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Epilepsy and bone health in adults
Epilepsy & Behavior Epilepsy & Behavior 5 (2004) S24–S29 www.elsevier.com/locate/yebeh
Epilepsy and bone health in adults Alison M. Pack* and Martha J. Morrell Epilepsy Division, Department of Neurology, Columbia University, 710 West 168th Street, New York, NY 10032, USA Received 21 November 2003; accepted 21 November 2003
Abstract Adults taking antiepileptic drugs (AEDs) have an augmented risk for osteopenia and osteoporosis because of abnormalities of bone metabolism associated with AEDs. The increased fracture rates that have been described among patients with epilepsy may be related both to seizures and to AEDs. The hepatic enzyme–inducing AEDs phenytoin, phenobarbital, and primidone have the clearest association with decreased bone mineral density (BMD). Carbamazepine, also an enzyme-inducing drug, and valproate, an enzyme inhibitor, may also adversely affect bone, but further study is needed. Little information is available about specific effects of newer AEDs on bone. Physicians are insufficiently aware of the association between AEDs and bone disease; a survey found that fewer than one-third of neurologists routinely evaluated AED-treated patients for bone disease, and fewer than 10% prescribed prophylactic calcium and vitamin D. Physicians should counsel patients taking AEDs about good bone health practices, and evaluation of bone health by measuring BMD is warranted after 5 years of AED treatment or before treatment in postmenopausal women. Ó 2003 Elsevier Inc. All rights reserved. Keywords: Antiepileptic drugs; Bone; Bone mineral density; Phenytoin; Phenobarbital; Primidone; Carbamazepine; Valproate
1. Introduction Persons with epilepsy taking some antiepileptic drugs (AEDs) are at risk for bone disease. In adults, peak bone mineral density (BMD) is attained between the ages of 20 and 30 years. After age 30, there is a gradual decline in BMD. In women this is most pronounced in the years following the onset of menopause. AEDs may superimpose an additional effect on bone health; therefore, adults taking AEDs are at even greater risk for bone diseases such as osteopenia/osteoporosis, and for fracture. Identifying those AEDs that are more likely to adversely affect bone is important when choosing an AED for an adult, especially for adults with other risk factors for bone disease including Caucasian or Asian race, small frame, family history of osteoporosis and fracture, smoking history, and alcohol history. Identifying AED-treated persons with bone disease is also important, as other AEDs may have a more beneficial effect on bone, and numerous treatment options for * Corresponding author. Fax: 1-212-305-1450. E-mail address: [email protected] (A.M. Pack).
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bone disease exist. This review discusses the effects of AEDs on bone in adults, the specific AEDs associated with bone disease, treatment options, and recommendations for good bone health practices and screening for bone disease in AED-treated persons. 2. Biochemical abnormalities Bone loss and consequent fracture appear to be a manifestation of biochemical abnormalities of bone metabolism associated with specific AEDs. These abnormalities include hypocalcemia, hypophosphatemia, reduced serum levels of biologically active vitamin D metabolites, and hyperparathyroidism. In addition, bone turnover is accelerated, as measured by markers of bone formation and bone resorption. Calcium homeostasis and an appropriate concentration of phosphate are essential to maintain normal bone metabolism. Calcium and phosphate levels are affected by some AEDs. Hypocalcemia affects between 3 and 30% of persons with epilepsy receiving AEDs [1–5]. Reduced serum phosphate has also been described in patients prescribed AEDs [6–8].
