Osteoporosis is typically considered to be

THE IMPACT OF LONG-TERM ANTIEPILEPTIC DRUG USE ON BONE HEALTH * Alison M. Pack, MD ABSTRACT A growing amount of scientific literature describing long-term follow-up in patients taking antiepileptic drugs (AEDs) indicates a probable relationship between osteoporosis and the longterm use of these drugs. However, the exact influence on fracture risk is not yet clear. Osteoporosis in patients with epilepsy is a serious problem. Detriments in bone health can be measured as radiographic, pathologic, and biochemical abnormalities. Most of the data showing bone disease and increased fractures with AED use are in patients taking the older drugs. Several new AEDs have become available in the past decade, but the data for them in this regard is limited. Multiple treatments are available for bone disease, including calcium and vitamin D supplementation, bisphosphonates, hormone replacement, calcitonin, and parathyroid hormone. The efficacy and safety of these treatments in the general population are established but there are few studies of these treatments involving patients taking AEDs. Clinicians might consider a monitoring schedule for patients taking phenytoin and phenobarbital, particularly if these patients have other risk factors that contribute to bone disease. Clinicians should discuss a regimen of recommended daily allowances of calcium and vitamin D with all patients taking AEDs, regardless of the patient s age or sex. (Adv Stud Med. 2005;5(6C):S567-S571) *Based on a presentation given by Dr Pack at the 2004 Annual Meeting of the American Epilepsy Society. Assistant Professor of Clinical Neurology, Columbia University, New York, New York. Address correspondence to: Alison M. Pack, MD, Assistant Professor of Clinical Neurology, Columbia University, 710 West 168th Street, New York, NY 10032. E-mail: ap390@columbia.edu. Osteoporosis is typically considered to be a disease of postmenopausal women and is not often considered by neurologists during routine patient management. However, a growing amount of scientific literature describing long-term follow-up in patients taking antiepileptic drugs (AEDs) indicates a probable relationship between osteoporosis and the long-term use of these drugs. Although the exact influence on fracture risk is not yet clear, epilepsy and AEDs have been associated with an increased risk of fractures. 1-5 Osteoporosis in patients with epilepsy is a serious problem: patients with epilepsy already are at an increased risk of fractures because of falls during seizures; epilepsy can be a lifelong disorder requiring lifelong treatment; women constitute a significant portion of patients with epilepsy and are at an increased risk of osteoporosis simply because of their hormonal changes; there is a paucity of studies examining bone health with many of the newer AEDs, thus those patients risks are not yet known; and a recent study indicates that a minority of neurologists (40% of pediatric neurologists and 28% of neurologists treating adult patients) screen for bone disease in their patients taking AEDs. 6 MANIFESTATION OF BONE DISEASE Bone health is a dynamic process, a coupling of bone resorption by osteoclasts and bone formation by osteoblasts. Poor bone health can manifest as osteopenia, osteoporosis, osteomalacia, and fractures. Osteopenia is a precursor to osteoporosis and is marked by decreased calcification, decreased bone density, or reduced bone mass. These conditions result from accelerated bone resorption so that the rate of bone formation lags behind and bone mass overall decreases. The standard for assessing bone density is through dual x-ray absorptiometry. Several studies have S567

documented decreased bone mass in several body sites in patients taking AEDs, in cohorts ranging in age from children to the elderly. 7-13 At Columbia University, we performed a retrospective study to measure bone mineral density in an adult outpatient population (n = 153) who were receiving AEDs (specifically, those drugs that induce hepatic cytochrome P450 enzymes). Study results showed significantly increased osteoporosis and osteopenia in younger men and women (<50 years). In fact, the rate of osteoporosis was 10 times greater in the study group than the expected rate for the general population (Figure). 14 Osteomalacia describes softening of the bone as a result of increased osteoid or unmineralized bone, thus it increases risk of fracture. Osteomalacia was originally described in the 1960s and 70s in institutionalized patients, but it has not been frequently reported since then. The apparent decrease in prevalence is most likely explained by the inadequate diet, poor sunlight exposure, and limited exercise of institutionalized patients versus community-dwelling patients with epilepsy. Fractures are the most important manifestation of bone-mineral density decline. Patients with epilepsy are at an increased risk of injury and fractures as a result of their seizures; however, fractures have been described at multiple sites (ie, hip, radius, ankle, and vertebrae) in patients taking AEDs. 3,15-19 Results in some studies did not suggest a relationship between AED use and increased fracture risk; however, some studies found that the increase in fractures was independent of seizure frequency, suggesting that AED use increases the risk of fracture. 