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Year : 2006  |  Volume : 9  |  Issue : 2  |  Page : 90-97

Epilepsy, antiepileptic drugs and bone health

1 Departments of Neurology, Amrita Institute of Medical Sciences, Cochin - 682 026, Kerala, India
2 Departments of Endocrinology, Amrita Institute of Medical Sciences, Cochin - 682 026, Kerala, India

Correspondence Address:
K P Vinayan
Department of Neurology, Amrita Institute of Medical Sciences, Cochin - 682026, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-2327.25980

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There is a growing body of literature, describing disorders of bone health in epilepsy. Patients with epilepsy have a higher incidence of skeletal fractures due to multiple reasons. Postmenopausal women and elderly men are particularly vulnerable to osteoporosis. A major convulsive seizure can often lead to falls and may result in fractures. Antiepileptic therapy may have seemingly contradictory effects on bone health. It can effectively reduce the incidence of major seizures and prevent the seizure related falls and fractures. However, the central nervous system effects of these drugs increase the risk of falls, especially in the vulnerable population. Long-term antiepileptic therapy may lead to a reduction in bone mineral density, with consequent increase in bone fragility. This can increase the risk for fractures with attendant high morbidity and mortality. Dual energy X-ray absorptiometry (DXA) is currently the gold standard for assessing bone mineral density. Multiple pathophysiologic mechanisms have been proposed for the reduction in bone mineral density associated with antiepileptic therapy. Most of the available data are from the patients treated with conventional antiepileptic drugs (AED). There is a need for monitoring the effects of the newer AEDs on the bone mineral metabolism. This is of added significance in view of an ageing population and also an increase in the prevalence of epilepsy in the elderly. Physicians treating patients with epilepsy should be made aware of this problem and adequate preventive measures should be advised especially in patients with multiple risk factors. A multidisciplinary approach with the help of an endocrinologist may be needed in severe bone disease.

Keywords: Antiepileptic drugs, bone mineral density, epilepsy

How to cite this article:
Vinayan K P, Nisha B. Epilepsy, antiepileptic drugs and bone health. Ann Indian Acad Neurol 2006;9:90-7

How to cite this URL:
Vinayan K P, Nisha B. Epilepsy, antiepileptic drugs and bone health. Ann Indian Acad Neurol [serial online] 2006 [cited 2021 Sep 22];9:90-7. Available from:

Patients with epilepsy are particularly vulnerable for multiple associated co-morbidities. These can be attributed to various factors such as a common etiology, the effect of ongoing uncontrolled seizures and the management issues like the adverse effects of long term antiepileptic drug (AED) intake.

The association of AED with bone disease has been known for more than 30 years. Early studies performed in institutionalized patients revealed florid bone disease in pathological biopsies.[1] These findings might have been influenced by multiple confounding variables such as inadequate sunlight exposure, poor nutrition and limited mobility. As a result, the extrapolation of these findings to everyday practice of patients with epilepsy was not considered feasible.[2] However, several recent studies in ambulatory patients with epilepsy describe multiple abnormalities such as decreased bone mineral density (BMD), disorders of bone mineral metabolism and increased incidence of fractures.[3],[4],[5],[6]

In this review, the complex interrelationship among epilepsy, AED and bone health is examined from multiple perspectives; including the incidence of fractures in patients with epilepsy, its etiologic association with falls and increased bone fragility, the pathophysiologic mechanisms leading to the increase in bone fragility and reduced BMD in persons taking AEDs. Finally, available methods for the clinical assessment of bone health are discussed along with the preventive and treatment strategies, which will be helpful in disorders of BMD in patients with epilepsy.

  Bone Health, Fractures and Epilepsy Top

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk for the development of bone fragility and fractures.[7] Bone strength primarily reflects the integration of bone density and bone quality. Bone density is in turn determined by peak bone mass and amount of bone loss. Bone quality refers to architecture, turnover, damage accumulation (e.g., microfractures) and mineralization. A fracture results when even a minimal force is applied to an osteoporotic bone. Thus, osteoporosis is a significant risk factor for fractures.[7] It is estimated that around 8-10 million people in the United States are affected by osteoporosis, which contribute to around 1.5 million fractures annually.[8] Osteoporosis has been classically considered to be a disorder of postmenopausal females. It is estimated that one in two postmenopausal women will have an osteoporotic fracture some time during their lifetime.

