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Effects of Antiepileptic Drugs on Bone Health and Growth Potential in Children with Epilepsy

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Abstract

Background

Bone health may be impaired in children with epilepsy.

Objectives

Our objective was to characterize bone mineral density (BMD) and bone growth in children receiving antiepileptic drugs (AEDs) and to assess the effects of co-morbidity, vitamin D deficiency, and type of drugs used.

Data sources

Data were sourced from PubMed, Embase, and Web of Science.

Eligibility criteria

Cross-sectional, cohort, case-control, or randomized controlled trials reporting BMD or parameters of bone growth.

Participants

Children with epilepsy compared with controls.

Interventions

AEDS or ketogenic diet.

Study appraisal

The studies were evaluated by one author.

Synthesis methods

Studies were categorized as reporting reduced BMD or not at any skeletal site as outcome. A logistic regression was performed for age, percent boys, study design, type of AED, co-morbidity or not, and signs of vitamin D deficiency/osteomalacia or not.

Results

Carbamazepine and valproate were analyzed as monotherapy in 11 studies, and for both drugs a limited decrease in BMD seemed present. For oxcarbazepine, levetiracetam, phenytoin, phenobarbital, and topiramate, only one study with monotherapy was found for each drug, none of which reported decreased bone density. Polytherapy with AEDs seemed to be associated with a larger decrease in bone density than was monotherapy. Although few studies were available on bone growth, these did indicate that bone growth may be impaired among users of AEDs. Ketogenic diet may be associated with decreased bone density. The main determinant of normal BMD was absence of vitamin D deficiency/osteomalacia.

Limitations

The studies differed in skeletal sites studied and most were cross-sectional. No head-to-head comparisons of AEDs were performed. Children treated with polytherapy or ketogenic diet may have more complicated and severe disease than those treated with monotherapy. The underlying cause of epilepsy and vitamin D deficiency may contribute to impaired bone growth and density.

Conclusions

Reduced bone density, impaired bone growth, and vitamin D deficiency may be seen in children treated with drugs against epilepsy.

Implications

Measures to correct vitamin D deficiency, calcium intake should be taken.

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References

  1. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of anti-epileptic drugs. Epilepsia. 2004;45:1330–7.

    Article  CAS  PubMed  Google Scholar 

  2. Vestergaard P. Epilepsy, osteoporosis and fracture risk: a meta-analysis. Acta Neurol Scand. 2005;112:277–86.

    Article  CAS  PubMed  Google Scholar 

  3. Takahashi A, Onodera K, Shinoda H, et al. Phenytoin and its metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin, show bone resorption in cultured neonatal mouse calvaria. Jpn J Pharmacol. 2000;82:82–4.

    Article  CAS  PubMed  Google Scholar 

  4. Blake G, Adams J, Bishop N. DXA in adults and children. In: Rosen C, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Ames: Wiley; 2014. pp. 249–263.

  5. Glüer C. Quantitative computed tomography in children and adults. In: Rosen C, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Ames: Wiley; 2014. pp. 264–276.

  6. Blake G, Wahner H, Fogelman I. The evaluation of osteoporosis: dual energy X-ray absorptiometry and ultrasound in clinical practice. London: Martin Dunitz; 1999.

    Google Scholar 

  7. Gissel T, Poulsen C, Vestergaard P. Adverse effects of antiepileptic drugs on bone mineral density in children. Expert Opin Drug Saf. 2007;6:267–78.

    Article  CAS  PubMed  Google Scholar 

  8. Roende G, Ravn K, Fuglsang K, et al. DXA measurements in Rett syndrome reveal small bones with low bone mass. J Bone Miner Res. 2011;26:2280–6.

    Article  CAS  PubMed  Google Scholar 

  9. Leslie W, Adler R, El Hajj FG, et al. Application of the 1994 WHO classification to populations other than postmenopausal Caucasian women: the 2005 ISCD Official Positions. J Clin Densitom. 2006;9:22–30.

