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Molecular mechanisms responsible for the impact of antiepileptic therapy on bone mineral density of epileptic patients

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Antiepileptic drugs (AEDs) may have a negative effect on bone tissue, by increasing the risk of fractures in epileptic patients compared to the general population. Many investigations have shown lower bone mineral density and a higher risk for osteopenia and osteoporosis in patients taking traditional and novel AEDs. Multidrug therapy and the duration of AED intake are associated with the most significant risk for lower bone mineral density. Nevertheless, the molecular mechanisms of action of different AEDs on bone tissue remain little studied.

About the Authors

I. A. Zhidkova
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation
Department of Nervous System Diseases, Faculty of General Medicine

T. V. Kaznacheeva
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation
Department of Reproductive Medicine and Surgery, Faculty of Additional

E. Yu. Demidova
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation
Department of Nervous System Diseases, Faculty of General Medicine

V. V. Berseneva
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation
Department of Reproductive Medicine and Surgery, Faculty of Additional


1. Sato Y, Kondo I, Ishida S, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology. 2001;57:445-9. doi: 10.1212/WNL.57.3.445

2. Eisenberg E, River Y, Shifrin A, Krivoy N. Antiepileptic drugs in the treatment of neuropathic pain. Drugs. 2007;67:1265-89. doi: 10.2165/00003495-200767090-00003

3. Mintzer S, Boppana P, Toguri J, DeSantis A. Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilepsia. 2006;47:510-5. doi: 10.1111/j.1528-1167.2006.00460.x

4. Ketter TA, Wang PW, Becker OV, et al. The diverse roles of anticonvulsants in bipolar disorder. Ann Clin Psychiatry. 2003;15:95-108. doi: 10.3109/10401230309085675

5. Антонюк МВ. Дифференцированный подход к диагностике и лечению эпилепсии у женщин в климактерии: Дисc. … докт. мед. наук. Москва; 2009 [ Antonyuk MV. Differentsirovannyi podkhod k diagnostike i lecheniyu epilepsii u zhenshchin v klimakterii: Diss. … dokt. med. nauk [Differentiated approach to the diagnosis and treatment of epilepsy in women in menopause: Diss. ... Doct. Med. Sci.]. Moscow; 2009].

6. Feldkamp J, Becker A, Witte OW, et al. Long-term anticonvulsant therapy leads to low bone mineral density – evidence for direct drug effects of phenytoin and carbamazepine on human osteoblast-like cells. Exp Clin Endocrinol Diabetes. 2000;108:37-43.

7. Korinthenberg R, Bukart P, Woefle C, et al. Pharmacology, efficacy and tolerability of potassium bromide in childhood Epilepsy. J Child Neurol. 2007;22:414-8. doi: 10.1177/0883073807302758

8. Pack AM, Morrell MJ, Marcus R, et al. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann Neurol. 2005;57:252-7. doi: 10.1002/ana.20378

9. Айламазян ЭК, редактор. Гинекология от пубертата до постменопаузы. Москва: МЕДпрессинформ; 2007. 495 с. [Ailamazyan EK, editor. Ginekologiya ot pubertata do postmenopauzy [Gynecology from puberty to menopause]. Moscow: MEDpressinform; 2007. 495 p.].

10. Andress DL, Ozuna J, Tirschwell D, et al. Antiepileptic drug-induced bone loss in young male patients who have seizures. Arch Neurol. 2002;59:16-78. doi: 10.1001/archneur. 59.5.781

11. Зоткин ЕГ, Косульникова ЕН. Остеопороз: от организации помощи больным к лечению. Медлайн-Экспресс. 2007;1(190):56-9 [Zotkin EG, Kosul'nikova EN. steoporosis: from the organization of care for patients to treatment. Medlain-Ekspress. 2007;1(190):56-9 (In Russ.)].

