SpringerLink
Log in

Treatment of Epilepsy to Optimize Bone Health

  • Epilepsy
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Opinion statement

When treating a person with epilepsy, one must consider many factors in addition to the obvious need to treat the seizures. Both epilepsy itself and treatment with antiepileptic drugs (AEDs) subject one to numerous potential secondary long-term health concerns. Poor bone health is one of these concerns. Studies suggest that persons with epilepsy treated with AEDs have an increased risk of fracture, low bone mineral density (BMD), and abnormalities in bone metabolism. Multiple factors likely contribute to the increased risk. Falls during generalized tonic-clonic seizures, secondary effects of AEDs on balance, inactivity, low BMD, reduced calcium intake, reduced active vitamin D metabolites, and a genetic predisposition to low BMD may all contribute. Studies suggest a differential influence of AEDs. Phenytoin, phenobarbital, and primidone are most consistently associated with a negative impact on bone. Carbamazepine and valproate may also result in bone abnormalities, but data are mixed. Current studies suggest that lamotrigine has limited (if any) effect, but again, data are inconsistent. Other AEDs have received limited study. Screening for poor bone health includes serologic testing of vitamin D metabolites (notably 25-hydroxyvitamin D) as well as BMD testing using dual energy x-ray absorptiometry. Optimizing intake of calcium and vitamin D is important for all persons with epilepsy treated with AEDs. Although many treatments for low BMD are available, these agents have not been studied in persons with epilepsy treated with AEDs. Overall, physicians treating persons with epilepsy must consider the potential effect of having epilepsy and its main treatment, AED therapy, on bone health. For patients in whom bone health is a particular concern (eg, those with diagnosed bone disease or with significant risk factors for bone disease, including glucocorticosteroid use), it is best to avoid AEDs known to negatively affect bone. In addition, practitioners should work with other treating physicians to optimize bone health in these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Pack A. Bone health in people with epilepsy: Is it impaired and what are the risk factors? Seizure. 2008;17(2):18.

    Article  Google Scholar 

  2. Souverein PC, Webb DJ, Petri H, et al. Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General Practice Research Database. Epilepsia. 2005;46(2):304–10.

    Article  PubMed  Google Scholar 

  3. Petty SJ, Hill KD, Haber NE, et al. Balance impairment in chronic antiepileptic drug users: a twin and sibling study. Epilepsia 2010, 51(2):280–8.

    Article  PubMed  CAS  Google Scholar 

  4. Vestergaard P. Epilepsy, osteoporosis and fracture risk—a meta-analysis. Acta Neurol Scand. 2005;112(5):277–86.

    Article  PubMed  CAS  Google Scholar 

  5. Pack AM, Walczak TS. Bone health in women with epilepsy: clinical features and potential mechanisms. Int Rev Neurobiol. 2008;83:305–28.

    Article  PubMed  Google Scholar 

  6. Persson HB, Alberts KA, Farahmand BY, Tomson T. Risk of extremity fractures in adult outpatients with epilepsy. Epilepsia. 2002;43(7):768–72.

    Article  PubMed  Google Scholar 

  7. Souverein PC, Webb DJ, Weil JG, Van Staa TP, Egberts AC. Use of antiepileptic drugs and risk of fractures: case-control study among patients with epilepsy. Neurology. 2006;66(9):1318–24.

    Article  PubMed  CAS  Google Scholar 

  8. Tsiropoulos I, Andersen M, Nymark T, et al. Exposure to antiepileptic drugs and the risk of hip fracture: a case-control study. Epilepsia. 2008;49(12):2092–9.

    Article  PubMed  Google Scholar 

  9. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia. 2004;45(11):1330–7.

    Article  PubMed  CAS  Google Scholar 

  10. Andress DL, Ozuna J, Tirschwell D, et al. Antiepileptic drug–induced bone loss in young male patients who have seizures. Arch Neurol. 2002;59(5):781–6.

    Article  PubMed  Google Scholar 

  11. Farhat G, Yamout B, Mikati MA, et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology. 2002;58(9):1348–53.

    PubMed  CAS  Google Scholar 

  12. 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(3):445–9.