2,3,16,18 Biochemical abnormalities, in addition to radiographic and pathologic abnormalities, have been described in patients taking AEDs. As summarized in Table 1, calcium, phosphate, and vitamin D metabolites are decreased in patients taking AEDs. However, markers of bone formation and resorption, in addition to parathyroid hormone (which is involved in homeostasis of calcium levels), are increased compared to normal levels. 20-23 ANTIEPILEPTIC DRUGS ASSOCIATED WITH BONE DISEASE Most of the data showing bone disease and increased fractures with AED use are in patients taking the older drugs. However, several new AEDs have become available in the past decade, but data in this regard are limited. Phenytoin, phenobarbital, and primidone are the most commonly reported agents associated with adverse effects on bone health. These agents are all potent inducers of the hepatic cytochrome P450 enzyme system. Studies of patients taking these medications reveal decreased bone density; reduced serum calcium, phosphate, and vitamin D levels; and increased bone turnover. 3,13,20 Carbamazepine is also an inducer of the cytochrome P450 enzyme system; however, the data regarding indices of bone and mineral metabolism and bone turnover and bone mineral density are conflicting. Some studies find no changes in measures of bone health, whereas other studies find significant changes in patients taking this drug. 10,20,22-28 One study using Figure. Comparison of Bone Mineral Density Between Antiepileptic Drug Users and the General Population Patients, % 100 80 60 40 20 0 84.1 49.5 Normal density 15.3 40.2 Osteopenia Expected Women and men with epilepsy 0.6 10.3 Osteoporosis Percentages of normal density, osteopenia, and osteoporosis at the femoral neck of the hip in 50-yearold men and women receiving antiepileptic drugs compared to expected percentages from a healthy population of white postmenopausal women. Reprinted with permission from Pack et al. Epilepsy Behav. 2003;4:169-174. 14 S568 Vol. 5 (6C) June 2005

ultrasonography revealed decreased cortical bone mass with carbamazepine use, whereas a recent study showed limited increase in fracture risk. 2,25 Of note, the study showing limited increase in fracture risk is the only study to examine individual AEDs; the other studies tended to analyze AED use as a group. Another study evaluated markers of bone turnover before treatment with carbamazepine in adolescent girls and boys and repeated these measurements after 1 and then 2 years of initiating treatment. The findings were compared to a control population matched by age, sex, and pubertal status. 22,23 The results showed significantly elevated markers of bone turnover in the group treated with carbamazepine compared to the control group. 2 These results are important for their insights into the bone effects of a single AED and a comparison to bone health before treatment initiation and because bone density increases during the first 20 to 30 years of life to obtain peak bone mineral density. The increased turnover during these years suggests that the peak bone mineral density will be affected by treatment with carbamazepine. Adolescents taking AEDs may not be able to build the same bone mineral density as other healthy children and young adults. A leading theory to explain the effects of enzyme-inducing AEDs on bone health is that hepatic induction of the cytochrome P450 enzyme system leads to increased catabolism of vitamin D, secondary hyperparathyroidism, and increased bone turnover. 29 Valproate, by contrast, inhibits the cytochrome P450 enzymes. Interestingly, a study comparing valproate with carbamazepine use in children showed bone loss with valproate only. 8 Another study involving adults also found decreased bone mineral density and elevated markers of bone turnover when compared to a control group without epilepsy who were not taking AEDs. 21 There are few studies assessing bone health with the newer AEDs (eg, lamotrigine, topiramate, and zonisamide). One study of a pediatric population found bone loss with lamotrigine use, but the authors suggest that the short stature, low bone mineral density, and reduced bone formation may have been caused by limited activity rather than the AEDs because the measures of bone density correlated with activity level. 