Patients with epilepsy are at increased risk for developing fractures, compared to the general population.[9] This will be immediately attributed to an increased risk for falls as a result of seizures. However, it has been shown that a significant number of these fractures are not related to a specific seizure event.[10] Epidemiologic studies indicate an approximate doubling of fracture incidence among persons taking AEDs, even in the absence of clinical seizures.[11] Fractures of the hip and vertebrae, especially in the elderly, will make the patient bed-bound with subsequent medical complications like venous thrombosis and aspiration pneumonia. It has been estimated that around 30% of the patients with a fracture of the hip, will die within one year as a result of such complications.[12]

There are no prospective studies that looked at the frequency of fractures in patients with epilepsy. The available publications are case control studies, retrospective analyses and case reports. The populations studied also differ widely, ranging from institutionalized patients with other associated motor and mental handicaps, to ambulatory outpatients with otherwise normal function. In a series of 87 institutionalized patients with epilepsy taking phenytoin, a six-fold rise of overall fracture incidence was reported.[10] In a study of 202 institutionalized patients, there was a five-fold rise in the incidence of fracture femur, as compared to the normal population. Out of these, only 35% of fractures occurred during a specific seizure event.[13] In another case control study, the relative risk for vertebral fractures in patients taking AEDs were found to be comparable to that seen in patients taking steroids.[14]

Even though the majority of fractures during seizure events are related to the traumatic falls, there are several reports of fractures without obvious falls.[15],[16] The majority of these fractures were detected in the vertebrae. It is postulated that extreme pathologic contractions of the axial musculature occurring in a generalized tonic clonic seizure (GTCS) may produce hyperflexion of spine leading to fractures, especially of the thoracic vertebra. Patients with epilepsy may present with ill-localized back pain along with radiological evidence of fracture of vertebrae, without any history of trauma or fall.[17] Elderly people and postmenopausal females are particularly vulnerable for this type of fractures. Increased susceptibility of the bone to fracture as a result of defective bone density, is an important causative factor in this setting.

The risk factors for fractures in patients with epilepsy are given in [Table - 1].

AED, falls and fractures

The relationship between AED and fractures is really complex. On the one hand, AED may reduce the incidence of major seizures and related falls and fractures.[11] At the same time, the intake of AEDs can increase the propensity for fractures through multiple mechanisms. AED can affect central nervous system functions, producing drowsiness, slowing of protective reflexes and incoordination. This is especially important in elderly people, leading to clumsy walking and falls. AED may also produce weakening of bones by reducing the bone mineral density and increase the fracture risk.

  Bone Mineral Density and Epilepsy Top

Bone is a metabolically active organ, undergoing constant reorganization throughout the life span of an individual. The major cells within the bone are osteoblasts, osteoclasts and osteocytes. Osteoblasts form unmineralized bone matrix through the production of collagenous and noncollagenous proteins. These cells contain a specific isoform of alkaline phosphatase that may be used as an indirect marker of osteoblastic activity. They synthesize and process type 1 collagen. Osteocytes, cells incorporated into the calcified matrix of bone, are responsible for the exchange of nutrients. Osteoclasts are derived from the monocyte-macrophage lineage and they help in resorption of bone matrix.[18]

Bone plays a central role in the metabolism of calcium and phosphorus through the continuous remodeling process of bone resorption and formation. In a normal skeleton, a complete remodeling cycle takes about 100 days for the cortical bone and 200 days for the trabecular bone.[18] Both calcium and phosphorus are required for this process. Vitamin D acts at multiple levels in this bone mineral homeostasis. Apart from helping to maintain the serum levels of calcium and phosphorus in the physiological range through its action in the intestine and kidney, it also regulates the differentiation and function of both osteoblasts and osteoclasts.[19] Other hormonal influences on the bone remodelling process are parathyroid hormone (PTH) and calcitonin. PTH stimulates bone resorption by osteoclasts and matrix production by osteoblasts, at the same time. Calcitonin inhibits osteoclast- mediated bone resorption. Gonadal steroid hormones including estrogens and androgens play an important role in attainment and maintenance of bone mass. Deficiency of these hormones will increase bone resorption, possibly by increasing the synthesis and sensitivity of the bone to local cytokines. Thyroid hormone, growth hormone, glucocorticoids, insulin, various growth factors and locally produced cytokines are the other influences on this continuous remodeling process.[18] In an adult, it is estimated that approximately 25% of trabecular bone and 3% of cortical bone are resorbed and replaced annually.[20] As a result, any process that affects this continuous remodeling process tends to affect the trabecular bones early and predominantly.

In childhood, bone is much more dynamic with active mineralization, as a result of the physical growth.[21] Consequently, bone mineral density increases all through the childhood and adolescence, reaching a peak by the age of 20-30 years. Then the BMD plateaus for approximately next 10 years and starts to progressively decrease by the age of 40 years [Figure - 1]. In women, there is an increase in bone resorption after menopause, due to a reduction of estrogens and other factors that normally mediate osteoclast apoptosis. Both genetic and environmental factors influence the peak bone mineral density and its rate of reduction [Table - 2].