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Vitamin D is necessary for gastrointestinal absorption of calcium and for the proper development and maintenance of bone. Sources of vitamin D include diet (vitamin D2 ) and sunlight (vitamin D3 ). Vitamin D is metabolized initially to active metabolites and then to an inactive, inert metabolite, calcitroic acid. Its metabolism occurs in the liver and kidney. Vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D (25[OH]D), and then further hydroxylation occurs in the kidney to 1,25-dihydroxyvitamin D (1,25[OH]2 D). The level of 25(OH)D is the commonly used index of vitamin D status, and 1,25(OH)2 D is the most active metabolite of vitamin D. Some studies report reductions in 25(OH)D and 1,25(OH)2 D with some AEDs [2,5,6,9–13], whereas others find that vitamin D levels are normal [14–16]. Parathyroid hormone (PTH) is secreted by the parathyroid gland and regulates serum calcium. When the serum calcium level is decreased, PTH increases bone breakdown or resorption to increase calcium. Women and men taking some AEDs, when compared with controls, have been reported to have higher PTH levels [3,17], but other studies find no differences in PTH levels [18,19]. Markers of bone resorption and bone formation as measured in serum and urine are elevated in persons receiving AEDs [14,18–20]. Markers of bone resorption reflect bone degradation and measure activity of osteoclasts, the cells responsible for bone breakdown, whereas markers of bone formation reflect activity of osteoblasts. In certain bone diseases, such as osteoporosis, bone resorption exceeds formation. Markers of bone formation include procollagen markers, bone-specific alkaline phosphatase, and osteocalcin. Alkaline phosphatase is the most commonly used marker of bone formation. Increases are seen in adults receiving some AEDs [5,7,8,14]. Serum total alkaline phosphatase is derived from bone, liver, and other sources. However, studies that measure alkaline phosphatase isoenzymes find that the increase in total alkaline phosphatase is due mainly to increases in the bone fraction [9,10]. Osteocalcin (also known as bone gla protein) is a small noncollagenous protein, specific for bone tissue and dentin, that is predominantly synthesized by osteoblasts. High serum levels of osteocalcin are described in persons receiving some AEDs [14,18,20]. Procollagen type I molecules are secreted by osteoblastic cells. Subsequent cleavage of the aminoterminal and carboxy-terminal domains creates extension peptides. The C-terminal extension peptide of type I procollagen (PICP) is a putative serum marker of bone formation, and significant elevations are described in persons taking some AEDs [14,18,19]. Specific markers of bone resorption can be measured in the urine and serum. Crosslinked carboxy-terminal telopeptide of human type I collagen is a serum marker of bone degradation, and hydroxyproline is a marker in
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the urine. These markers are elevated in patients with epilepsy receiving long-term AED therapy [14,19,20] and after recent initiation of therapy [18].
3. Bone density abnormalities Osteomalacia literally means softening of bone and results from reduction in bone matrix mineralization [21]. Bone biopsies of patients with AED-induced osteomalacia are histologically characterized by an increase in osteoid or unmineralized bone and reveal a mineralization defect that causes prolonged mineralization. Serum calcium, phosphate, and active vitamin D levels are abnormally low. Early reports described osteomalacia in patients treated with AEDs [1,22]. However, these reports concerned primarily institutionalized patients, in whom lack of nutrition and sunlight exposure probably influenced the outcome. In ambulatory persons, evidence of osteomalacia is seldom found [17,23]. Bone mass is inversely correlated with fracture risk, as decreased BMD increases the risk of fracture. Multiple factors may contribute to decreased BMD, and AEDs are a recognized secondary cause. Adults receiving AEDs have been reported to have decreased BMD at multiple sites including the ribs, femoral neck, and spine [14,15,20,24,25]. Some studies find that duration of treatment is correlated with low BMD [15,24], but this is not a consistent finding [25,26]. The present ‘‘gold standard’’ for BMD measurement is dual-energy X-ray absorptiometry (DXA). DXA measures bone mineral content at multiple sites and can detect a 5% decrement in BMD [27]. Higher rates of osteopenia and osteoporosis are found in adults receiving AEDs [14,15,20,24,25].
4. Fracture The most important clinical sequelae of bone disease are fractures. Fractures are associated with multiple morbidities, including hospitalization and loss of independence, and death. The most common fractures involve the spine and hip. Identifying patients with epilepsy who are at risk for fracture is important; particularly vulnerable are those patients who have inadequate seizure control and may sustain a fracture during a seizure. Increased fracture rates have been described in patients with epilepsy [28–32]. Although some studies have found this increased risk to be related to seizures, AED use may be independently associated with fracture risk. One study in postmenopausal women found that women treated with AEDs had twice the rate of hip fracture when compared with controls [29]. A recent meta-analysis identified AED use as a high risk factor for fracture [32].
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The majority of published reports describing an effect of AEDs on bone include patients receiving phenytoin, phenobarbital, or both drugs. Fewer studies have evaluated the effect of other AEDs including carbamazepine, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, valproate, and zonisamide. In addition, in many studies subjects are treated with polytherapy, which has been shown to be associated with a higher risk of bone metabolism abnormalities compared with monotherapy [3,5]; therefore, it is difficult to determine the effect of individual AEDs in these studies.
sorptive response to PTH could lead to hypocalcemia. Fetal rats treated with phenytoin or phenobarbital demonstrated an impaired response to PTH [39]. Accumulating evidence suggests that poor vitamin K status may be an independent risk factor for postmenopausal bone loss [40]. Vitamin K is a cofactor in the posttranslational carboxylation of several bone proteins, especially osteocalcin, a marker of bone formation. Rats treated with phenytoin had more bone loss over a 5week period than rats treated with phenytoin and vitamin K2 (menatetrenone) [41]. These findings suggest that insufficient vitamin K may contribute to bone loss secondary to phenytoin exposure.