9 At Columbia University, we studied bone mineral density and indices of bone and mineral metabolism, including markers of bone turnover, in normally cycling premenopausal women taking phenytoin, carbamazepine, valproate, and lamotrigine. Those women taking lamotrigine had significantly higher calcium levels when compared to the other women. Bone-specific alkaline phosphatase (a marker of bone resorption) was significantly elevated in women taking phenytoin compared to lamotrigine, suggesting that lamotrigine has less effect on bone than phenytoin. 30 To date, there are no published data regarding the effects of carbonic anhydrase inhibitors (topiramate and zonisamide) on bone health. One study showed a bone-sparing effect of acetazolamide in patients with glaucoma. 31 RISK FACTORS Several other risk factors for osteoporosis are well defined: age, small body frame, white or Asian ethnicity, family history of osteoporosis, alcohol use, and smoking history. Therefore, patients who are taking AEDs even the newer agents who also have these risk factors should be considered for prophylactic treatment for osteoporosis and monitoring of bone mineral density. TREATMENT As described earlier in this article, results from a survey of neurologists practice patterns regarding bone and mineral effects of AEDs indicated that most neurologists do not screen for bone disease. Of those neurologists who screen and find evidence, approximately 40% administer calcium and vitamin D as treatment and approximately 55% refer these patients to a specialist (Table 2). Although only approximately Table 1. Biochemical Abnormalities of Bone Metabolism Associated with Antiepileptic Drug Use Calcium Phosphate Parathyroid hormone Vitamin D metabolite levels Markers of bone formation Markers of bone resporption Data from Valimaki et al 20 ; Sato et al 21 ; Verrotti et al. 22,23 Serum Serum Serum/urine S569

5% of the neurologists neither treat nor refer, fewer than 10% of neurologists talk to their patients about prophylactic calcium and vitamin D during AED use. These results suggest that most neurologists are not aware of the effects of AEDs on bone health, and the appropriate treatment options are not routinely used when there is evidence of bone disease. 6 Multiple treatments are available for bone disease, including calcium and vitamin D supplementation, bisphosphonates, hormone replacement, calcitonin, and parathyroid hormone. The efficacy and safety of these treatments in the general population are established, but there are few studies of these treatments in patients taking AEDs. For example, the only studies of vitamin D use in patients taking AEDs used broad ranges of high doses. Bone mineral density increased with vitamin D supplementation, but a safe recommended dose based on this study is unclear. 25 Clinicians should counsel all patients taking AEDs about taking the recommended daily allowance of calcium and vitamin D. The recommended daily allowance of calcium ranges between 1000 to 1500 mg/day, depending on age, sex, and reproductive status (Table 3). 32,33 Daily vitamin D intake for prophylaxis of bone mineral depletion is 400 to 2000 IU/day, and the endocrinology community recommends higher doses for the treatment of osteopenia and osteoporosis (2000 4000 IU/day), and even higher doses for the treatment of osteomalacia (5000 15000 IU/day). 34 Table 2. Practice Patterns of Neurologists Regarding Detection,Treatment, and Prevention of Bone Disease in Patients Taking Antiepileptic Drugs Table 3. Optimal Calcium Requirements Neurologists, n (%) Pediatric Adult (n = 404) (n = 624) Screen for bone disease 160 (41) 174 (28) Of neurologists who screen and find evidence of bone disease Treat with calcium or vitamin D 62 (40) 61 (37) Refer to a specialist 83 (54) 94 (57) Neither treat nor refer 8 (5) 11 (7) Prescribe prophylactic calcium or vitamin D 35 (9) 46 (7) Reprinted with permission from Valmadrid et al. Arch Neurol. 2001;58:1369-1374. 6 CONCLUSIONS Antiepileptic drugs appear to negatively influence bone health, especially in patients with risk factors that also may contribute to the disease. The exact relationship between AED use and bone mineral density is not yet described completely. The most compelling evidence of a deleterious effect on bone health is with the use of phenytoin and phenobarbital. Patients taking those 2 drugs should have their bone mineral density monitored regularly. For patients taking carbamazepine and valproate, in addition to the newer medications, the recommendations are less clear. Clinicians should also consider a monitoring schedule for patients taking these drugs, particularly if they have other risk factors that contribute to bone disease. Physicians should discuss the recommended daily allowances of calcium and vitamin D with all patients taking AEDs, regardless of their age or sex. This conversation is a simple initiative that can create a long-term beneficial health outcome for patients. Group Optimal Daily Intake, mg Infants Birth to 6 months 400 6 months to 1 year 600 Children 1 5 years 800 6 10 years 800 1200 Adolescents/young adults 11 24 years 1200 1500 Men 25 65 yrs 1000 Older than 65 years 1500 Women 25 50 years 1000 Older than 50 years (postmenopausal) 1000 Taking estrogens 1500 Not taking estrogens 1500 Older than 65 years 1200 1500 Pregnant and nursing Reprinted with permission from Pack and Morrell. Epilepsy Behav. 2004;5:S24-29. 33 S570 Vol. 5 (6C) June 2005