    Article  PubMed  Google Scholar 

  10. Majumdar S. Magnetic resonance imaging of bone. In: Rosen C, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Ames: Wiley; 2014. pp. 277–282.

  11. Forwood M. Growing a healthy skeleton: the importance of mechanical loading. In: Rosen C, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Ames: Wiley; 2014. pp. 149–155.

  12. Norris S, Micklesfield L, Pettifor J. Ethnic differences in bone acquisition. In: Rosen C, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Ames: Wiley; 2014. pp. 135–141.

  13. Yang T, Grover M, Joeng K, et al. Human fetal and neonatal bone development. In: Rosen C, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Ames: Wiley; 2014. pp. 119–126.

  14. Wang Q, Seeman E. Skeletal growth and peak bone strength. In: Rosen C, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Ames: Wiley; 2014. pp. 127–134.

  15. Naylor K, Eastell R. Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol. 2012;8:379–89.

    Article  CAS  PubMed  Google Scholar 

  16. Akin R, Okutan V, Sarici U, et al. Evaluation of bone mineral density in children receiving antiepileptic drugs. Pediatr Neurol. 1998;19:129–31.

    Article  CAS  PubMed  Google Scholar 

  17. Aksoy A, Sönmez FM, Deger O, et al. The effects of antiepileptic drugs on the relationships between leptin levels and bone turnover in prepubertal children with epilepsy. J Pediatr Endocrinol Metab. 2011;24:703–8.

    Article  CAS  PubMed  Google Scholar 

  18. Babayigit A, Dirik E, Bober E, et al. Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol. 2006;35:177–81.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  20. Chou I, Lin K, Wang H, et al. Evaluation of bone mineral density in children receiving carbamazepine or valproate monotherapy. Acta Paediatr Taiwan. 2007;48:317–22.

    PubMed  Google Scholar 

  21. Chung S, Ahn C. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Develop. 1994;16:382–85.

  22. Coppola G, Verrotti A, Mainolfi C, et al. Bone mineral density in angelman syndrome. Pediatr Neurol. 2007;37:411–6.

    Article  PubMed  Google Scholar 

  23. Ecevit C, Aydoğan A, Kavakli T, et al. Effect of carbamazepine and valproate on bone mineral density. Pediatr Neurol. 2004;31:279–82.

    Article  PubMed  Google Scholar 

  24. Erbayat AE, Serdaroglu A, Tumer L, et al. Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid. J Pediatr Endocrinol Metab. 2001;13:933–9.

    Google Scholar 

  25. Farhat G, Yamout B, Mikati M, et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology. 2002;58:1348–53.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

  27. Gniatkowska-Nowakowska A. Fractures in epilepsy children. Seizure. 2010;19:324–5.

    Article  PubMed  Google Scholar 

  28. Guo C, Ronen G, Atkinson S. Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy. Epilepsia. 2001;42:1141–7.

    Article  CAS  PubMed  Google Scholar 

  29. Hahn TJ, Halstead LR, DeVivo DC. Disordered mineral metabolism produced by ketogenic diet therapy. Calcif Tissue Int. 1979;28:17–22.

    Article  CAS  PubMed  Google Scholar 

  30. Kafali G, Erselcan T, Tanzer F. Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12 years. Clin Pediatr (Phila). 1999;38:93–8.

    Article  CAS  Google Scholar 

  31. Koo DL, Joo EY, Kim D, et al. Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy. Epilepsy Res. 2013;104:134–9.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  33. 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;18:93–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Oner N, Kaya M, Karasalihoglu S, et al. Bone mineral metabolism changes in epileptic children receiving valproic acid. J Paediatr Child Health. 2004;40:470–3.

    Article  CAS  PubMed  Google Scholar 

  36. Phabphal K, Limapichat K, Sathirapanya P, et al. Bone mineral density following long-term use of antiepileptic drugs in a tropical Asian country. Epileptic Disord. 2008;10:213–8.

    PubMed  Google Scholar 

  37. Phabphal K, Geater A, Limapichart K, et al. The association between BsmI polymorphism and bone mineral density in young patients with epilepsy who are taking phenytoin. Epilepsia. 2013;54:249–55.