5.1. Phenytoin, phenobarbital, primidone
5.2. Carbamazepine
The AEDs most commonly associated with altered bone metabolism and decreased bone density are inducers of the cytochrome P450 enzyme system, including phenytoin, primidone, and phenobarbital [5,7,14]. The earliest reports of bone disease in patients taking AEDs in the late 1960s and the 1970s involved patients receiving these medications [1,22,33,34]. Biochemical findings include reduced calcium, phosphate, and 25(OH)D levels and elevated markers of bone formation and resorption. Induction of the cytochrome P450 system may cause increased conversion of vitamin D to polar inactive metabolites in the liver microsomes, reducing bioavailable vitamin D [5,35]. Decreased biologically active vitamin D leads to decreased absorption of calcium in the gut, resulting in hypocalcemia and an increase in circulating PTH. PTH then increases the mobilization of bone calcium stores and subsequent bone turnover. Decreased levels of active vitamin D and calcium as well as elevated PTH have been described in adults taking enzyme-inducing AEDs including phenobarbital, phenytoin, and primidone [1–6,9–13,17]. Phenytoin treatment is associated with increased bone turnover as demonstrated by elevated markers of bone resorption and bone formation in adults receiving AEDs [14]. Studies in mice and in vitro provide further evidence of increased bone turnover. Neonatal mouse calvaria treated with phenytoin and a metabolite of phenytoin (5[4-hydroxyphenyl]-5-phenylhydantoin) had increased bone resorption as demonstrated by significantly increased calcium in the medium when compared with controls [36]. In vitro proliferation of human osteoblastlike cells was inhibited by treatment with phenytoin and carbamazepine at concentrations equivalent to therapeutic doses for the treatment of epilepsy [37]. Decreased calcium levels in phenytoin-treated adults may also be explained by impaired calcium absorption. Markedly decreased calcium absorption was found in rats treated with phenytoin but not in those given phenobarbital [38]. In addition, inhibition of the bone re-
Like phenytoin and phenobarbital, carbamazepine is an inducer of the cytochrome P450 enzyme system; however, studies find conflicting results when evaluating its effect on bone and mineral metabolism and BMD. Some studies report disturbances in bone and mineral metabolism and bone turnover, while others find no abnormalities. Tjellesen et al. [13,42,43] studied 30 outpatients receiving carbamazepine monotherapy and found normal concentrations of 25(OH)D, decreased serum calcium concentrations, and elevated total alkaline phosphatase concentrations. In a study of 21 outpatients treated with carbamazepine, hypocalcemia was found in 3, hypophosphatemia in 1, and elevated total alkaline phosphatase in 4 of the cases [44]. In contrast to the studies of Tjellesen et al., serum 25(OH)D levels were significantly lower than in controls. Two recent studies in adolescents found biochemical evidence of increased bone turnover, with elevated markers of bone formation and resorption after 1 year [18] and 2 years [19] of treatment. However, 25(OH)D levels were not reduced. In contrast, a study of 21 healthy male adults without epilepsy treated with carbamazepine for 10 weeks did not find significant elevations of markers of bone formation and resorption [45]. Studies of bone mass also reveal conflicting results. In one study using single-photon absorptiometry, normal bone mass was reported [43]. In adults treated with carbamazepine monotherapy, BMD as determined by DXA was also not significantly decreased [14]. Although the difference was not significant, BMD in a recent study was decreased in men and women treated with enzyme-inducing AEDs compared with those receiving noninducing AEDs. The effect in those receiving carbamazepine monotherapy was not reported [15]. Decreased cortical bone mass as measured by quantitative ultrasonography of the phalanges has been described in patients treated with carbamazepine monotherapy [46,47]. The differing results suggest that the effects of carbamazepine monotherapy on bone and mineral metabolism and BMD have not been adequately determined.
5. AEDs associated with bone disease
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5.3. Valproate Valproate is an inhibitor of the cytochrome P450 enzyme system, and emerging data suggest that it may also adversely affect bone. Early reports evaluating indexes of bone metabolism in patients taking valproate found no significant abnormalities [5,11]. Twenty-two men and women treated with valproate monotherapy had no significant reductions in calcium or 25(OH)D levels [5]. Similarly, alkaline phosphatase was not increased in those subjects receiving valproate monotherapy. Davie et al. [11] found similar results in an institutionalized population treated with valproate. However, recent studies find different results. A study of 40 adults receiving long-term valproate monotherapy found increased serum concentrations of calcium, low levels of vitamin D metabolites, increased markers of bone resorption and formation, and decreased BMD [20]. The increased calcium was postulated to reflect increased bone resorption. Similar findings have been reported in children [48,49]. As with carbamazepine, future studies will elucidate these recent findings.
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the effects of bone health therapies on bone disease associated with AEDs.