Any interference with bone mineralization during childhood will result in a lower peak BMD in adulthood. This will cause the patient to enter the years of bone involution with less reserve and increase the risk for fracture in the subsequent years. Any chronic illness that affects the physical growth of the child, reduces the mineralization process. Chronic renal disease is the classical example. Many of the medications used for long term, will also affect bone mineralization. This was clearly shown in the case of long-term corticosteroid administration.[22]

Epilepsy and its comorbidities like cerebral palsy that limit the normal mobility or the long-term treatment with AED, may affect the active bone mineralization. Cerebral palsy and infantile hemiplegia that frequently accompany symptomatic epilepsies, produce limb muscular and skeletal hypoplasia with consequent higher risk for fractures in adult life.[21]

  Bone Health in Women with Epilepsy Top

Women with epilepsy are inherently vulnerable and face more problems related to bone health as a consequence of the low BMD, when compared to their male counterparts.[23] Estrogen deficiency, either due to late menarche, primary or secondary amenorrhea or early natural or surgical menopause, is the most important risk factor contributing to the accelerated bone loss in women.[24] It is estimated that women lose around 35-50% of their bone mass throughout their life. Before menopause, this loss is minimal and may involve only cancellous bone such as vertebral bodies or the hip. During the 3-4 years preceding menopause and after menopause, there is an accelerated bone loss[25] [Figure - 1]. In view of these factors, evaluation of bone health becomes particularly important in the optimal management of women with epilepsy.

  Antiepileptic Drugs Associated with Bone Disease Top

There is an extensive body of literature presently available, dealing with the effects of antiepileptic drugs on the bone mineral density.[26] Sophisticated radiological, biochemical and pathological techniques are used now for the documentation of these abnormalities. Most of the available data pertains to the conventional antiepileptic agents such as phenytoin, phenobarbitone, primidone, carbamazepine and valproate.[27]

AEDs, most commonly associated with reduced BMD, are the inducers of the hepatic cytochrome P450 (CYP) system.[2] These include phenytoin, phenobarbitone, carbamazepine and primidone. However, there are several recent studies that show a reduction in BMD on therapy with valproate, an inhibitor of CYP. One of them showed a reduction in BMD of 14%, in adult patients on valproate monotherapy.[28] Another study in children showed a significant reduction in BMD on valproate monotherapy, compared to carbamazepine intake.[29] There are very few studies evaluating the effects of newer AEDs on the BMD and no definite conclusions can be drawn as of now.[30],[31] Clearly there is a need for assessment of this factor when monitoring for the long-term safety issues in newer AEDs, as it will be of much clinical significance. An agent with negligible effect on the BMD, may be the initial choice in elderly persons and postmenopausal females or in people with other risk factors for osteopenia.

Pathophysiology of AED induced bone loss

Traditionally, AED-induced bone loss is considered to be due to hepatic induction of cytochrome P 450 hydroxylase (CYP 450) enzymes, leading to increased metabolism of vitamin D and consequent reduction in serum levels of its active metabolite 1, 25 dihydroxycholecalciferol (1, 25 vitamin D 3). Since this agent is essential for the normal calcium homeostasis, its deficiency leads to secondary hyperparathyroidism and subsequent reduction in BMD. In severe cases, especially with associated nutritional deficiency and reduced sunlight exposure as occurs in severely disabled patients, this may lead to frank osteomalacia, which is a complete failure of mineralization of the bone matrix.

Vitamin D deficiency has been documented in several studies in patients on antiepileptic therapy. In an earlier study, it was reported that the mean serum levels of vitamin D in adults on long term antiepileptic treatment was only 4.8 ng/ml, compared to a control value of 16 ng/ml ( P < 0.001).[32] Many of these patients were having frank osteomalacia. However, a majority of these patients were institutionalized with other probable risk factors. In another study among patients taking phenobarbitone and phenytoin, increased metabolism of vitamin D, vitamin D deficiency and hypocalcemia were seen.[33]

