AAN.com
Quick search in Citations
AnywhereCitation
Advanced Search
Trending Terms:
Articles
May 8, 2006

Use of antiepileptic drugs and risk of fractures
Case–control study among patients with epilepsy

P. C. Souverein, PhD, D. J. Webb, MSc, J. G. Weil, MD, PhD, T. P. Van Staa, MD, PhD, and A.C.G. Egberts, PhDAuthors Info & Affiliations
May 9, 2006 issue
66 (9) 1318-1324
https://doi.org/10.1212/01.wnl.0000210503.89488.88
Letters to the Editor
Get Access

Abstract

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.

Get full access to this article

View all available purchase options and get full access to this article.

Get Access

References

1.
Souverein PC, Webb DJ, Petri H, Weil J, Van Staa TP, Egberts ACG. Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General Practice Research Database. Epilepsia 2005;46:304–310.
PubMed
Google Scholar
2.
Vestergaard P. Epilepsy, osteoporosis and fracture risk: a meta analysis. Acta Neurol Scand 2005;112:277–286.
PubMed
Google Scholar
3.
Mattson RH, Gidal BE. Fractures, epilepsy, and antiepileptic drugs. Epilepsy Behav 2004;5 (suppl 2):S36–S40.
PubMed
Google Scholar
4.
Pack A. The association between antiepileptic drugs and bone disease. Epilepsy Currents 2003;3:91–95.
PubMed
Google Scholar
5.
Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms and therapeutic implications. CNS Drugs 2001;15:633–642.
PubMed
Google Scholar
6.
Persson HB, Alberts KA, Farahmand BY, Tomson T. Risk of extremity fractures in adult outpatients with epilepsy. Epilepsia 2002;43:768–772.
PubMed
Google Scholar
7.
Vestergaard P, Tigaran S, Rejnmark L, Tigaran C, Dam M, Mosekilde L. Fracture risk is increased in epilepsy. Acta Neurol Scand 1999;99:269–275.
PubMed
Google Scholar
8.
Ali II, Schuh L, Barkley GL, Gates JR. Antiepileptic drugs and reduced bone mineral density. Epilepsy Behav 2004;5:296–300.
PubMed
Google Scholar
9.
Sheth RD. Bone health in epilepsy. Lancet Neurol 2004;3:516.
PubMed
Google Scholar
10.
Walley T, Mantgani A. The UK General Practice Research Database. Lancet 1997;350:1097–1099.
PubMed
Google Scholar
11.
Van Staa TP, Abenhaim L, Cooper C, Zhang B, Leufkens HGM. The use of a large pharmacoepidemiologic database to study exposure to oral corticosteroids and risk of fractures: validation of study population and results. Pharmacoepidemiol Drug Safety 2000;9:359–366.
PubMed
Google Scholar
12.
Pack AM, Olarte LS, Morrell MJ, Flaster E, Resor SR, Shane E. Bone mineral density in an outpatient population receiving enzyme-inducing antiepileptic drugs. Epilepsy Behav 2003;4:169–174.
PubMed
Google Scholar
13.
Ensrud KE, Walczak TS, Blackwell T, Ensrud ER, Bowman PJ, Stone KL. Antiepileptic drug use increases rates of bone loss in older women: a prospective study. Neurology 2004;62:2051–2057.
PubMed
Google Scholar
14.
Petty SJ, Paton LM, O'Brien TJ, et al. Effect of antiepileptic medication on bone mineral measures. Neurology 2005;65:1358–1363.
PubMed
Google Scholar
15.
Lawn ND, Bamlet WR, Radhakrishnan K, O'Brien PC, So EL. Injuries due to seizures in persons with epilepsy: a population-based study. Neurology 2004;63:1565–1570.
PubMed
Google Scholar
16.
Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia 2004;45:1330–1337.
PubMed
Google Scholar
17.
Stephen LJ, McLellan AR, Harrison JH, et al. Bone density and antiepileptic drugs: a case-controlled study. Seizure 1999;8:339–342.
PubMed
Google Scholar
18.
Boluk A, Guzelipek M, Savli H, Temel I, Ozisik HI, Kaygusuz A. The effect of valproate on bone mineral density in adult epileptic patients. Pharmacol Res 2004;50:93–97.
PubMed
Google Scholar
19.
Sato Y, Kondo I, Ishida S, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001;57:445–449.
PubMed
Google Scholar

Information & Authors

Information

Published In

Neurology®
Volume 66 • Number 9 • May 9, 2006
Pages: 1318-1324

Copyright

© 2006.

Publication History

Published online: May 8, 2006
Published in print: May 9, 2006

Permissions

Request permissions for this article.