7. Physician awareness of AED-associated bone disease Although the association between AEDs and bone disease was first described in the late 1960s, few physicians are aware of this long-term side effect of AEDs. A study by Valmadrid et al. [50] highlights this lack of awareness. U.S. board-certified or board-eligible pediatric and adult neurologists were surveyed about their practice patterns regarding methods of screening for bone disorders and recommendations for treatment and prophylaxis. One-third of the neurologists surveyed routinely evaluated AED-treated patients for bone disease, and of those who did evaluate patients and found evidence of bone disease, fewer than 50% prescribed calcium and vitamin D supplementation, and approximately 50% referred patients with disease to a specialist. Fewer than 10% of the neurologists prescribed prophylactic calcium and vitamin D supplementation to patients treated with AEDs.
5.4. Newer AEDs A number of new AEDs have been approved in the past 10 years. Few studies have evaluated the effect of these medications on bone mineral metabolism and BMD. One study in adults looked at the effect of lamotrigine, topiramate, vigabatrin, and gabapentin on bone mineral metabolism and BMD and found no significant abnormalities [26]. However, as most of the subjects were taking the new AEDs in combination with other AEDs, and the number of individuals receiving a new AED in monotherapy was small ( 6 2), the effect of the individual new AEDs cannot be ascertained from the results of this study. A recent report found no significant reductions in calcium or markers of bone resorption and bone formation in young women treated with lamotrigine monotherapy [16]. More studies are needed to determine whether any of the newer AEDs cause abnormalities in bone.
6. Treatment Although multiple therapies for bone disease are available, few studies have evaluated the effectiveness of various treatments in bone disease associated with AEDs. Calcium and vitamin D supplementation, bisphosphonates, hormone replacement therapy, selective estrogen modulators, and calcitonin are all approved treatments for bone loss. Although not approved by the U.S. Food and Drug Administration, vitamin K supplementation is being studied as a potential therapy for bone loss. Future studies are necessary to clearly define
8. Recommendations Physicians treating adults with AEDs should discuss good bone health practices. Good bone health practices include adequate sunlight exposure, adequate intake of calcium and vitamin D, regular weight-bearing exercise,
Table 1 Optimal calcium requirements Group Infants Birth to 6 months 6 months to 1 year Children 1–5 years 6–10 years Adolescents/young adults 11–24 years Men 25–65 years Older than 65 years Women 25–50 years Older than 50 years (postmenopausal) Taking estrogens Not taking estrogens Older than 65 years Pregnant and nursing
Optimal daily intake (mg) 400 600 800 800–1200 1200–1500 1000 1500 1000 1000 1500 1500 1200–1500
Source. Adapted from: Optimal calcium intake. National Institutes of Health Consensus Development Conference Statement. June 6–8, 1994. Available at: http://consensus.nih.gov/cons/097/097_statement. htm#CDC97T1.
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and avoidance of other risk factors associated with bone disease such as alcohol use and smoking. Recommended levels of calcium intake, by age and sex, are given in Table 1. No definitive screening or treatment guidelines are available to identify and treat persons receiving AEDs who may be at risk for bone disease. Although the length of time after which some AEDs significantly affect bone is not known, several prospective studies have found changes in both markers of bone turnover and BMD after 1 year of treatment [18,19,24]. We recommend evaluating bone by quantifying BMD as measured by DXA after 5 years of treatment and before treatment in postmenopausal women. If DXA yields a T-score greater than )1, calcium and vitamin D supplementation and weight-bearing exercise should be encouraged. For T-scores between )1 and )2, supplementation and weight-bearing exercise should also be encouraged, and the study repeated in 1–2 years. Subjects with T-scores less than )2 may require further intervention and referral to an internist or endocrinologist expert in the treatment of bone disease.
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A.M. Pack, M.J. Morrell / Epilepsy & Behavior 5 (2004) S24–S29 [31] Vestergaard P, Tigaran S, Rejnmark L, Tigaran C, Dam M, Mosekilde L. Fracture risk is increased in epilepsy. Acta Neurol Scand 1999;99:269–75. [32] 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;12:811–22. [33] Kruse R. Osteopathien bei antiepileptischer Langzeittherapie. Monatasschr Kinderheilkd 1968;116:378–81. [34] Hunter J, Maxwell JD, Stewart DA, Parsons V, Williams R. Altered calcium metabolism in epileptic children on anticonvulsants. Br Med J 1971;4:202–4. [35] Perucca E. Clinical implications of hepatic microsomal enzyme induction by anti-epileptic drugs. Pharmacol Ther 1987;33:130–44. [36] Takahashi A, Ondera 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;82:82–4. [37] Feldkamp J, Becker A, Witte OW, Scharff D, Scherbaum WA. 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. [38] Koch HV, Kraft D, von Herrath D, Schaefer K. Influence of diphenylhydantoin and phenobarbital on intestinal calcium transport in the rat. Epilepsia 1972;13:829–41. [39] Hahn TJ, Hendin BA, Scharp CR, et al. Serum 25-hydroxy calciferol levels and bone mass in children on chronic antiepileptic therapy. N Engl J Med 1975;292:550–4. [40] Braam LA, Knapen MH, Geusens P, et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int 2003;73:21–6.
