Alison M. Pack

Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy

Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25‐hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone‐specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross‐linked N‐telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine (p = 0.008). Insulin growth factor‐I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine (p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone‐specific alkaline phosphatase (p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long‐term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long‐term adverse effects on bone. Ann Neurol 2005;57:252–257

Enzyme induction with antiepileptic drugs: Cause for concern?

Several commonly prescribed antiepileptic drugs (AEDs)—including phenobarbital, phenytoin, and carbamazepine—stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid‐ and non–lipid‐soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme‐inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme‐inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, non–enzyme‐inducing AEDs.

Epilepsy and bone health in adults

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.

Bone health in people with epilepsy: is it impaired and what are the risk factors?

Diseases of the bone are becoming increasingly prevalent. Persons with epilepsy treated with antiepileptic drugs (AEDs) are at greater risk as evidenced by changes in bone turnover, osteoporosis, alterations in bone quality, and fracture. Biochemical indices of bone and mineral metabolism including calcium, vitamin D, parathyroid hormone, and bone turnover markers can be affected. AED exposure is a cause of secondary osteoporosis with decreased bone mineral density (BMD) secondary to poor bone accrual in children or accelerated bone loss in adults. Early reports described osteomalacia, a change in bone quality with increased unmineralized bone. Recent studies do not reveal osteomalacia, but there may be more subtle changes in bone quality. Multiple studies have found an increased risk of fractures in association with epilepsy and AED exposure. Cytochrome P450 enzyme inducing AEDs are most commonly associated with a negative impact on bone, but studies also suggest an effect of valproate. There is limited data regarding the newer AEDs. No single mechanism has emerged to explain all the changes in bone in association with epilepsy and AEDs. Although multiple therapies are available for the treatment of bone disease, there is limited study in persons with epilepsy. It is recommended that all persons obtain adequate amounts of calcium and vitamin D. In addition BMD screening is warranted for persons with long-term AED exposure particularly if they have other risk factors for bone disease.

Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy

Objective: Antiepileptic drugs (AEDs) may have adverse effects on bone mineral density (BMD) and metabolism. We previously reported biochemical evidence of increased bone turnover in premenopausal women with epilepsy on phenytoin monotherapy compared with those on carbamazepine, lamotrigine, and valproate. We therefore hypothesized that rates of bone loss would be higher in young women treated with phenytoin. Methods: Ninety-three premenopausal women with epilepsy receiving a single AED (carbamazepine, lamotrigine, phenytoin, or valproate) participated. Subjects completed nutritional and physical activity questionnaires. Biochemical indices of bone and mineral metabolism and BMD of the proximal femur and lumbar spine were measured at baseline and 1 year. Results: Participants reported high calcium intake (>1,000 mg/day) and were physically active. Significant loss (2.6%) was seen at the femoral neck in the phenytoin group. BMD remained stable in the other AED groups. Bone turnover markers and calciotropic hormones were unchanged after 1 year in all groups except for a significant decline in urine N-telopeptide in the phenytoin group. In women receiving phenytoin, lower serum 25-hydroxyvitamin D concentrations were associated with higher parathyroid hormone, bone alkaline phosphatase, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling. Conclusion: In this study, young women treated with phenytoin had significant femoral neck bone loss over 1 year. In contrast, those treated with carbamazepine, lamotrigine, and valproate did not have detectable adverse effects on bone turnover or bone mineral density. These results raise concerns about the long-term effects of phenytoin monotherapy on bone in young women with epilepsy. GLOSSARY: 1,25(OH)2D = 1,25-dihydroxyvitamin D; AED = antiepileptic drug; ANOVA = analysis of variance; BCE = bone collagen equivalent; BMD = bone mineral density; BMI = body mass index; BSAP = bone-specific alkaline phosphatase; CBZ = carbamazepine; FN = femoral neck; LS = lumbar spine; LTG = lamotrigine; NTx = cross-linked N-telopeptide of type I bone collagen; OHD = 25-hydroxyvitamin D; PHT = phenytoin; PTH = parathyroid hormone; TH = total hip; VPA = valproate.