    PubMed  CAS  Google Scholar 

  13. Sheth RD, Wesolowski CA, Jacob JC, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr. 1995;127(2):256–62.

    Article  PubMed  CAS  Google Scholar 

  14. Sheth RD, Binkley N, Hermann BP. Gender differences in bone mineral density in epilepsy. Epilepsia. 2008;49(1):125–31.

    Article  PubMed  Google Scholar 

  15. Samaniego EA, Sheth RD. Bone consequences of epilepsy and antiepileptic medications. Semin Pediatr Neurol. 2007;14(4):196–200.

    Article  PubMed  Google Scholar 

  16. Coppola G, Fortunato D, Auricchio G, et al. Bone mineral density in children, adolescents, and young adults with epilepsy. Epilepsia. 2009;50(9):2140–6.

    Article  PubMed  Google Scholar 

  17. Sheth RD, Binkley N, Hermann BP. Progressive bone deficit in epilepsy. Neurology. 2008;70(3):170–6.

    Article  PubMed  Google Scholar 

  18. Henderson RC, Lark RK, Gurka MJ, et al. Bone density and metabolism in children and adolescents with moderate to severe cerebral palsy. Pediatrics. 2002;110(1 Pt 1):e5.

    Article  PubMed  Google Scholar 

  19. Menon B, Harinarayan CV. The effect of anti epileptic drug therapy on serum 25-hydroxyvitamin D and parameters of calcium and bone metabolism–a longitudinal study. Seizure. 2010;19(3):153–8.

    Article  PubMed  Google Scholar 

  20. Rauchenzauner M, Griesmacher A, Tatarczyk T, et al. Chronic antiepileptic monotherapy, bone metabolism, and body composition in non-institutionalized children. Dev Med Child Neurol. 2010;52(3):283–8.

    Article  PubMed  Google Scholar 

  21. Nettekoven S, Ströhle A, Trunz B, et al. Effects of antiepileptic drug therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy. Eur J Pediatr. 2008;167(12):1369–77.

    Article  PubMed  CAS  Google Scholar 

  22. Szulc P, Delmas PD. Biochemical markers of bone turnover in osteoporosis. In: Rosen CJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. New York: Lippincott Williams & Williams; 2009. p. 174–9.

    Google Scholar 

  23. Pack AM, Morrell MJ, Randall A, McMahon DJ, Shane E. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology. 2008;70(18):1586–93.

    Article  PubMed  CAS  Google Scholar 

  24. Sowers M, Crutchfield M, Bandekar R, et al. Bone mineral density and its change in pre- and perimenopausal white women: the Michigan Bone Health Study. J Miner Res. 1998;13(7):1134–40.

    Article  CAS  Google Scholar 

  25. 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(11):2051–7.

    PubMed  CAS  Google Scholar 

  26. Verrotti A, Greco R, Morgese G, Chiarelli F. Increased bone turnover in epileptic patients treated with carbamazepine. Ann Neurol. 2000;47(3):385–8.

    Article  PubMed  CAS  Google Scholar 

  27. Verrotti A, Greco R, Latini G, Morgese G, Chiarelli F. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia. 2002;43(12):1488–92.

    Article  PubMed  CAS  Google Scholar 

  28. Kim SH, Lee JW, Choi KG, Chung HW, Lee HW. A 6-month longitudinal study of bone mineral density with antiepileptic drug monotherapy. Epilepsy and Behavior. 2007;10(2):291–5.

    Article  PubMed  Google Scholar 

  29. Mintzer S, Boppana P, Toguri J, et al. Vitamin D levels and bone turnover in epilepsy taking carbamazepine or oxcarbazepine. Epilepsia. 2006;47(3):510–5.

    Article  PubMed  CAS  Google Scholar 

  30. Cansu A, Yesilkaya E, Serdaroğlu A, et al. Evaluation of bone turnover in epileptic children using oxcarbazepine. Pediatr Neurol. 2008;39(4):266–71.