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[41] Ondera K, Takahashi A, Sakurada S, Okana Y. Effects of phenytoin and/or vitamin K2 (menatetrenone) on bone mineral density in the tibiae of growing rats. Life Sci 2002;70:1533–42. [42] Tjellesen L, Nilas L, Christiansen C. Does carbamazepine cause disturbances in calcium metabolism in epileptic patients? Acta Neurol Scand 1983;68:13–9. [43] 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;68:424–8. [44] Hoikka V, Alhava EM, Karjalainen P, et al. Carbamazepine and bone mineral metabolism. Acta Neurol Scand 1984;70:77– 80. [45] Bramswig S, Zittermann A, Berthold HK. Carbamazepine does not alter biochemical parameters of bone turnover in healthy male adults. Calcif Tissue Int 2003; Jul 24 [Epub ahead of print]. [46] 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;23:553–8. [47] 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;30:895–9. [48] Sheth RD, Wesolowski CA, Jacob JC, et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995;127:256–62. [49] Guo C, 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;42:1141–7. [50] Valmadrid C, Voorhees C, Litt B, Schneyer CR. Practice parameters of neurologists regarding bone and mineral effects of antiepileptic drug therapy. Arch Neurol 2001;58:1369–74.
Epilepsy and bone health in adults Alison M. Pack* and Martha J. Morrell Epilepsy Division, Department of Neurology, Columbia University, 710 West 168th Street, New York, NY 10032, USA Received 21 November 2003; accepted 21 November 2003
Abstract Adults taking antiepileptic drugs (AEDs) have an augmented risk for osteopenia and osteoporosis because of abnormalities of bone metabolism associated with AEDs. The increased fracture rates that have been described among patients with epilepsy may be related both to seizures and to AEDs. The hepatic enzyme–inducing AEDs phenytoin, phenobarbital, and primidone have the clearest association with decreased bone mineral density (BMD). Carbamazepine, also an enzyme-inducing drug, and valproate, an enzyme inhibitor, may also adversely affect bone, but further study is needed. Little information is available about specific effects of newer AEDs on bone. Physicians are insufficiently aware of the association between AEDs and bone disease; a survey found that fewer than one-third of neurologists routinely evaluated AED-treated patients for bone disease, and fewer than 10% prescribed prophylactic calcium and vitamin D. Physicians should counsel patients taking AEDs about good bone health practices, and evaluation of bone health by measuring BMD is warranted after 5 years of AED treatment or before treatment in postmenopausal women. Ó 2003 Elsevier Inc. All rights reserved. Keywords: Antiepileptic drugs; Bone; Bone mineral density; Phenytoin; Phenobarbital; Primidone; Carbamazepine; Valproate
1. Introduction Persons with epilepsy taking some antiepileptic drugs (AEDs) are at risk for bone disease. In adults, peak bone mineral density (BMD) is attained between the ages of 20 and 30 years. After age 30, there is a gradual decline in BMD. In women this is most pronounced in the years following the onset of menopause. AEDs may superimpose an additional effect on bone health; therefore, adults taking AEDs are at even greater risk for bone diseases such as osteopenia/osteoporosis, and for fracture. Identifying those AEDs that are more likely to adversely affect bone is important when choosing an AED for an adult, especially for adults with other risk factors for bone disease including Caucasian or Asian race, small frame, family history of osteoporosis and fracture, smoking history, and alcohol history. Identifying AED-treated persons with bone disease is also important, as other AEDs may have a more beneficial effect on bone, and numerous treatment options for * Corresponding author. Fax: 1-212-305-1450. E-mail address: [email protected] (A.M. Pack).
1525-5050/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2003.11.029
bone disease exist. This review discusses the effects of AEDs on bone in adults, the specific AEDs associated with bone disease, treatment options, and recommendations for good bone health practices and screening for bone disease in AED-treated persons. 2. Biochemical abnormalities Bone loss and consequent fracture appear to be a manifestation of biochemical abnormalities of bone metabolism associated with specific AEDs. These abnormalities include hypocalcemia, hypophosphatemia, reduced serum levels of biologically active vitamin D metabolites, and hyperparathyroidism. In addition, bone turnover is accelerated, as measured by markers of bone formation and bone resorption. Calcium homeostasis and an appropriate concentration of phosphate are essential to maintain normal bone metabolism. Calcium and phosphate levels are affected by some AEDs. Hypocalcemia affects between 3 and 30% of persons with epilepsy receiving AEDs [1–5]. Reduced serum phosphate has also been described in patients prescribed AEDs [6–8].