    Article  CAS  PubMed  Google Scholar 

  38. Rieger-Wettengl G, Tutlewski B, Stabrey A, et al. Analysis of the musculoskeletal system in children and adolescents receiving anticonvulsant monotherapy with valproic acid or carbamazepine. Pediatrics. 2001;108:E107.

    Article  CAS  PubMed  Google Scholar 

  39. Sheth R, Wesolowski C, Jacob J, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr. 1995;127:256–62.

    Article  CAS  PubMed  Google Scholar 

  40. Sheth RD, Hermann BP. Bone in idiopathic and symptomatic epilepsy. Epilepsy Res. 2008;78:71–6.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  43. Suzuki K, Ueda S, Umezu R, et al. Evaluation of bone mineral density using digital image processing in children receiving anticonvulsants. No To Hattatsu. 2007;39:351–5.

    PubMed  Google Scholar 

  44. Tekgul H, Dizdarer G, Demir N, et al. Antiepileptic drug-induced osteopenia in ambulatory epileptic children receiving a standard vitamin D3 supplement. J Pediatr Endocrinol Metab. 2005;18:585–8.

    Article  CAS  PubMed  Google Scholar 

  45. Timperlake R, Cook S, Thomas K, et al. Effects of anticonvulsant drug therapy on bone mineral density in a pediatric population. J pediatr Orthop. 1988;8:467–70.

    Article  CAS  PubMed  Google Scholar 

  46. Tsukahara H, Kimura K, Todoroki Y, et al. Bone mineral status in ambulatory pediatric patients on long-term anti-epileptic drug therapy. Pediatr Int. 2002;44:247–53.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang J, Wang K, Wei Y, et al. Effect of topiramate and carbamazepine on bone metabolism in children with epilepsy. Zhongguo Dang Dai Er Ke Za Zhi. 2010;12:96–8.

    CAS  PubMed  Google Scholar 

  48. Baer M, Kozlowski B, Blyler E, et al. Vitamin D, calcium, and bone status in children with developmental delay in relation to anticonvulsant use and ambulatory status. Am J Clin Nutr. 1997;65:1042–51.

    CAS  PubMed  Google Scholar 

  49. Onoe S, Mimaki T, Seino Y, et al. Delayed bone development in epileptic children assessed by microdensitometer. Dev Pharmacol Ther. 1988;11:24–31.

    CAS  PubMed  Google Scholar 

  50. Lee H, Wang S, Salter DM, et al. The impact of the use of antiepileptic drugs on the growth of children. BMC Pediatr. 2013;13:211.

    Article  PubMed Central  PubMed  Google Scholar 

  51. Barden HS, Smith E. Bone mineral in mentally retarded patients receiving long-term anticonvulsive therapy. Growth. 1975;39:371–88.

    CAS  PubMed  Google Scholar 

  52. Coppola G, Fortunato D, Mainolfi C, et al. Bone mineral density in a population of children and adolescents with cerebral palsy and mental retardation with or without epilepsy. Epilepsia. 2012;53:2172–7.

    Article  PubMed  Google Scholar 

  53. Wietholtz H, Zysset T, Kreiten K, et al. Effect of phenytoin, carbamazepine, and valproic acid on caffeine metabolism. Eur J Clin Pharmacol. 1989;36:401–6.

    Article  CAS  PubMed  Google Scholar 

  54. Tjellesen L, Nilas L, Christiansen C. Does carbamazepine cause disturbances in calcium metabolism in epileptic patients? Acta Neurol Scand. 1983;68:13–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  56. Larkin JG, McKee PJ, Forrest G, et al. Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects. Br J Clin Pharmacol. 1991;31:65–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Zerwekh J, Homan R, Tindall R, et al. Decreased serum 24,25-dihydroxyvitamin D concentration during long-term anticonvulsant therapy in adult epileptics. Ann Neurol. 1982;12:184–6.