12. Campos LMA, Liphaus BL, Silva CAA, et al. Osteoporosis in childhood and adolescence. J Pediatr (Rio J). 2003;79(6):481-8. doi: 10.2223/jped.1107

13. Kaufman KR, Kugler SL, Sachdeo RC. Tiagabine in the management of postencephalitic epilepsy and impulse control disorder. Epilepsy Behav. 2002;(3):190-4. doi: 10.1006/ebeh.2002.0319

14. Landmark CJ. Antiepileptic drugs in nonepilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs. 2008;22:27-47. doi: 10.2165/00023210-200822010-00003

15. Sussman N, Ettinger AB. Psychotropic properties of antiepileptic drugs. In: Ettinger AB, Kanner AM, editors. Psychiatric issues in epilepsy: a practical guide to diagnosis and treatment. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2007. P. 67-82.

16. Schacht E, Richy F, Reginster JY. The therapeutic effects of alfacalcidol on bone strength, muscle metabolism and prevention of falls and fractures. J Musculoskelet Neuronal Interact. 2005;5(3):273-84.

17. Steingrimsdottir L, Gunnarsson O, Indridason OS, et al. Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA. 2005;294(18):2336-41. doi: 10.1001/jama.294.18.2336

18. Holic MF. McCollum Award Lecture, 1994: Vitamin D - new horizons for the 21 century. Am J Clin Nutr. 1994;60:610-30.

19. Pack AM. Treatment of epilepsy to optimize bone health. Curr Treat Options Neurol. 2011; 13(4):346-54. doi: 10.1007/s11940-011-0133-x

20. Pascussi JM, Robert A, Nguyen M, et al. Possible involvement of pregnane X receptorenhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest. 2005;115:177-86. doi: 10.1172/JCI21867

21. Valsamis HA, Arora SK, Labban B, McFarlane SI. Antiepileptic drugs and bone metabolism. Nutr Metab (Lond). 2006;3:36. doi: 10.1186/1743-7075-3-36

22. Larsen ER, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: A pragmatic populationbased 3-year intervention study. J Bone Miner Res. 2004;19:270-8. doi: 10.1359/jbmr.0301240

23. Koch HU, Kraft D, von Herrath D, Schaefer K. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia. 1972;13:829. doi: 10.1111/j.1528-1157.1972.tb05167.x

24. Mosekilde L, Hansen HH, Christensen MS, et al. Fractional intestinal calcium absorption in epileptics on anticonvulsant therapy. Short-term effect of 1,25 dihydroxycholecalciferol and 25-hydroxycholecalciferol. Acta Med Scand. 1979;205:405. doi: 10.1111/j.0954-6820.1979.tb06073.x

25. Takahashi A, Onodera K, Shinoda H, Mayanagi H. Phenytoin and its metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin, show bone resorption in cultured neonatal mouse calvaria. Jpn J Pharmacol. 2000;82:82. doi: 10.1254/jjp.82.82

26. Onodera K, Takahashi A, Sakurada S, Okano Y. Effects of phenytoin and/or vitamin K2 (menatetrenone) on bone mineral density in the tibiae of growing rats. Life Sci. 2002;70:15-33. doi: 10.1016/S0024-3205(01)01522-3

27. Vernillo AT, Rifkin BR, Hauschka PV. Phenytoin affects osteocalcin secretion from osteoblastic rat osteosarcoma 17/2.8 cells in culture. Bone. 1990;11:309. doi: 0.1016/8756- 3282(90)90085-D

28. Elliott JO, Jacobson MP, Haneef Z. Homocysteine and bone loss in epilepsy. Seizure. 2007;16:22. doi: 10.1016/j.seizure.2006.10.001

29. Tsukahara H, Kimura K, Todoroki Y, et al. Bone mineral status in ambulatory pediatric patients on long-term antiepileptic drug therapy. Pediatr Int. 2002;44:247-53. doi: 10.1046/j.1442-200X.2002.01561.x

30. Tekgul H, Serdaroglu G, Huseyinov A, Gц kben S. Bone mineral status in pediatric outpatients on antiepileptic drug monotherapy. J Child Neurol. 2006;21:411-4.

31. Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics and sedatives and risk of fractures: effects of half-life. Calcif Tissue Int. 2008;82: 34-43. doi: 10.1007/s00223-007-9095-0

32. Pack AM, Morrell MJ, Randall A, et al. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology. 2008;29:1586-93. doi: 10.1212/

33. El-Hajj Fuleihan G, Dib L, Yamout B, et al. Predictors of bone density in ambulatory patients on antiepileptic drugs. Bone. 2008;43:149-55. doi: 10.1016/j.bone. 2008.03.002

34. Petty SJ, Paton LM, O'Brien TJ, et al. Effect of antiepileptic medication on bone mineral measures. Neurology. 2005;65:1358-65. doi: 10.1212/01.wnl.0000180910.72487.18

35. Kim SH, Lee JW, Choi KG, et al. A 6-month longitudinal study of bone mineral density with antiepileptic drug monotherapy. Epilepsy Behav. 2007;10:291-5. doi: 10.1016/j.yebeh.2006.11.007

36. Tjellesen L, Christiansen C. Serum vitamin D metabolites in epileptic patients treated with 2 different anti-convulsants. Acta Neurol Scand. 1982;66:335-41. doi: 10.1111/j.1600- 0404.1982.tb06853.x

37. Kumandas S, Koklu E, Gemes H, et al. Effect of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-3. J Pediatr Endocrinol Metab. 2006;19(4):529-34.

38. Verrotti A, Greco R, Latini G, Morgese G, Chiarelli F. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia. 2002;43:1488-92. doi: 10.1046/j.1528-1157.2002.13002.x

39. Verrotti A, Greco R, Morgese G, Chiarelli F. Increased bone turnover in epileptic patients treated with carbamazepine. Ann Neurol. 2000;47(3):385-8. doi: 10.1002/1531- 8249(200003)47:3<385::AID-ANA18>3.0. CO;2-W

40. Селютина ТВ. Состояние минеральной плотности костной ткани у больных эпилепсией: Дисс. … канд. мед. наук. Москва; 2008 [Selyutina TV. Sostoyanie mineral'noi lotnosti kostnoi tkani u bol'nykh epilepsiei: Diss. … kand. med. nauk [Status of bone mineral density in patients with epilepsy: Diss. ... Cand. Med. Sci.]. Moscow; 2008].

41. Заседателева ИЮ. Особенности минерального обмена и гормонального статуса у больных эпилепсией: Дисс. … канд. мед. наук. Санкт-Петербург; 2005 [Zasedateleva IYu. Osobennosti mineral'nogo obmena i gormonal'nogo statusa u bol'nykh epilepsiei: Diss. … kand. med. nauk [Features of mineral metabolism and hormonal status in patients with epilepsy: Diss. ... Cand. Med. Sci.]. St. Petersburg; 2005].

42. Valimaki MJ, Tiihonen M, Laitinen K, et al. Bone mineral density measured by dual- energy X-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J Bone Miner Res. 1994;9:631-7.

43. Ensrud KE, Walczak TS, Blackwell T, et al. Antiepileptic drug use increases rates of bone loss in older women: a prospective study. Neurology. 2004;62:2051-7. doi: 10.1212/01.WNL.0000125185.74276.D2

44. Stephen LJ, Sills GJ, Leach JP, et al. Sodium valproate versus lamotrigine: a randomized comparison of efficacy, tolerabil-ity and effects on circulating androgenic hormones in newly diagnosed epilepsy. Epilepsy Res. 2007;75:9122-9. doi: 10.1016/j.eplepsyres. 2007.04.009

