Antiepileptic drugs and bone disease
- Alison M Pack, MD
Alison M Pack, MD
- Associate Professor of Clinical Neurology
- Columbia University College of Physicians and Surgeons
- Elizabeth Shane, MD
Elizabeth Shane, MD
- Professor of Medicine
- Columbia University College of Physicians and Surgeons
- Section Editors
- Timothy A Pedley, MD
Timothy A Pedley, MD
- Editor-in-Chief — Neurology
- Section Editor — Epilepsy
- Henry and Lucy Moses Professor of Neurology
- Columbia University College of Physicians and Surgeons
- Marc K Drezner, MD
Marc K Drezner, MD
- Section Editor — Bone Disease
- Professor of Medicine
- University of Wisconsin Medical School
Epilepsy is a chronic condition that affects over two million people in the United States, approximately 1 percent of the population . Antiepileptic drugs (AEDs) remain the mainstay of treatment for epilepsy. In addition, these agents now have numerous other indications, including the treatment of migraine headaches, bipolar disorder, and chronic pain.
Both epilepsy and AEDs are associated with adverse effects on bone health. Persons with epilepsy treated with AEDs have increased rates of bone loss and abnormalities in bone and mineral metabolism [2,3]. These adverse effects may contribute to an increased risk of fracture [4-7].
This topic will review the association between AEDs and disorders of bone and mineral metabolism, including osteomalacia/rickets and osteoporosis or low bone mass. In addition, the screening, treatment, and prevention of AED-related bone disease will be discussed.
The management of epilepsy and the pharmacology of AEDs are discussed elsewhere. (See "Overview of the management of epilepsy in adults" and "Initial treatment of epilepsy in adults" and "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects".)
METABOLIC BONE DISEASE
The first reports linking antiepileptic drug (AED) therapy to skeletal disease were published in the late 1960s . Affected patients had florid bone disease with clinical, biochemical, and histological abnormalities consistent with rickets and osteomalacia. However, these early reports included mostly institutionalized patients.
- Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia 1993; 34:453.
- Pack AM. Bone disease in epilepsy. Curr Neurol Neurosci Rep 2004; 4:329.
- Pack AM, Morrell MJ. Epilepsy and bone health in adults. Epilepsy Behav 2004; 5 Suppl 2:S24.
- Vestergaard P, Tigaran S, Rejnmark L, et al. Fracture risk is increased in epilepsy. Acta Neurol Scand 1999; 99:269.
- Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia 2004; 45:1330.
- 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; 332:767.
- Desai KB, Ribbans WJ, Taylor GJ. Incidence of five common fracture types in an institutional epileptic population. Injury 1996; 27:97.
- Kruse R. [Osteopathies in antiepileptic long-term therapy (preliminary report)]. Monatsschr Kinderheilkd 1968; 116:378.
- 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; 71:723.
- Vestergaard P. Epilepsy, osteoporosis and fracture risk - a meta-analysis. Acta Neurol Scand 2005; 112:277.
- 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.
- NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285:785.
- Painter SE, Kleerekoper M, Camacho PM. Secondary osteoporosis: a review of the recent evidence. Endocr Pract 2006; 12:436.
- Jaglal SB, Kreiger N, Darlington GA. Lifetime occupational physical activity and risk of hip fracture in women. Ann Epidemiol 1995; 5:321.
- Espallargues M, Sampietro-Colom L, Estrada MD, et al. Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements: a systematic review of the literature. Osteoporos Int 2001; 12:811.
- 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; 46:304.
- Tsiropoulos I, Andersen M, Nymark T, et al. Exposure to antiepileptic drugs and the risk of hip fracture: a case-control study. Epilepsia 2008; 49:2092.
- Jetté N, Lix LM, Metge CJ, et al. Association of antiepileptic drugs with nontraumatic fractures: a population-based analysis. Arch Neurol 2011; 68:107.
- Carbone LD, Johnson KC, Robbins J, et al. Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: findings from the women's health initiative (WHI). J Bone Miner Res 2010; 25:873.
- 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.
- Koppel BS, Harden CL, Nikolov BG, Labar DR. An analysis of lifetime fractures in women with epilepsy. Acta Neurol Scand 2005; 111:225.
- Persson HB, Alberts KA, Farahmand BY, Tomson T. Risk of extremity fractures in adult outpatients with epilepsy. Epilepsia 2002; 43:768.
- Sheth RD. Bone health in pediatric epilepsy. Epilepsy Behav 2004; 5 Suppl 2:S30.