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Vitamin D is necessary for gastrointestinal absorption of calcium and for the proper development and maintenance of bone. Sources of vitamin D include diet (vitamin D2 ) and sunlight (vitamin D3 ). Vitamin D is metabolized initially to active metabolites and then to an inactive, inert metabolite, calcitroic acid. Its metabolism occurs in the liver and kidney. Vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D (25[OH]D), and then further hydroxylation occurs in the kidney to 1,25-dihydroxyvitamin D (1,25[OH]2 D). The level of 25(OH)D is the commonly used index of vitamin D status, and 1,25(OH)2 D is the most active metabolite of vitamin D. Some studies report reductions in 25(OH)D and 1,25(OH)2 D with some AEDs [2,5,6,9–13], whereas others find that vitamin D levels are normal [14–16]. Parathyroid hormone (PTH) is secreted by the parathyroid gland and regulates serum calcium. When the serum calcium level is decreased, PTH increases bone breakdown or resorption to increase calcium. Women and men taking some AEDs, when compared with controls, have been reported to have higher PTH levels [3,17], but other studies find no differences in PTH levels [18,19]. Markers of bone resorption and bone formation as measured in serum and urine are elevated in persons receiving AEDs [14,18–20]. Markers of bone resorption reflect bone degradation and measure activity of osteoclasts, the cells responsible for bone breakdown, whereas markers of bone formation reflect activity of osteoblasts. In certain bone diseases, such as osteoporosis, bone resorption exceeds formation. Markers of bone formation include procollagen markers, bone-specific alkaline phosphatase, and osteocalcin. Alkaline phosphatase is the most commonly used marker of bone formation. Increases are seen in adults receiving some AEDs [5,7,8,14]. Serum total alkaline phosphatase is derived from bone, liver, and other sources. However, studies that measure alkaline phosphatase isoenzymes find that the increase in total alkaline phosphatase is due mainly to increases in the bone fraction [9,10]. Osteocalcin (also known as bone gla protein) is a small noncollagenous protein, specific for bone tissue and dentin, that is predominantly synthesized by osteoblasts. High serum levels of osteocalcin are described in persons receiving some AEDs [14,18,20]. Procollagen type I molecules are secreted by osteoblastic cells. Subsequent cleavage of the aminoterminal and carboxy-terminal domains creates extension peptides. The C-terminal extension peptide of type I procollagen (PICP) is a putative serum marker of bone formation, and significant elevations are described in persons taking some AEDs [14,18,19]. Specific markers of bone resorption can be measured in the urine and serum. Crosslinked carboxy-terminal telopeptide of human type I collagen is a serum marker of bone degradation, and hydroxyproline is a marker in
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the urine. These markers are elevated in patients with epilepsy receiving long-term AED therapy [14,19,20] and after recent initiation of therapy [18].
3. Bone density abnormalities Osteomalacia literally means softening of bone and results from reduction in bone matrix mineralization [21]. Bone biopsies of patients with AED-induced osteomalacia are histologically characterized by an increase in osteoid or unmineralized bone and reveal a mineralization defect that causes prolonged mineralization. Serum calcium, phosphate, and active vitamin D levels are abnormally low. Early reports described osteomalacia in patients treated with AEDs [1,22]. However, these reports concerned primarily institutionalized patients, in whom lack of nutrition and sunlight exposure probably influenced the outcome. In ambulatory persons, evidence of osteomalacia is seldom found [17,23]. Bone mass is inversely correlated with fracture risk, as decreased BMD increases the risk of fracture. Multiple factors may contribute to decreased BMD, and AEDs are a recognized secondary cause. Adults receiving AEDs have been reported to have decreased BMD at multiple sites including the ribs, femoral neck, and spine [14,15,20,24,25]. Some studies find that duration of treatment is correlated with low BMD [15,24], but this is not a consistent finding [25,26]. The present ‘‘gold standard’’ for BMD measurement is dual-energy X-ray absorptiometry (DXA). DXA measures bone mineral content at multiple sites and can detect a 5% decrement in BMD [27]. Higher rates of osteopenia and osteoporosis are found in adults receiving AEDs [14,15,20,24,25].
4. Fracture The most important clinical sequelae of bone disease are fractures. Fractures are associated with multiple morbidities, including hospitalization and loss of independence, and death. The most common fractures involve the spine and hip. Identifying patients with epilepsy who are at risk for fracture is important; particularly vulnerable are those patients who have inadequate seizure control and may sustain a fracture during a seizure. Increased fracture rates have been described in patients with epilepsy [28–32]. Although some studies have found this increased risk to be related to seizures, AED use may be independently associated with fracture risk. One study in postmenopausal women found that women treated with AEDs had twice the rate of hip fracture when compared with controls [29]. A recent meta-analysis identified AED use as a high risk factor for fracture [32].