45. Pack AM, Olarte LS, Morrell MJ, et al. Bone mineral density in an outpatient population receiving enzyme-inducing antiepileptic drugs. Epilepsy Behav. 2003;4(2):169-74. doi: 10.1016/S1525-5050(03)00036-2

46. Boluk A, Guzelipek M, Savli H, et al. The effect of valproate on bone mineral density in adult epileptic patients. Pharmacol Res. 2004;50:93-7. doi: 10.1016/j.phrs.2003.11.011

47. Babayigit A, Dirik E, Bober E, Cakmakci H. Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol. 2006;35:177-81. doi: 10.1016/j.pedatrnerol. 2006.03.004

48. Erbayat Altay E, Serdaroglu A, Tь mer L, et al. Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid. J Pediatr Endocrinol Metab. 2000;13:33-9. doi: 10.1515/JPEM.2000.13.7.933

49. Cansu A, Yesilkaya E, Serdaroglu A, et al. Evaluation of bone turnover in epileptic children using oxcarbazepine. Pediatr Neurol. 2008;39:266-71. doi: 0.1016/j.pediatrneurol. 2008.07.001

50. Andreasen AH, Brosen K, Damkier P. A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on cyp3a4. Epilepsia. 2007;48:490-6. doi: 10.1111/j.1528- 1167.2007.00924.x

51. Cetinkaya Y, Kurtulmus YS, Tutkavul K, Tireli H. The effect of oxcarbazepine on bone metabolism. Acta Neurol Scand. 2009;120: 170-5. doi: 10.1111/j.1600-0404.2008.01148.x

52. Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acidbase balance: extent, mechanism and effects. Br J Clin Pharmacol. 2009;68:655-61. doi: 10.1111/j.1365-2125.2009.03521.x

53. Vacek TP, Kalani A, Voor MJ, et al. The role of homocysteine in bone remodeling. Clin Chem Lab Med. 2013;51:579-90. doi: 10.1515/cclm-2012-0605

54. Zhang J, Wang KX, Wie Y, et al. Effect of topiramate and carbamazepine on bone metabolism in children with epilepsy. Zhongguo Dang Dai Er Ke Za Zhi = Chin J Contemp Paediatr. 2010;12:96-8 (In Chin.).

55. Heo K, Rhee Y, Lee HW, et al. The effect of topiramate monotherapy on bone mineral density and markers of bone and mineral metabolism in premenopausal women with epilepsy. Epilepsia. 2011;52:1884-9. doi: 10.1111/j.1528-1167.2011.03131.x

56. Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology. 2000;55:236-42. doi: 10.1212/WNL.55.2.236

57. Карлов ВА, Власов ПН. Результаты двухлетнего применения кеппры для лечения эпилепсии у взрослых. Журнал неврологии и психиатрии им. С.С. Корсакова. 2006;106(7):24-30 [Karlov VA, Vlasov PN. The results of the two-year use of Keppra in the treatment of epilepsy in adults. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova =S.S. Korsakov Journal of Neurology and Psychiatry. 2006;106(7):24-30 (In Russ.)].

58. Карлов ВА, Власов ПН, Комелькова ЕГ, Шахабасова ЗС. Длительная монотерапия леветирацетамом парциальной эпилепсии у взрослых. Журнал неврологии и психиатрии им. С.С. Корсакова. 2010;(2):15-20 [Karlov VA, Vlasov PN, Komel'kova EG, Shakhabasova ZS. Long-term monotherapy with levetiracetam partial epilepsy in adults. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. 2010;(2):15-20 (In Russ.)].

59. Dooley M, Plosker GL. Levetiracetam: a review of its adjunctive use in the management of partial onset seizures. Drugs. 2000;60:871-93. doi: 10.2165/00003495- 200060040-00004

60. Blais L, Sheehy O, St Hilaire JM, et al. Economic evaluation of levetiracetam as an addon therapy in patients with refractory epilepsy. Pharmacoeconomics. 2005;23:493-503. doi: 10.2165/00019053-200523050-00008

61. Ali II, Horrigan T., Kellough L, Tietjen GE. Measurement of bone mineral density in patients on levetiracetam monotherapy. Am Epilepsy Soc Abstr. 2006;(2):150.