    Article  CAS  PubMed  Google Scholar 

  58. Xiao D, Chen Y, Yang D, et al. Age-related inducibility of carboxylesterases by the antiepileptic agent phenobarbital and implications in drug metabolism and lipid accumulation. Biochem Pharmacol. 2012;84:232–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Verrotti A, Coppola G, Parisi P, et al. Bone and calcium metabolism and antiepileptic drugs. Clin Neurol Neurosurg. 2010;112:1–10.

    Article  PubMed  Google Scholar 

  60. Christiansen C, Rodbro P, Lund M. Effect of vitamin D on bone mineral mass in normal subjects and in epileptic patients on anticonvulsants: a controlled therapeutic trial. BMJ. 1973;2:208–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Christiansen C, Rodbro P. Initial and maintenance dose of vitamin D2 in the treatment of anticonvulsant osteomalacia. Acta Neurol Scand. 1974;50:631–41.

    Article  CAS  PubMed  Google Scholar 

  62. Bergqvist AGC, Schall JI, Stallings VA, et al. Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr. 2008;88:1678–84.

    Article  CAS  PubMed  Google Scholar 

  63. Bertoli S, Striuli L, Testolin G, et al. Nutritional status and bone mineral mass in children treated with ketogenic diet. Recenti Prog Med. 2002;93:671–5.

    PubMed  Google Scholar 

  64. Bertoli S, Trentani C, Ferraris C, et al. Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: a case series. Nutrition. 2014;30:726–8.

    Article  CAS  PubMed  Google Scholar 

  65. Verrotti A, Agostinelli S, Coppola G, et al. A 12-month longitudinal study of calcium metabolism and bone turnover during valproate monotherapy. Eur J Neurol. 2010;17:232–7.

    Article  CAS  PubMed  Google Scholar 

  66. Ranganathan L, Ramaratnam S. Vitamins for epilepsy. Cochrane Database Syst Rev. 2005;2:CD004304.

  67. Pack AM. Treatment of epilepsy to optimize bone health. Curr Treat Options Neurol. 2011;13:346–54.

    Article  PubMed  Google Scholar 

  68. Bolland MJ, Grey A, Avenell A, et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.

    Article  PubMed Central  PubMed  Google Scholar 

  69. Leventis P, Kiely PDW. The tolerability and biochemical effects of high-dose bolus vitamin D2 and D3 supplementation in patients with vitamin D insufficiency. Scand J Rheumatol. 2009;38:149–53.

    Article  CAS  PubMed  Google Scholar 

  70. Avenell A, Gillespie WJ, Gillespie LD, et al. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2009;4:CD000227.

  71. Beaudart C, Buckinx F, Rabenda V, et al. The effects of vitamin D on skeletal muscle strength, muscle mass and muscle power: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2014;99(11):4336–45.

    Article  CAS  PubMed  Google Scholar 

  72. Sebestyen JF, Srivastava T, Alon US. Bisphosphonates use in children. Clin Pediatr (Phila). 2012;51:1011–24.

    Article  Google Scholar 

  73. Vestergaard P, Mosekilde L, Langdahl B. Fracture prevention in postmenopausal women. Clin Evid (Online). 2011; 2011:pii1109.

  74. O’Donnell S, Cranney A, Wells G, et al. Strontium ranelate for preventing and treating postmenopausal osteoporosis. Cochrane Database Syst Rev 2006;(4):CD005326.

  75. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65.

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Acknowledgments

Professor Vestergaard has no conflicts of interest that are relevant to this review. No funding was received for the preparation of this review.

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  1. Departments of Clinical Medicine and Endocrinology, Aalborg University Hospital, Mølleparkvej 4, 9100, Aalborg, Denmark

    Peter Vestergaard

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Correspondence to Peter Vestergaard.

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Vestergaard, P. Effects of Antiepileptic Drugs on Bone Health and Growth Potential in Children with Epilepsy. Pediatr Drugs 17, 141–150 (2015). https://doi.org/10.1007/s40272-014-0115-z

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