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The majority of published reports describing an effect of AEDs on bone include patients receiving phenytoin, phenobarbital, or both drugs. Fewer studies have evaluated the effect of other AEDs including carbamazepine, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, valproate, and zonisamide. In addition, in many studies subjects are treated with polytherapy, which has been shown to be associated with a higher risk of bone metabolism abnormalities compared with monotherapy [3,5]; therefore, it is difficult to determine the effect of individual AEDs in these studies.
sorptive response to PTH could lead to hypocalcemia. Fetal rats treated with phenytoin or phenobarbital demonstrated an impaired response to PTH [39]. Accumulating evidence suggests that poor vitamin K status may be an independent risk factor for postmenopausal bone loss [40]. Vitamin K is a cofactor in the posttranslational carboxylation of several bone proteins, especially osteocalcin, a marker of bone formation. Rats treated with phenytoin had more bone loss over a 5week period than rats treated with phenytoin and vitamin K2 (menatetrenone) [41]. These findings suggest that insufficient vitamin K may contribute to bone loss secondary to phenytoin exposure.
5.1. Phenytoin, phenobarbital, primidone
5.2. Carbamazepine
The AEDs most commonly associated with altered bone metabolism and decreased bone density are inducers of the cytochrome P450 enzyme system, including phenytoin, primidone, and phenobarbital [5,7,14]. The earliest reports of bone disease in patients taking AEDs in the late 1960s and the 1970s involved patients receiving these medications [1,22,33,34]. Biochemical findings include reduced calcium, phosphate, and 25(OH)D levels and elevated markers of bone formation and resorption. Induction of the cytochrome P450 system may cause increased conversion of vitamin D to polar inactive metabolites in the liver microsomes, reducing bioavailable vitamin D [5,35]. Decreased biologically active vitamin D leads to decreased absorption of calcium in the gut, resulting in hypocalcemia and an increase in circulating PTH. PTH then increases the mobilization of bone calcium stores and subsequent bone turnover. Decreased levels of active vitamin D and calcium as well as elevated PTH have been described in adults taking enzyme-inducing AEDs including phenobarbital, phenytoin, and primidone [1–6,9–13,17]. Phenytoin treatment is associated with increased bone turnover as demonstrated by elevated markers of bone resorption and bone formation in adults receiving AEDs [14]. Studies in mice and in vitro provide further evidence of increased bone turnover. Neonatal mouse calvaria treated with phenytoin and a metabolite of phenytoin (5[4-hydroxyphenyl]-5-phenylhydantoin) had increased bone resorption as demonstrated by significantly increased calcium in the medium when compared with controls [36]. In vitro proliferation of human osteoblastlike cells was inhibited by treatment with phenytoin and carbamazepine at concentrations equivalent to therapeutic doses for the treatment of epilepsy [37]. Decreased calcium levels in phenytoin-treated adults may also be explained by impaired calcium absorption. Markedly decreased calcium absorption was found in rats treated with phenytoin but not in those given phenobarbital [38]. In addition, inhibition of the bone re-
Like phenytoin and phenobarbital, carbamazepine is an inducer of the cytochrome P450 enzyme system; however, studies find conflicting results when evaluating its effect on bone and mineral metabolism and BMD. Some studies report disturbances in bone and mineral metabolism and bone turnover, while others find no abnormalities. Tjellesen et al. [13,42,43] studied 30 outpatients receiving carbamazepine monotherapy and found normal concentrations of 25(OH)D, decreased serum calcium concentrations, and elevated total alkaline phosphatase concentrations. In a study of 21 outpatients treated with carbamazepine, hypocalcemia was found in 3, hypophosphatemia in 1, and elevated total alkaline phosphatase in 4 of the cases [44]. In contrast to the studies of Tjellesen et al., serum 25(OH)D levels were significantly lower than in controls. Two recent studies in adolescents found biochemical evidence of increased bone turnover, with elevated markers of bone formation and resorption after 1 year [18] and 2 years [19] of treatment. However, 25(OH)D levels were not reduced. In contrast, a study of 21 healthy male adults without epilepsy treated with carbamazepine for 10 weeks did not find significant elevations of markers of bone formation and resorption [45]. Studies of bone mass also reveal conflicting results. In one study using single-photon absorptiometry, normal bone mass was reported [43]. In adults treated with carbamazepine monotherapy, BMD as determined by DXA was also not significantly decreased [14]. Although the difference was not significant, BMD in a recent study was decreased in men and women treated with enzyme-inducing AEDs compared with those receiving noninducing AEDs. The effect in those receiving carbamazepine monotherapy was not reported [15]. Decreased cortical bone mass as measured by quantitative ultrasonography of the phalanges has been described in patients treated with carbamazepine monotherapy [46,47]. The differing results suggest that the effects of carbamazepine monotherapy on bone and mineral metabolism and BMD have not been adequately determined.