However, this mechanism fails to explain the osteopenic effects of other AEDs, especially the inhibitors of CYP enzyme system like valproate. In addition, several recent studies using Dual energy X-ray absorptiometry (DXA) failed to demonstrate the constant association between low BMD and reduced vitamin D levels, in patients on chronic AED therapy.[18],[30] This discordance may be because BMD indicates the chronic effect of AEDs, while vitamin D levels are affected by the acute fluctuations in the serum levels of AEDs.[18] Another confounding factor is the high prevalence of low vitamin D levels in the general population, making it a less reliable marker of osteopenia.[34] Surprisingly, even in tropical countries with good exposure to sunlight, the prevalence of vitamin D deficiency in otherwise healthy population is rather high.[35] Farhat et al studied 61 patients in the age group 5-64 years, with history of antiepileptic drug intake for a minimum period of 6 months. Some of the patients in this cohort received newer AEDs like lamotrigine, topiramate or gabapentin. 59% of adults showed low BMD by DXA, compared to 34% showing serum vitamin D levels in the deficient range. However, another 43% had lower vitamin D levels, not reaching the threshold for frank deficiency. The levels correlated with the duration of AED therapy. Polytherapy, duration of AED therapy and generalized seizures significantly correlated with low BMD in this cohort.[30]

In view of these lacunae in the vitamin D hypothesis, several recent theories are being put forward to explain the possible mechanism of AED- induced osteopenia. Among these, increased bone turnover is now considered to be the main and the most important mechanism. Bone biopsies in patients on long term AED intake show several indicators of increased bone turnover, like increased bone matrix formation with normal mineralization, accelerated mineralization and decreased mineralization lag time.[36] Surrogate markers of increased bone turnover in the serum like alkaline phosphatase, osteocalcin and procollagen peptides are also increased in patients on AED.[37] Another marker for increased bone turnover is urinary deoxypyridinoline, which is also shown to be increased in patients taking AED.[38]

The various pathophysiological mechanisms proposed for the reduced BMD in patients taking AED, is summarized in [Table - 3]. For each AED, one or more of these mechanisms may be responsible for the effect on BMD. As a result, a polytherapy regimen may produce additive osteopenic effects.

  Evaluation and Measurement of Bone Mass Top

Generally, evaluation of bone mass is carried out in patients who present with a low impact fracture or in whom osteoporosis is suspected on clinical grounds. Assessment of bone mass provides a quantitative measurement of current skeletal status and a baseline for further monitoring. It also helps in formulating fracture prevention strategies in patients with confirmed osteoporosis. A plain X-ray is the simplest and widely available investigation to detect osteopenia. However, its sensitivity is very low. About 30-40% of bone should be lost before the plain X-ray detects the loss.[39] Even though there are several newer sophisticated techniques used for measuring BMD, DXA is currently the gold standard for this purpose. It has high sensitivity to detect 5% decrement or less of bone mass.[40] Single energy X-ray absorptiometry (SXA), quantitative ultrasound (QUS) and quantitative computed tomography (QCT) are the other methods used.

DXA uses a combination of high energy and low energy X-rays. Soft tissue and bone absorbs these X-rays differentially and this differential absorption is made use of for selectively measuring the BMD.[41] Thus, DXA reliably assesses the available bone mass at different sites that is related to fracture risk. However, DXA does not measure the volumetric density. BMD is measured from bone mineral content (BMC) and the bone area scanned and is expressed in g/square cm and so represents the "areal" bone density. Commonly, the BMD is measured in the lumbar spine and femoral neck, which are called the "central" sites. It is commonly reported in terms of T-score, which is defined as the standard deviation from the normative value for BMD of a healthy young adult. These values are highly dependant on the reference population, particular instrument used and are also likely to be influenced by the race and sex of the individual. For the Caucasian population, World Health Organization (WHO) has defined osteopenia as a T-score between -1 and -2.5. If T - score is -2.5 or lower, it is osteoporosis.[42] This cut off T score of -2.5 SD is derived from the estimate that with this threshold, 30% of white women older than 50 years will have osteoporosis, which equals the lifetime risk of fracture. Even though originally standardized for assessment of fracture risk among postmenopausal white females, T score is now approved for clinical use in males over 50 years also.[43] It has been estimated that for each SD by which BMD is lower, the fracture risk of the individual doubles approximately. A person with a T-score of -2 has twice the risk for fractures, compared to an individual of the same age with a T score of -1. For children and young adults who have not yet attained the peak bone mass, instead of T- score, Z-score is used, which is the standard deviation from the expected value for individuals of the same age, sex and body size.[39]

Several markers of bone turnover were assessed in patients with osteopenia and osteoporosis on AED, in multiple clinical trials [Table - 4]. Monitoring of these serum markers demonstrated a rapid response to treatment, compared to the standard BMD measurement by DXA. However, their utility in clinical practice is unclear. Serum vitamin D and calcium levels alone are not reliable for the reasons already described. However, these biochemical markers can be used as a supplementary evidence for a more severe disorder of BMD.

