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Use of antiepileptic drugs and risk of fractures

Case–control study among patients with epilepsy

From the Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (P.C.S., T.P.V.S., A.C.G.E.); GlaxoSmithKline, WorldWide Epidemiology, New Frontiers Science Park, Harlow, UK (D.J.W., J.G.W.); and Medical Research Council, Environmental Epidemiology Unit, Southampton University Hospital, Southampton, UK (T.P.V.S.). T.P.V.S. is currently with the General Practice Research Database, Medicines and Healthcare Products Regulatory Agency, London, UK.

Address correspondence and reprint requests to Dr Souverein, Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, PO Box 80082, 3508 TB Utrecht, The Netherlands; e-mail: p.c.souverein{at}pharm.uu.nl

Objective: To study the association between use of antiepileptic drugs (AEDs) and risk of fractures.

Methods: The authors obtained data from the General Practice Research Database (GPRD). A case–control study was nested within a cohort of patients with active epilepsy. Cases were patients with a first fracture after cohort entry. Up to four controls were matched to each case by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history. Cumulative exposure to AEDs was assessed by summing the duration of all AED prescriptions. A distinction was made between AEDs that induce the hepatic cytochrome P-450 enzyme system and AEDs that do not.

Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs.

Results: The study population comprised 1,018 cases and 1,842 matched controls. The risk of fractures increased with cumulative duration of exposure (p for trend < 0.001), with the strongest association for greater than 12 years of use: adjusted OR 4.15 (95% CI 2.71 to 6.34). Risk estimates were higher in women than in men. There was no difference between users of AEDs that induce and AEDs that do not induce the hepatic cytochrome P-450 system.

Conclusions: Long-term use of AEDs was associated with an increased risk of fractures, especially in women. More research on mechanisms of AED-induced bone breakdown and female vulnerability to the effects of AEDs on bone health is warranted.

Disclosure: This study was funded by an unrestricted grant from GlaxoSmithKline, Harlow, UK.

Received June 20, 2005. Accepted in final form January 19, 2006.

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