5. AEDs associated with bone disease
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5.3. Valproate Valproate is an inhibitor of the cytochrome P450 enzyme system, and emerging data suggest that it may also adversely affect bone. Early reports evaluating indexes of bone metabolism in patients taking valproate found no significant abnormalities [5,11]. Twenty-two men and women treated with valproate monotherapy had no significant reductions in calcium or 25(OH)D levels [5]. Similarly, alkaline phosphatase was not increased in those subjects receiving valproate monotherapy. Davie et al. [11] found similar results in an institutionalized population treated with valproate. However, recent studies find different results. A study of 40 adults receiving long-term valproate monotherapy found increased serum concentrations of calcium, low levels of vitamin D metabolites, increased markers of bone resorption and formation, and decreased BMD [20]. The increased calcium was postulated to reflect increased bone resorption. Similar findings have been reported in children [48,49]. As with carbamazepine, future studies will elucidate these recent findings.
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the effects of bone health therapies on bone disease associated with AEDs.
7. Physician awareness of AED-associated bone disease Although the association between AEDs and bone disease was first described in the late 1960s, few physicians are aware of this long-term side effect of AEDs. A study by Valmadrid et al. [50] highlights this lack of awareness. U.S. board-certified or board-eligible pediatric and adult neurologists were surveyed about their practice patterns regarding methods of screening for bone disorders and recommendations for treatment and prophylaxis. One-third of the neurologists surveyed routinely evaluated AED-treated patients for bone disease, and of those who did evaluate patients and found evidence of bone disease, fewer than 50% prescribed calcium and vitamin D supplementation, and approximately 50% referred patients with disease to a specialist. Fewer than 10% of the neurologists prescribed prophylactic calcium and vitamin D supplementation to patients treated with AEDs.
5.4. Newer AEDs A number of new AEDs have been approved in the past 10 years. Few studies have evaluated the effect of these medications on bone mineral metabolism and BMD. One study in adults looked at the effect of lamotrigine, topiramate, vigabatrin, and gabapentin on bone mineral metabolism and BMD and found no significant abnormalities [26]. However, as most of the subjects were taking the new AEDs in combination with other AEDs, and the number of individuals receiving a new AED in monotherapy was small ( 6 2), the effect of the individual new AEDs cannot be ascertained from the results of this study. A recent report found no significant reductions in calcium or markers of bone resorption and bone formation in young women treated with lamotrigine monotherapy [16]. More studies are needed to determine whether any of the newer AEDs cause abnormalities in bone.
6. Treatment Although multiple therapies for bone disease are available, few studies have evaluated the effectiveness of various treatments in bone disease associated with AEDs. Calcium and vitamin D supplementation, bisphosphonates, hormone replacement therapy, selective estrogen modulators, and calcitonin are all approved treatments for bone loss. Although not approved by the U.S. Food and Drug Administration, vitamin K supplementation is being studied as a potential therapy for bone loss. Future studies are necessary to clearly define
8. Recommendations Physicians treating adults with AEDs should discuss good bone health practices. Good bone health practices include adequate sunlight exposure, adequate intake of calcium and vitamin D, regular weight-bearing exercise,
Table 1 Optimal calcium requirements Group Infants Birth to 6 months 6 months to 1 year Children 1–5 years 6–10 years Adolescents/young adults 11–24 years Men 25–65 years Older than 65 years Women 25–50 years Older than 50 years (postmenopausal) Taking estrogens Not taking estrogens Older than 65 years Pregnant and nursing
Optimal daily intake (mg) 400 600 800 800–1200 1200–1500 1000 1500 1000 1000 1500 1500 1200–1500
Source. Adapted from: Optimal calcium intake. National Institutes of Health Consensus Development Conference Statement. June 6–8, 1994. Available at: http://consensus.nih.gov/cons/097/097_statement. htm#CDC97T1.
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and avoidance of other risk factors associated with bone disease such as alcohol use and smoking. Recommended levels of calcium intake, by age and sex, are given in Table 1. No definitive screening or treatment guidelines are available to identify and treat persons receiving AEDs who may be at risk for bone disease. Although the length of time after which some AEDs significantly affect bone is not known, several prospective studies have found changes in both markers of bone turnover and BMD after 1 year of treatment [18,19,24]. We recommend evaluating bone by quantifying BMD as measured by DXA after 5 years of treatment and before treatment in postmenopausal women. If DXA yields a T-score greater than )1, calcium and vitamin D supplementation and weight-bearing exercise should be encouraged. For T-scores between )1 and )2, supplementation and weight-bearing exercise should also be encouraged, and the study repeated in 1–2 years. Subjects with T-scores less than )2 may require further intervention and referral to an internist or endocrinologist expert in the treatment of bone disease.
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