Management strategies

For an optimal bone health in patients with epilepsy, the treating physician has to maintain a very fine balance between two seemingly contradictory management strategies. On the one hand, major seizures have to be controlled completely with an aggressive therapeutic regimen. The potential for the AED to induce or aggravate osteopenia should be kept in mind while prescribing AEDs, particularly in the high risk group such as elderly, post menopausal women and those on steroid hormones.

Prevention of fractures

The most obvious measure for the prevention of fractures in patients with epilepsy is good control of generalized seizures and partial seizures leading to falls. When seizure control is not possible with optimal medical or surgical strategies, environmental modifications to minimize the risk for a fracture are to be considered. Monitoring for the central nervous system adverse events of AEDs like visual blurring, dizziness, ataxia and cognitive slowing, which increase the risk for falls is worthwhile, particularly in high risk patients like elderly and postmenopausal females. The other important measure is the prevention and treatment of increased bone fragility as a result of reduced BMD.

Prevention and treatment of AED induced bone disease

Several therapeutic options are available for the prevention and treatment of reduced bone mineral density and a number of newer agents have also been approved recently. These include calcium and vitamin D supplementation, bisphosphonates, calcitonin, selective estrogen receptor modulators (SERM), hormone replacement therapy and recombinant PTH.[44] However, very few studies are available on the specific issue of prevention and treatment of bone disease associated with long term AED intake.[36] Barden et al , in a study of institutionalized patients on AED, reported that a minimum daily intake of 400 IU of vitamin D protected against reduction in BMD.[45] For the treatment of established bone disease, the required daily dose of vitamin D may be any where between 2000-4000 IU.[46] The need for vitamin D may be higher in patients with multiple risk factors like the elderly, those with reduced activity and those on a poor diet. In such cases, an intake of around 4000 IU of vitamin D is recommended.[47] Environmental and dietary modifications will further help in maintaining bone health in such situations. Even though antiresorptive agents are the new definitive agents for osteopenia in general, there is no data specifically looking at the subset of population taking AEDs. In documented severe bone disease with multiple risk factors, these can be tried in consultation with a specialist. There is a need for further prospective trials, testing the safety and efficacy of these drugs in AED induced osteopenia.

Physician awareness of AED induced bone disease- a treatment gap?

Even though there are a lot of studies linking AED with bone disease, very few physicians dealing with patients with epilepsy are aware of this long-term side effect of AED. A knowledge, aptitude and practice study conducted among board-certified neurologists in USA, had revealed this awareness and treatment gap. Only one third of the surveyed neurophysicians were aware of such an entity and evaluated their patients with epilepsy for bone disease. Fewer than 10% prescribed prophylactic calcium and vitamin D supplementation to patients on long-term antiepileptic therapy.[48] The situation among practitioners in India is likely to be similar, if not worse.

Summary and practice recommendations

There is a growing body of evidence-linking disorders of BMD with long-term antiepileptic drug intake, in patients with epilepsy. Most of these data came from patients treated with conventional antiepileptic agents. There is an urgent need for monitoring the effect of the newer AEDs in the bone mineral metabolism. As patients with epilepsy are more prone for falls due to multiple etiologies, their increased bone fragility can easily translate into increased occurrence of skeletal fractures, with attendant high morbidity and mortality. This is of added significance in view of an ageing population and an increase in the prevalence of epilepsy in the elderly. Women with epilepsy are particularly vulnerable to disorders of bone health, as a result of the differences in hormonal and physiological parameters when compared to their male counterparts. Physicians treating patients with epilepsy need to be aware of this problem. They also need to take in to consideration, the potential for AED induced osteopenia and its prevention or treatment, especially in patients with multiple risk factors such as post menopausal women and elderly men. Good bone health practices should be discussed with the patients, such as adequate intake of calcium and vitamin D, regular weight bearing exercises, adequate exposure to sunlight and avoidance of cigarette smoking and alcohol intake. Recommended daily allowance for calcium across the life cycle is given in [Table - 5]. There are no evidence-based therapeutic guidelines for AED- associated bone disease. The American Epilepsy Society practice committee has come forward with some useful recommendations, which are summarized in [Table - 6]. A multidisciplinary approach with the help of an endocrinologist, may be needed in severe bone disease. Further prospective comparative trials of the available therapeutic modalities are urgently required, for gathering better evidence to guide clinical practice[49].

  Acknowledgments Top

KPV was supported by a fellowship from Japanese Epilepsy Research Foundation and was undergoing training at the National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan during the preparation of this manuscript. He has also received a grant from Indian Epilepsy Association.

We would like to thank Dr. Yushi Inoue, Vice Director, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan for the critical review of this manuscript.

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[Figure - 1]


[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]

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