidence, versus those treated with non-EIAEDs.

Methods: We searched MedLine, EMBase, CENTRAL, and CINAHL prior to November 2014 for all studies comparing fracture risk, or BMD change, in PWE treated for ≥ 1 year with EIAEDs versus non-EIAEDs.

Results: Thirteen observational studies met eligibility criteria. These studies, representing 68,973 adult PWE, were significantly heterogeneous, making meta-analysis impossible. Study results were split, with 5 studies showing decreased BMD in EIAED users, 5 studies showing no effect of EIAED on BMD, 2 studies showing increased fracture incidence in EIAED users, and 1 study showing no difference in fracture risk. The largest study (n = 63,259), which was also the most methodologically rigorous, showed an increased hazard ratio of 9-22% for any fracture, and 49-53% for hip fracture, in EIAED users.

Significance: The literature is divided regarding the bone effects of EIAEDs; however, current best evidence supports an increased fracture risk in PWE treated with an EIAED compared to those treated with non-EIAEDs. A single article dominated our review, and other large methodologically rigorous studies are needed to confirm or refute its results. Further small studies, with limited power to control for multiple potentially confounding variables, are not likely to help.