- Annegers JF, Melton LJ 3rd, Sun CA, Hauser WA. Risk of age-related fractures in patients with unprovoked seizures. Epilepsia 1989; 30:348.
- Stephen LJ, McLellan AR, Harrison JH, et al. Bone density and antiepileptic drugs: a case-controlled study. Seizure 1999; 8:339.
- 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.
- Farhat G, Yamout B, Mikati MA, et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002; 58:1348.
- Andress DL, Ozuna J, Tirschwell D, et al. Antiepileptic drug-induced bone loss in young male patients who have seizures. Arch Neurol 2002; 59:781.
- Pack AM, Olarte LS, Morrell MJ, et al. Bone mineral density in an outpatient population receiving enzyme-inducing antiepileptic drugs. Epilepsy Behav 2003; 4:169.
- 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.
- Sheth RD, Wesolowski CA, Jacob JC, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995; 127:256.
- Chung S, Ahn C. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Dev 1994; 16:382.
- 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.
- Guo 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; 42:1141.
- Oner N, Kaya M, Karasalihoğlu S, et al. Bone mineral metabolism changes in epileptic children receiving valproic acid. J Paediatr Child Health 2004; 40:470.
- Akin R, Okutan V, Sarici U, et al. Evaluation of bone mineral density in children receiving antiepileptic drugs. Pediatr Neurol 1998; 19:129.
- Erbayat Altay E, Serdaroğlu A, Tümer L, et al. Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid. J Pediatr Endocrinol Metab 2000; 13:933.
- Babayigit A, Dirik E, Bober E, Cakmakci H. Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol 2006; 35:177.
- Sheth RD, Binkley N, Hermann BP. Progressive bone deficit in epilepsy. Neurology 2008; 70:170.
- Coppola G, Fortunato D, Auricchio G, et al. Bone mineral density in children, adolescents, and young adults with epilepsy. Epilepsia 2009; 50:2140.
- Heller HJ, Sakhaee K. Anticonvulsant-induced bone disease: a plea for monitoring and treatment. Arch Neurol 2001; 58:1352.
- 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.
- 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.
- Välimäki 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.
- Verrotti A, Greco R, Morgese G, Chiarelli F. Increased bone turnover in epileptic patients treated with carbamazepine. Ann Neurol 2000; 47:385.
- Verrotti A, Greco R, Latini G, et al. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia 2002; 43:1488.
- 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 out-patients with epilepsy. Q J Med 1986; 59:569.
- O'Hare JA, Duggan B, O'Driscoll D, Callaghan N. Biochemical evidence for osteomalacia with carbamazepine therapy. Acta Neurol Scand 1980; 62:282.
- Bogliun G, Beghi E, Crespi V, et al. Anticonvulsant drugs and bone metabolism. Acta Neurol Scand 1986; 74:284.
- Skillen AW, Pierides AM. Serum gamma glutamyl transferase and alkaline phosphatase activities in epileptics receiving anticonvulsant therapy. Clin Chim Acta 1976; 72:245.
- Okesina AB, Donaldson D, Lascelles PT. Isoenzymes of alkaline phosphatase in epileptic patients receiving carbamazepine monotherapy. J Clin Pathol 1991; 44:480.
- Pettifor JM. Nutritional and drug-induced rickets and osteomalacia. In: Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th, ASBMR, Favus MJ (Eds), Lippincott, Williams and Wilkins, Washington, DC 2006. p.330.
- Dent CE, Richens A, Rowe DJ, Stamp TC. Osteomalacia with long-term anticonvulsant therapy in epilepsy. Br Med J 1970; 4:69.
- Richens A, Rowe DJ. Disturbance of calcium metabolism by anticonvulsant drugs. Br Med J 1970; 4:73.
- Mosekilde L, Melsen F. Dynamic differences in trabecular bone remodeling between patients after jejunoileal bypass for obesity and epileptic patients receiving anticonvulsant therapy. Metab Bone Dis Relat Res 1980; 2:77.
- 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.
- Borgstedt AD, Bryson MF, Young LW, Forbes GB. Long-term administration of antiepileptic drugs and the development of rickets. J Pediatr 1972; 81:9.
- Perucca E. Clinical implications of hepatic microsomal enzyme induction by antiepileptic drugs. Pharmacol Ther 1987; 33:139.
- Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms and therapeutic implications. CNS Drugs 2001; 15:633.
- Fitzpatrick LA. Pathophysiology of bone loss in patients receiving anticonvulsant therapy. Epilepsy Behav 2004; 5 Suppl 2:S3.
