Hip Fracture Risk in Antiepileptic Drug Initiators and Non-Initiators with Alzheimer’s Disease

Federica Pisa,1– 3 Jonas Reinold,1– 3 Piia Lavikainen,1,2 Marjaana Koponen,1,2,4 Heidi Taipale,1,2,5,6 Antti Tanskanen,5– 7 Jari Tiihonen,5,6 Sirpa Hartikainen,1,2 Anna-Maija Tolppanen1,2 1School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 2Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland; 3Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 4Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia; 5Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 6Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland; 7Impact Assessment Unit, National Institute for Health and Welfare, Helsinki, FinlandCorrespondence: Federica PisaBayer, Müllerstrasse 178, Berlin, 13353, GermanyEmail federica.pisa@bayer.comObjective: To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).Methods: In the Medication use and AD (MEDALZ) cohort of 70,719 Finnish community dwellers with clinically verified incident AD diagnosis in 2005– 2011, we identified all incident users of AEDs using national Prescription register. AEDs were classified as older (valproate, carbamazepine, clonazepam, phenytoin, levetiracetam, primidone) or newer (pregabalin, gabapentin, oxcarbazepine, lamotrigine, topiramate). We matched each user to 2 non-users. Incident hip fractures until 2015 were identified from the Care register for health care. We calculated inverse probability of treatment weighted hazard ratios (HR), with 95% confidence intervals, using Cox regression.Results: Altogether 5522 incident users were identified and matched to 11,044 non-users (in both groups, women: 65%; median age: 81 years). Altogether 53.3% of users initiated with newer AEDs (pregabalin 79.8%, gabapentin 10.2%) while 46.7% initiated with older AEDs (valproate 67.6%, carbamazepine 13.0%). Age- and sex-adjusted IR of hip fracture per 100 person-years was 1.8 (95% CI 1.6– 1.9) in non-users and 2.0 (95% CI 1.8– 2.2) in users. Increased risk of hip fracture was observed in users (HR 1.17, 95% CI 1.05– 1.30) compared with non-users. The risk was higher for short duration of use (< 14 weeks, HR 3.64, 95% CI 2.90– 4.58) than for medium duration (14 to < 64 weeks, HR 1.74, 95% CI 1.48– 2.05) or ≥ 64 weeks’ use (HR 1.23, 95% CI 1.08– 1.40), compared to non-users with same follow-up time. Older AEDs had HR of 1.46 (1.03– 2.08) compared with newer AEDs.Conclusion: Our results imply that AED use is associated with an increased risk of hip fracture in people with AD. These findings prompt careful consideration before prescribing AEDs to persons with AD. Persons with AD treated with antiepileptics should be carefully monitored due to their increased risk of falling and fractures.Keywords: antiepileptic drugs, hip fracture, Alzheimer´s disease, pharmacoepidemiology