CNS Drugs

, Volume 15, Issue 8, pp 633–642 | Cite as

Adverse Effects of Antiepileptic Drugs on Bone Structure

Epidemiology, Mechanisms and Therapeutic Implications
  • Alison M. Pack
  • Martha J. Morrell
Review Article


Antiepileptic drugs (AEDs) were first associated with disorders of bone in both adults and children in the late 1960s. The most severe manifestations of these disorders are osteopenia/osteoporosis, osteomalacia and fractures. Bone disease has been described in several groups of patients receiving AEDs. Groups identified as being more vulnerable to AED-associated bone disease include institutionalised patients, postmenopausal women, older men and children.

Radiological and histological evidence of bone disease is found in patients taking AEDs. Numerous biochemical abnormalities of bone metabolism have also been described. The severity of bone and biochemical abnormalities is thought to correlate with the duration of AED exposure and the number of AEDs used. In monotherapy, the AEDs most commonly associated with altered bone metabolism are phenytoin, primidone and phenobarbital (phenobarbitone). To date there have been no reports of altered bone metabolism in individuals receiving the newer anticonvulsants (specifically lamotrigine, topiramate, vigabatrin and gabapentin).

The mechanisms of AED-associated bone disease are not clearly elucidated; however, several theories have been proposed to explain the link. No definitive guidelines for evaluation or treatment have yet been determined.