- Pack AM, Morrell MJ, McMahon DJ, Shane E. Normal vitamin D and low free estradiol levels in women on enzyme-inducing antiepileptic drugs. Epilepsy Behav 2011; 21:453.
- 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.
- 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.
- 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.
- 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; 70:1533.
- Vernillo AT, Rifkin BR, Hauschka PV. Phenytoin affects osteocalcin secretion from osteoblastic rat osteosarcoma 17/2.8 cells in culture. Bone 1990; 11:309.
- Elliott JO, Jacobson MP, Haneef Z. Homocysteine and bone loss in epilepsy. Seizure 2007; 16:22.
- Wu S, Legido A, De Luca F. Effects of valproic acid on longitudinal bone growth. J Child Neurol 2004; 19:26.
- Davie MW, Emberson CE, Lawson DE, et al. Low plasma 25-hydroxyvitamin D and serum calcium levels in institutionalized epileptic subjects: associated risk factors, consequences and response to treatment with vitamin D. Q J Med 1983; 52:79.
- Hoikka V, Savolainen K, Alhava EM, et al. Osteomalacia in institutionalized epileptic patients on long-term anticonvulsant therapy. Acta Neurol Scand 1981; 64:122.
- Bouillon R, Reynaert J, Claes JH, et al. The effect of anticonvulsant therapy on serum levels of 25-hydroxy-vitamin D, calcium, and parathyroid hormone. J Clin Endocrinol Metab 1975; 41:1130.
- Hahn TJ, Hendin BA, Scharp CR, Haddad JG Jr. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med 1972; 287:900.
- 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: Antiepileptic therapy: Chronic toxicity of antiepileptic drugs, Oxley J, Janz D, Meinardi H (Eds), Raven Press, New York 1983. p.185.
- 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; 116:1703.
- Pascussi JM, Robert A, Nguyen M, et al. Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest 2005; 115:177.
- Pack AM, Morrell MJ, Randall A, et al. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology 2008; 70:1586.
- Brämswig S, Zittermann A, Berthold HK. Carbamazepine does not alter biochemical parameters of bone turnover in healthy male adults. Calcif Tissue Int 2003; 73:356.
- Tjellesen L, Nilas L, Christiansen C. Does carbamazepine cause disturbances in calcium metabolism in epileptic patients? Acta Neurol Scand 1983; 68:13.
- 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.
- Koo DL, Joo EY, Kim D, Hong SB. 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.
- Phabphal K, Geater A, Limapichat K, et al. Effect of switching hepatic enzyme-inducer antiepileptic drug to levetiracetam on bone mineral density, 25 hydroxyvitamin D, and parathyroid hormone in young adult patients with epilepsy. Epilepsia 2013; 54:e94.
- Hall TJ, Higgins W, Tardif C, Chambers TJ. A comparison of the effects of inhibitors of carbonic anhydrase on osteoclastic bone resorption and purified carbonic anhydrase isozyme II. Calcif Tissue Int 1991; 49:328.
- Yildizdas D, Topaloglu AK, Mungan NO, et al. Bone mineral changes in acute metabolic acidosis due to acute gastroenteritis. Calcif Tissue Int 2004; 75:380.
- Pierce WM Jr, Nardin GF, Fuqua MF, et al. Effect of chronic carbonic anhydrase inhibitor therapy on bone mineral density in white women. J Bone Miner Res 1991; 6:347.
- Harden CL. Menopause and bone density issues for women with epilepsy. Neurology 2003; 61:S16.
- Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav 2004; 5 Suppl 2:S41.
- Valmadrid C, Voorhees C, Litt B, Schneyer CR. Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy. Arch Neurol 2001; 58:1369.
- 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.
- 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.
- Sherk HH, Cruz M, Stambaugh J. Vitamin D prophylaxis and the lowered incidence of fractures in anticonvulsant rickets and osteomalacia. Clin Orthop Relat Res 1977; :251.
- Heaney RP. The case for improving vitamin D status. J Steroid Biochem Mol Biol 2007; 103:635.
- METABOLIC BONE DISEASE
- - Fracture
- - Bone mineral density
- - Markers of bone turnover
- Osteomalacia and rickets
- EFFECT OF AED TYPE
- - Valproate
- - Other AEDs
- Clinical risk factor assessment
- Bone mineral density
- Laboratory evaluation
- TREATMENT AND PREVENTION
- Lifestyle measures
- Calcium and vitamin D
- Pharmacologic therapy
- SUMMARY AND RECOMMENDATIONS