    Article  PubMed  Google Scholar 

  31. Gou CY, Ronen GM, Atkinson SA. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia. 2001;42(9):1141–7.

    Google Scholar 

  32. Verrotti A, Agostinelli S, Coppola G, Parisi P, Chiarelli F. A 12-month longitudinal study of calcium metabolism and bone turnover during valproate monotherapy. Eur J Neurol. 2010;17(2):232–7.

    Article  PubMed  CAS  Google Scholar 

  33. Ensrud KE, Walczak TS, Blackwell TL, et al. Antiepileptic drug use and rates of hip bone loss in older men: a prospective study. Neurology 2008, 71(10):723–30.

    Article  PubMed  CAS  Google Scholar 

  34. Sheth RD, Hermann BP. Bone mineral density with lamotrigine monotherapy for epilepsy. Pediatr Neurol. 2007;37(4):250–4.

    Article  PubMed  Google Scholar 

  35. Pierce Jr WM, Nardin GF, Fuqua MF, et al. Effect of chronic carbonic anhydrase inhibitor therapy on bone and mineral density in white women. J Bone Miner Res. 1991;6(4):347–54.

    Article  PubMed  Google Scholar 

  36. Nissen-Meyer LS, Svalheim S, Tauboll E, et al. Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism. Epilepsia. 2007;48(10):1–11.

    Article  Google Scholar 

  37. Pascussi JM, Robert A, Nguyen M, et al. Possible involvement of pregnane X receptor-enhanced CYP 24 expression in drug-induced osteomalacia. J Clin Invest. 2005;115(1):177–86.

    PubMed  CAS  Google Scholar 

  38. Zhou C, Assem M, Tay JC, et al. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest. 2006;116(6):1703–12.

    Article  PubMed  CAS  Google Scholar 

  39. Pack AM, Morrell MJ, Marcus R, et al. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann Neurol. 2005;57(2):781–6.

    Article  Google Scholar 

  40. Stephen LJ, McLellan AR, Harrison JH, et al. Bone density and antiepileptic drugs: a case-controlled study. Seizure. 1999;8(6):339–42.

    Article  PubMed  CAS  Google Scholar 

  41. Bhatt R, Bhatt S, Hameed M, Rameshwar P, Siegel A. Amygdaloid kindled seizures can induce functional and pathological changes in thymus of rat: role of the sympathetic nervous system. Neurobiol Dis. 2006;21(1):127–37.

    Article  PubMed  CAS  Google Scholar 

  42. Lambrinoudaki I, Kaparos G, Armeni E, et al. BsmI vitamin D receptor’s polymorphism and bone mineral density in men and premenopausal women on long-term antiepileptic therapy. Eur J Neurol 2011;18(1):93–8.

    Article  PubMed  CAS  Google Scholar 

  43. Pack AM. Genetic variation may clarify the relationship between epilepsy, antiepileptic drugs, and bone health. Eur J Neurol. 2011;18(1):3–4.

    Article  PubMed  CAS  Google Scholar 

  44. Thakkinstian A, D’Este C, Eisman J, Nguyen T, Attia J. Meta-analysis of molecular association studies: vitamin D receptor gene polymorphisms and BMD as a case study. J Bone Miner Res. 2004;19:419–28.

    Article  PubMed  CAS  Google Scholar 

  45. FRAX®: WHO risk factor tool. Available at: http://www.sheffield.ac.uk/FRAX/. Accessed April 8, 2011.

  46. Mikati MA, Dib L, Yamout B, et al. Two randomized vitamin D trials in ambulatory patients on anticonvulsants: impact on bone. Neurology. 2006;67(11):2005–14.

    Article  PubMed  CAS  Google Scholar 

  47. IOM (Institute of Medicine). 2011. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press. Available at: http://www.iom.edu/vitamind. Accessed April 8, 2011.

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. 710 West 168th Street, New York, NY, 10032, USA

    Alison M. Pack MD, MPH

Authors
  1. Alison M. Pack MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alison M. Pack MD, MPH.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pack, A.M. Treatment of Epilepsy to Optimize Bone Health. Curr Treat Options Neurol 13, 346–354 (2011). https://doi.org/10.1007/s11940-011-0133-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11940-011-0133-x

Keywords

Search

Navigation