Bone Mineral Density Bone Disease Vigabatrin Increase Bone Turnover Institutionalise Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Jaglal SB, Kreiger N, Darlington GA. Lifetime occupational physical activity and risk of hip fracture in women. Ann Epidemiol 1995; 5(4): 321–4PubMedCrossRefGoogle Scholar
  2. 2.
    Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1995; 332(12): 767–73PubMedCrossRefGoogle Scholar
  3. 3.
    Desai KB, Ribbans WJ, Taylor GJ. Incidence of five common fractures in an institutionalized epileptic population. Injury 1996; 27(2): 97–100PubMedCrossRefGoogle Scholar
  4. 4.
    Vestergaard P, Tigaran S, Rejnmark L, et al. Fracture risk is increased in epilepsy. Acta Neurol Scand 1999; 99: 269–75PubMedCrossRefGoogle Scholar
  5. 5.
    Kruse R. Osteopathien bei antiepileptischer Langzeittherapie. Monatasschr Kinderheilkd 1968; 116: 378–81Google Scholar
  6. 6.
    Dent CE, Richens A, Rowe DFJ, et al. Osteomalacia with long-term anticonvulsant therapy in epilepsy. BMJ 1970; 4: 69–72PubMedCrossRefGoogle Scholar
  7. 7.
    Richens A, Rowe DFJ. Disturbance of calcium metabolism by anticonvulsant drugs. BMJ 1970; 4: 73–6PubMedCrossRefGoogle Scholar
  8. 8.
    Hunter J, Maxwell JD, Stewart DA, et al. Altered calcium metabolism in epileptic children on anticonvulsants. BMJ 1971; 4(781): 202–4PubMedCrossRefGoogle Scholar
  9. 9.
    Hoikka V, Savolainen K, Esko M, et al. Osteomalacia in institutionalized epileptic patients on long-term anticonvulsant therapy. Acta Neurol Scan 1981; 64: 122–31CrossRefGoogle Scholar
  10. 10.
    Nilsson OS, Lindholm TS, Elmstedt E, et al. Fracture incidence and bone disease in epileptics receiving long-term anticonvulsant drug treatment. Arch Orothop Trauma Surg 1986; 105(3): 146–9CrossRefGoogle Scholar
  11. 11.
    Ross PD, He Y-F, Davis JW, et al. Normal ranges for bone loss rates. Bone Miner 1994; 26: 169–80PubMedCrossRefGoogle Scholar
  12. 12.
    Stephen LJ, McLellan AR, Harrison JH, et al. Bone density and antiepileptic drugs: a case controlled study. Seizure 1999; 8(6): 339–42PubMedCrossRefGoogle Scholar
  13. 13.
    Sheth RD, Wesolowski CA, Jacob JC, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995; 127: 256–62PubMedCrossRefGoogle Scholar
  14. 14.
    Livingston S, Berman W, Pauli LL. Anticonvulsant drugs and vitamin D metabolism. J Am Med Assoc 1973; 24: 1634–5CrossRefGoogle Scholar
  15. 15.
    Hahn TJ, Scharp CR, Richardson CA. Interaction of diphenyl-hydantoin (phenytoin) and phenobarbital with hormonal mediation of fetal rat bone resorption in vitro. J Clin Invest 1978; 62: 406–14PubMedCrossRefGoogle Scholar
  16. 16.
    Mimaki T, Walson PD, Haussler MR. Anticonvulsant therapy and vitamin D metabolism: evidence for different mechanisms for phenytoin and Phenobarbital. Pediatr Pharmacol 1980; 1: 105–12Google Scholar
  17. 17.
    Chung S, Ahn C. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Dev 1994; 16: 382–5PubMedCrossRefGoogle Scholar
  18. 18.
    Mosekilde L, Melsen F. Anticonvulsant osteomalacia determined by quantitative analysis of bone changes. Acta Med Scand 1976; 199: 349–55PubMedCrossRefGoogle Scholar
  19. 19.
    Mosekilde L, Melsen F, Christensen MS, et al. Effect of long-term vitamin D2 treatment on bone morphometry and biochemical values in anticonvulsant osteomalacia. Acta Med Scand 1977; 210: 303–7Google Scholar
  20. 20.
    Hoikka V, Savolainen KE, Alhava EM, et al. Anticonvulsant osteomalacia in epileptic outpatients. Ann Clin Res 1982; 14: 129–32PubMedGoogle Scholar
  21. 21.
    Sotaniemi EA, Hakkarainen HK, Puranen JA, et al. Radiologic bone changes and hypocalcemia with anticonvulsant therapy in epilepsy. Ann Intern Med 1972; 77: 389–94PubMedGoogle Scholar
  22. 22.
    Christiansen C, Rodbro P, Lund M. Incidence of anticonvulsant osteomalacia and effect of vitamin D: controlled therapeutic trial. BMJ 1973; 4: 695–701PubMedCrossRefGoogle Scholar
  23. 23.
    Weinstein RS, Bryce GF, Sappington LJ, et al. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984; 58: 1003–9PubMedCrossRefGoogle Scholar
  24. 24.
    Fischer MH, Adkins Jr WN, Liebl BH, et al. Bone status in nonambulant epileptic institutionalized youth. Clin Pediatr 1988; 10: 499–505CrossRefGoogle Scholar
  25. 25.
    LeBlanc AD, Evans HJ, Marsh C, et al. Precision of dual photon absorptiometry measurements. J Nucl Med 1986 Aug; 27(8): 1362–5PubMedGoogle Scholar
  26. 26.
    Timperlake RW, Cook SD, Thomas KA, et al. Effects of anticonvulsant drug therapy on bone mineral density in a pediatric population. J Pediatr Orthop 1988; 8: 467–70PubMedCrossRefGoogle Scholar
  27. 27.
    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 anti-epileptic drugs. J Bone Miner Res 1994; 9: 631–7PubMedCrossRefGoogle Scholar
  28. 28.
    Seale CG, Morrell MJ, Marcus R, et al. Bone mineral density in AED treated women with epilepsy [abstract]. Epilepsia 1999; 40 Suppl. 7: H.01Google Scholar
  29. 29.
    Seale CG, Morrell MJ, Shane E, et al. Bone health in women with epilepsy [abstract]. Epilepsia 2000; 41 Suppl. 7: 3.096Google Scholar
  30. 30.
    Pluskiewicz W, Nowakowska J. Bone status after long-term anticonvulsant therapy in epileptic patients: evaluation using quantitative ultrasound of calcaneus and phalanges. Ultrasound Med Biol 1997; 23(4): 553–8PubMedCrossRefGoogle Scholar
  31. 31.
    Hahn TJ, Hendin B A, Scharp CR. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med 1972; 287(18): 900–4PubMedCrossRefGoogle Scholar
  32. 32.
    Bouillon R, Reynaert J, Claes JH, et al. The effect of anticonvulsant therapy on serum levels of 25-hydroxyvitamin D, calcium, and parathyroid hormone. J Clin Endocrinol Metab 1975; 41: 1130PubMedCrossRefGoogle Scholar