Adverse Effects of Antiepileptic Drugs on Bone Structure Epidemiology, Mechanisms and Therapeutic Implications

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 in an outpatient population receiving enzyme-inducing antiepileptic drugs

Antiepileptic drug (AED) use is identified as being associated with increased fracture risk. AEDs commonly associated with osteopathies are inducers of the hepatic cytochrome p450 enzyme system (EIAEDs). We performed a retrospective cross-sectional study assessing bone mineral density (BMD) in an adult outpatient population receiving EIAEDs. Patients were routinely referred for dual-energy X-ray absorptiometry to evaluate BMD. BMD was measured at the femoral neck of hip and lumbar spine. Results were presented as absolute BMD (g/cm(2)), T score, and Z score. T and Z scores were used in this analysis. As a group, those with BMD measurements represent people with intractable epilepsy. There were no statistically significant differences found in the T or Z scores by gender; therefore all analyses combined both men and women. Significant reductions in both T and Z scores were present in men and women <50 and >or=50.

Antiepileptic drug use in women of childbearing age.

Research on antiepileptic drug (AED) teratogenesis has demonstrated an increased risk for valproate. The impact of these findings on current AED prescribing patterns for women of childbearing age with epilepsy is uncertain. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective multicenter observational investigation that enrolled pregnant women with epilepsy on the most common AED monotherapies from October 1999 to February 2004 (carbamazepine, lamotrigine, valproate, and phenytoin). A 2007 survey of AED use in women of childbearing age at eight NEAD centers found a total of 932 women of childbearing age with epilepsy (6% taking no AED, 53% monotherapy, 41% polytherapy). The most common monotherapies were lamotrigine or levetiracetam. Since 2004, prescriptions of carbamazepine, phenytoin, and valproate have decreased, whereas those for levetiracetam have increased. Except for the top two AED monotherapies, there were marked differences in other monotherapies and in polytherapies between U.S. and UK centers. Future investigations are needed to examine reasons for drug choice.

Sexual dysfunction, sex steroid hormone abnormalities, and depression in women with epilepsy treated with antiepileptic drugs.

Women with epilepsy are believed to be at risk for sexual dysfunction. Disorders of sexual desire and sexual arousal, including dyspareunia, vaginismus, and lack of lubrication, affect an estimated 30 to 60% of women with epilepsy. In this study, 57 reproductive-aged women with either localization related (LRE) or primary generalized epilepsy (PGE) on antiepileptic drug (AED) monotherapy and 17 nonepileptic controls completed questionnaires examining sexual experience, arousability, anxiety, and symptoms, as well as an inventory of depression. An endocrine assessment was performed during the early follicular phase of the menstrual cycle. Sexual dysfunction was more common in women with LRE, in women receiving phenytoin, in women with low levels of estradiol and dehydroepiandrosterone sulfate, and in women with self-reported symptoms of mild depression. The mechanisms of sexual dysfunction in women with epilepsy are multifactorial, but AED choice appears to be one cause that is modifiable.

Treatment of epilepsy to optimize bone health.

Opinion statementWhen treating a person with epilepsy, one must consider many factors in addition to the obvious need to treat the seizures. Both epilepsy itself and treatment with antiepileptic drugs (AEDs) subject one to numerous potential secondary long-term health concerns. Poor bone health is one of these concerns. Studies suggest that persons with epilepsy treated with AEDs have an increased risk of fracture, low bone mineral density (BMD), and abnormalities in bone metabolism. Multiple factors likely contribute to the increased risk. Falls during generalized tonic-clonic seizures, secondary effects of AEDs on balance, inactivity, low BMD, reduced calcium intake, reduced active vitamin D metabolites, and a genetic predisposition to low BMD may all contribute. Studies suggest a differential influence of AEDs. Phenytoin, phenobarbital, and primidone are most consistently associated with a negative impact on bone. Carbamazepine and valproate may also result in bone abnormalities, but data are mixed. Current studies suggest that lamotrigine has limited (if any) effect, but again, data are inconsistent. Other AEDs have received limited study. Screening for poor bone health includes serologic testing of vitamin D metabolites (notably 25-hydroxyvitamin D) as well as BMD testing using dual energy x-ray absorptiometry. Optimizing intake of calcium and vitamin D is important for all persons with epilepsy treated with AEDs. Although many treatments for low BMD are available, these agents have not been studied in persons with epilepsy treated with AEDs. Overall, physicians treating persons with epilepsy must consider the potential effect of having epilepsy and its main treatment, AED therapy, on bone health. For patients in whom bone health is a particular concern (eg, those with diagnosed bone disease or with significant risk factors for bone disease, including glucocorticosteroid use), it is best to avoid AEDs known to negatively affect bone. In addition, practitioners should work with other treating physicians to optimize bone health in these patients.