REFERENCES 1. Lidgren L, Walloe A. Incidence of fracture in epileptics. Acta Orthop Scand. 1977;48:356-361. 2. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of antiepileptic drugs. Epilepsia. 2004; 45:1330-1337. 3. Vestergaard P, Tigaran S, Rejnmark L, et al. Fracture risk is increased in epilepsy. Acta Neurol Scand. 1999;99:269-275. 4. Cummings LN, Giudice L, Morrell MJ. Ovulatory function in epilepsy. Epilepsia. 1995;36:355-359. 5. 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;12:811-822. 6. Valmadrid C, Voorhees C, Litt B, Schneyer CR. Practice patterns of neurologists regarding bone and mineral effects of antiepileptic drug therapy. Arch Neurol. 2001;58:1369-1374. 7. Chung S, Ahn C. Effects of anti-epileptic drug therapy on bone mineral density in ambulatory epileptic children. Brain Dev. 1994;16:382-385. 8. Sheth RD, Wesolowski CA, Jacob JC, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr. 1995;127:256-262. 9. 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;42:1141-1147. 10. Farhat G, Yamout B, Mikati MA, et al. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology. 2002;58:1348-1353. 11. Andress DL, Ozuna J, Tirschwell D, et al. Antiepileptic druginduced bone loss in young male patients who have seizures. Arch Neurol. 2002;59:781-786. 12. 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;44:247-253. 13. Ensrud KE, Walczak TS, Blackwell T, et al. Antiepileptic drug use increases rates of bone loss in older women: a prospective study. Neurology. 2004;62:2051-2057. 14. Pack AM, Olarte LS, Morrell MJ, et al. Bone mineral density in an outpatient population receiving enzyme-inducing antiepileptic drugs. Epilepsy Behav. 2003;4:169-174. 15. Nilsson OS, Lindholm TS, Elmstedt E, et al. Fracture incidence and bone disease in epileptics receiving long-term anticonvulsant drug treatment. Arch Orthop Trauma Surg. 1986;105:146-149. 16. Annegers JF, Melton LJ 3rd, Sun CA, Hauser WA. Risk of age-related fractures in patients with unprovoked seizures. Epilepsia. 1989;30:348-355. 17. 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;332:767-773. 18. Desai KB, Ribbans WJ, Taylor GJ. Incidence of five common fracture types in an institutional epileptic population. Injury. 1996;27:97-100. 19. Persson HB, Alberts KA, Farahmand BY, Tomson T. Risk of extremity fractures in adult outpatients with epilepsy. Epilepsia. 2002;43:768-772. 20. 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;9:631-637. 21. Sato Y, Kondo I, Ishida S, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology. 2001;57:445-449. 22. Verrotti A, Greco R, Morgese G, Chiarelli F. Increased bone turnover in epileptic patients treated with carbamazepine. Ann Neurol. 2000;47:385-388. 23. Verrotti A, Greco R, Latini G, et al. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia. 2002;43:1488-1492. 24. Hoikka V, Alhava EM, Karjalainen P, et al. Carbamazepine and bone mineral metabolism. Acta Neurol Scand. 1984;70:77-80. 25. Pedrera JD, Canal ML, Carvajal J, et al. Influence of vitamin D administration on bone ultrasound measurements in patients on anticonvulsant therapy. Eur J Clin Invest. 2000;30:895-899. 26. Tjellesen L, Christiansen C. Serum vitamin D metabolites in epileptic patients treated with 2 different anti-convulsants. Acta Neurol Scand. 1982;66:335-341. 27. Tjellesen L, Nilas L, Christiansen C. Does carbamazepine cause disturbances in calcium metabolism in epileptic patients? Acta Neurol Scand. 1983;68:13-19. 28. Tjellesen L, Gotfredsen A, Christiansen C. Effect of vitamin D2 and D3 on bone-mineral content in carbamazepinetreated epileptic patients. Acta Neurol Scand. 1983;68:424-428. 29. Pack AM. Antiepileptic drugs and bone disease. Clin Rev Bone Miner Metab. 2004;2:159-166. 30. Pack AM, Morrell MJ, Marcus R, et al. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann Neurol. 2005;57:252-257. 31. 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;6:347-354. 32. Optimal calcium intake. NIH Consensus Development Conference Statement. June 6-8, 1994. National Institutes of Health Web site. Available at: http://consensus.nih. gov/cons/097/097_statement.htm#cdc97t1. Accessed April 11, 2005. 33. Pack AM, Morrell MJ. Epilepsy and bone health in adults. Epilepsy Behav. 2004;5(suppl 2):S24-S29. 34. Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav. 2004;5(suppl 2):S41-S47. S571