  33. 33.
    Berry JL, Mawer EB, Walker DA, et al. Effect of antiepileptic drug therapy and exposure to sunlight on vitamin D status in institutionalized patients. In: Oxley J, Janz D, Meinardi H, editors. Antiepileptic therapy: chronic toxicity of antiepileptic drugs, New York: Raven Press, 1983: 185–92Google Scholar
  34. 34.
    Gough H, Goggin T, Bissessar A, et al. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in outpatients with epilepsy. Q J Med 1986; 230: 569–77Google Scholar
  35. 35.
    O’Hare JA, Duggan B, O’Driscoll D, et al. Biochemical evidence for osteomalacia with carbamazepine therapy. Acta Neurol Scand 1980; 62: 282–6PubMedCrossRefGoogle Scholar
  36. 36.
    Bogliun G, Beghi E, Crespi V, et al. Anticonvulsant drugs and bone metabolism. Acta Neurol Scand 1986; 74: 284–8PubMedCrossRefGoogle Scholar
  37. 37.
    Brown AJ, Dusso A, Slatopolsky E. Vitamin D. AJP-Renal Physiol 1999; 277(2): F157–F75Google Scholar
  38. 38.
    Hoikka V, Alhava EM, Karjalainen P, et al. Carbamazepine and bone mineral metabolism. Acta Neurol Scand 1984; 69: 77–80CrossRefGoogle Scholar
  39. 39.
    Davie MW, Emberson CE, Lawson DEM, et al. Low plasma 25-hydroxyvitamin D and serum calcium in institutionalized epileptic subjects: associated risk factors, consequences and response to treatment with vitamin D. Q J Med 1983; 205: 79–91Google Scholar
  40. 40.
    Stamp TCB, Round JM, Haddad JG. Plasma levels and therapeutic effect of 25-hydroxycholecalciferol in epileptic patients taking anticonvulsant drugs. BMJ 1972; 4: 9–12PubMedCrossRefGoogle Scholar
  41. 41.
    Tjellesen L, Christiansen C. Serum vitamin D metabolites in epileptic patients treated with 2 different anti-convulsants. Acta Neurol Scand 1982; 66: 335–41PubMedCrossRefGoogle Scholar
  42. 42.
    Tjellesen L, Nilas L, Christiansen C. Does carbamazepine cause disturbances in calcium metabolism in epileptic patients? Acta Neurol Scand 1983; 68: 13–9PubMedCrossRefGoogle Scholar
  43. 43.
    Tolman KG, Jubiz W, Sannella JJ, et al. Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children. Pediatrics 1975; 56: 45–51PubMedGoogle Scholar
  44. 44.
    Skillen AW, Peirides AM. Serum gamma glutamyl transferase and alkaline phosphatase activities in epileptics receiving anticonvulsant therapy. Clin Chim Acta 1976; 72: 245–51PubMedCrossRefGoogle Scholar
  45. 45.
    Okesina AB, Donaldson D, Lascelles PT. Isoenzymes of alkaline phosphatase in epileptic patients receiving carbamazepine monotherapy. J Clin Pathol 1991; 44: 480–2PubMedCrossRefGoogle Scholar
  46. 46.
    Garnero P, Delmas PD. Biochemical markers of bone turnover. Endocrinol Metab Clin North Am 1998; 27(2): 303–23PubMedCrossRefGoogle Scholar
  47. 47.
    TakeshitaN, SeinoY, Ishida H, et al. Increased circulating levels of gamma-carboxyglutamic acid-containing protein and decreased bone mass in children on anticonvulsant therapy. Calcif Tissue Int 1989; 44: 80–5CrossRefGoogle Scholar
  48. 48.
    Verrotti A, Greco R, Morgese G, et al. Increased bone turnover in epileptic patients treated with carbamazepine. Ann Neurol 2000; 47: 385–8PubMedCrossRefGoogle Scholar
  49. 49.
    Nielsen HE, Melsen F, Lund B, et al. Bone histomorphometry, vitamin D metabolites and calcium phosphate metabolism in anticonvulsant treatment with carbamazepine. Calcif Tissue Int 1983; 35 Suppl. A58: 224Google Scholar
  50. 50.
    Tjellesen L, Gotfredsen A, Christiansen C. Effect of vitamin D2 and D3 on bone-mineral content in carbamazepine-treated epileptic patients. Acta Neurol Scand 1983; 68: 424–8PubMedCrossRefGoogle Scholar
  51. 51.
    Gough H, Bissesar A, Goggin T, et al. Factors associated with the biochemical changes in vitamin D and calcium metabolism in institutionalized patients with epilepsy. Ir J Med Sci 1986; 155(6): 181–9PubMedCrossRefGoogle Scholar
  52. 52.
    Perucca E. Clinical implications of hepatic microsomal enzyme induction by anti-epileptic drugs. Pharmacol Ther 1987; 33: 130–44CrossRefGoogle Scholar
  53. 53.
    Tjellesen L, Hummer L, Christiansen C, et al. Different metabolism on vitamin D2/D3 in epileptic patients treated with phenobarbitone/phenytoin. Bone 1986; 7: 337–42PubMedCrossRefGoogle Scholar
  54. 54.
    Collins N, Maher J, Cole M, et al. A prospective study to evaluate the dose of vitamin D required to correct low 25-hydroxyvitamin D levels, calcium, and alkaline phosphatase in patients at risk of developing antiepileptic drug-induced osteomalacia. Q J Med 1991; 78: 113–22PubMedGoogle Scholar
  55. 55.
    Hartwell D, Tjellesen L, Christiansen C, et al. Metabolism of vitamin D2 and vitamin D3 in patients on anticonvulsant therapy. Acta Neurol Scand 1989; 79: 487–92PubMedCrossRefGoogle Scholar
  56. 56.
    Koch HV, Kratf D, von Herrath D. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972; 13: 829–41PubMedCrossRefGoogle Scholar
  57. 57.
    Hahn TJ, Hendin BA, Scharp CR, et al. Serum 25-hydroxy calciferol levels and bone mass in children on chronic anti-epileptic therapy. N Engl J Med 1975; 292: 550–4CrossRefGoogle Scholar
  58. 58.
    Vernillo AT, Rifkin BR, Hauschka PV. Phenytoin affects osteo-blastic secretion form osteoblastic rat osteosarcoma 17/2.8 cells in culture. Bone 1990; 11: 309–12PubMedCrossRefGoogle Scholar
  59. 59.
    Kruse K, Suss A, Busse M, et al. Monomeric serum calcitonin and bone turnover during anticonvulsant treatment and in congenital hypothyroidism. J Pediatr 1987; 111: 57–63PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Neurological InstituteColumbia UniversityNew YorkUSA

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