Authors

Affiliations & Disclosures

P. C. Souverein, PhD
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.
View all articles by this author
D. J. Webb, MSc
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.
View all articles by this author
J. G. Weil, MD, PhD
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.
View all articles by this author
T. P. Van Staa, MD, PhD
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.
View all articles by this author
A.C.G. Egberts, PhD
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.
View all articles by this author

Notes

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: [email protected]

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

Cited By
    • Tatyana Sarycheva,
    • Piia Lavikainen,
    • Heidi Taipale,
    • Jari Tiihonen,
    • Antti Tanskanen,
    • Sirpa Hartikainen,
    • Anna-Maija Tolppanen,
    Antiepileptic drug use and mortality among community-dwelling persons with Alzheimer disease, Neurology, 94, 20, (e2099-e2108), (2023)./doi/10.1212/WNL.0000000000009435
    Abstract
    • K. E. Ensrud,
    • T. S. Walczak,
    • T. L. Blackwell,
    • E. R. Ensrud,
    • E. Barrett-Connor,
    • E. S. Orwoll,
    Antiepileptic drug use and rates of hip bone loss in older men, Neurology, 71, 10, (723-730), (2023)./doi/10.1212/01.wnl.0000324919.86696.a9
    Abstract
    • Mario Tombini,
    • Andrea Palermo,
    • Lorenzo Ricci,
    • Marilisa Boscarino,
    • Narducci Flavia,
    • Sancetta Biagio,
    • Anda Mihaela Naciu,
    • Gaia Tabacco,
    • Roberto Cesareo,
    • Vincenzo Di Lazzaro,
    • Giovanni Assenza,
    Evaluating the effect of calcifediol supplementation on seizure frequency in people with drug-resistant epilepsy, Epilepsy & Behavior, 145, (109334), (2023).https://doi.org/10.1016/j.yebeh.2023.109334
    Crossref
    • Matthew W. Cole,
    • Timothy L. Waters,
    • Bailey J. Ross,
    • Lacee K. Collins,
    • Garrett H. Williams,
    • William F. Sherman,
    The Impact of Epilepsy on Complication Rates After Total Joint Arthroplasty: A Propensity Score–Matched Cohort Study, The Journal of Arthroplasty, 38, 2, (209-214.e1), (2023).https://doi.org/10.1016/j.arth.2022.08.022
    Crossref
    • Joseph I. Boullata,
    Drug-nutrition interactions, Encyclopedia of Human Nutrition, (79-92), (2023).https://doi.org/10.1016/B978-0-12-821848-8.00012-3
    Crossref
    • Marija Babunovska,
    • Aleksandar Jovanovski,
    • Bojan Boskovski,
    • Marta Foteva,
    • Igor Kuzmanovski,
    • Gordana Kiteva Trencevska,
    • Emilija Cvetkovska,
    Fractures in people with epilepsy: A nationwide population‐based cohort study, Epilepsia Open, (2023).https://doi.org/10.1002/epi4.12776
    Crossref
    • Bliss Rogers,
    • Sina Famenini,
    • Jamie Perin,
    • Maria I. Danila,
    • Kristin Wipfler,
    • Kaleb Michaud,
    • Zsuzsanna H. McMahan,
    Clinical Features Associated With Rate of Fractures in Patients With Systemic Sclerosis: A US Cohort Study , Arthritis Care & Research, (2023).https://doi.org/10.1002/acr.25137
    Crossref
    • Attila Rácz,
    • Kathryn Menne,
    • Valeri Borger,
    • Kevin G. Hampel,
    • Hartmut Vatter,
    • Christoph Helmstaedter,
    • Christian E. Elger,
    • Rainer Surges,
    Outcome after resective epilepsy surgery in the elderly, Journal of Neurosurgery, 136, 6, (1617-1626), (2022).https://doi.org/10.3171/2021.4.JNS204013
    Crossref
    • Gustaf Linton,
    • Gunnar Hägglund,
    • Tomasz Czuba,
    • Ann I. Alriksson-Schmidt,
    Epidemiology of fractures in children with cerebral palsy: a Swedish population-based registry study, BMC Musculoskeletal Disorders, 23, 1, (2022).https://doi.org/10.1186/s12891-022-05813-9
    Crossref
    • Jingwei Gao,
    • Tomotsugu Seki,
    • Kiyohide Usami,
    • Di Fan,
    • Akio Ikeda,
    • Koji Kawakami,
    Complications associated with the use of enzyme-inducing and non-enzyme-inducing anti-seizure medications in the Japanese population: A retrospective cohort study, Epilepsy & Behavior, 129, (108610), (2022).https://doi.org/10.1016/j.yebeh.2022.108610
    Crossref
  11. See more

View Options

Get Access

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Save for later Item saved, go to cart
Purchase Options

Purchase this article to get full access to it.

Purchase Access, $39 for 24hr of access

View options

Full Text

View Full Text

Full Text HTML

View Full Text HTML

Media

Figures

Other

Tables

Share

Share

Share article link

Share

View full text|Download PDF