62. Nissen-Meyer LS, Svalheim S, Tauboll E, et al. Levetiracetam, phenytoin, and valproate act differently on rat bone mass, structure, and metabolism. Epilepsia. 2007;48:1850-60. doi: 10.1111/j.1528-1167.2007.01176.x

63. Beniczky SA, Viken J, Jensen LT, Andersen NB. Bone mineral density in adult patients treated with various antiepileptic drugs. Seizure. 2012;21:471-2. doi: 10.1016/j.seizure.2012.04.002

64. Fekete S, Simko J, Gradosova I, et al. The effect levetiracetam on rat bone mass, structure and metabolism. Epilepsy Res. 2013;13:217-9. doi: 10.1016/j.eplepsyres.2013.08.012

65. Aksoy D, Atakli D, Apraci B, et al. Effect of oxcarbazehine and levetiracetam as a monotherapy on calcium and vitamin D metabolism. Abstract from the 11 European Congress on Epileptology, Stockholm, Sweden; Jun 29-Jul 3 2014. Epilepsia. 2014;55(Suppl 2):44.

66. Sheth RD, Hermann BP. Bone mineral density with lamotrigine monotherapy for epilepsy. Pediatr Neurol. 2007;37:250-4. doi: 10.1016/j.pediatrneurol.2007.05.018

67. Takahashi A, Onodera K, Kamei J, et al. Effects of chronic administration of zonisamide, an antiepileptic drug, on bone mineral density and their prevention with alfacalcidol in growing rats. J Pharmacol Sci. 2003;91:313-8. doi: 10.1254/jphs.91.313

68. Morijiri Y, Sato T. Factors causing rickets in institutionalised handicapped children on anticonvulsant therapy. Arch Dis Child. 1981;56:446-9. doi: 10.1136/adc.56.6.446

69. Phabphal K, Geater A, Leelawattana R, et al. Prevalence and risk factors of low bone mineral density and 25-hydroxyvitamin D status in young healthy epileptic adult patients in a tropical Asian country taking antiepileptic drug. Bone. 2009;45:232-7. doi: 10.1016/j.bone.2009.04.235

70. Воронкова КВ, Петрухин АС, Пылаева ОА, Холин АА. Рациональная антиэпилептическая фармакотерапия (руководство для врачей). Москва: БИНОМ; 2008. 191 с. [Voronkova KV, Petrukhin AS, Pylaeva OA, Kholin AA. Ratsional'naya antiepilepticheskaya farmakoterapiya (rukovodstvo dlya vrachei) [Rational antiepileptic pharmacotherapy (manual for physicians)]. Moscow: BINOM; 2008. 191 p.].

71. Persson HB, Alberts KA, Farahmand BY, Tomson T. Risk of extremity fractures in adult outpatients with epilepsy. Epilepsia. 2002;43:768-72. doi: 10.1046/j.1528- 1157.2002.15801.x

72. Souverein PC, Webb DJ, Weil JG, et al. Use of antiepileptic drugs and risk of fractures: case-control study among patients with epilepsy. Neurology. 2006;66:1318-24. doi: 10.1212/01.wnl.0000210503.89488.88

73. Blum D. Total impact of epilepsy: biological, psychological, social, and economic aspects. Barrow Quarterly. 1999;15:1-20.

For citation:

Zhidkova I.A., Kaznacheeva T.V., Demidova E.Y., Berseneva V.V. Molecular mechanisms responsible for the impact of antiepileptic therapy on bone mineral density of epileptic patients. Neurology, Neuropsychiatry, Psychosomatics. 2016;(1S):59-65. (In Russ.)

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