Bone Health in Epilepsy

Epilepsy affects almost 1% of the population. Osteoporosis and related fractures also are very common. Approximately 40% of women and 13% of men in the general population older than 50 years will sustain an osteporotic fracture at either the hip, spine, or forearm 1. Given the frequency of epilepsy and osteoporosis, it is not surprising that there is considerable overlap. However, accumulating evidence suggests that the association may be more than casual. It appears that the nature of epilepsy and its treatment may directly contribute to osteoporosis. The consequence of osteoporotic fractures is great. Fractures and the attendant loss of ambulation have a devastating impact on quality of life and social costs in the elderly. Up to 30% of patients who have had a hip fracture will die within a year of the acute event. Despite this, a survey of practice patterns of neurologists caring for patients with epilepsy indicated a striking absence of screening for bone health or recommendations for calcium and vitamin D supplements 2. This state of affairs may be due to the latency of many decades between reductions in bone density and presentation of fractures as well as lack of general awareness of bone health and metabolism. In this issue of Epilepsia, Verrotti et al., in a longitudinal study, examine bone turnover in 60 adolescents taking carbamazepine (CBZ). CBZ is a P450 enzyme inducer that enhances breakdown of vitamin D. Reduced vitamin D levels have been proposed as the mechanism underlying increased bone turnover and osteopenia associated with the P450 enzyme–inducing antiepileptic drugs (AEDs). They compared serum markers of bone formation and resorption before initiation of CBZ and 2 years after initiation of therapy. Subjects were of normal growth, healthy except for epilepsy, and were treated with typical serum concentrations of CBZ. They were age and gender matched with controls and divided by developmental status into three groups: prepubertal, pubertal, and postpubertal. After 2 yeas of CBZ treatment, they found a significant increase in several serum markers of collagen and bone turnover. Urinary cross-linked N-telopeptides of type 1 collagen excretion, a marker of osteoclastic activity, was increased 10-fold. This effect occurred despite a normal calcium intake and in the face of similar parathyroid hormone and vitamin D serum concentrations. Furthermore, pubertal stage did not influence the association. Their findings are important because they suggest that increased bone turnover occurred despite normal levels of vitamin D. Although confirmation of these findings is important, increased bone turnover during a critical period of mineralization can have long-lasting consequence on bone health. While fractures manifest in the elderly, the origins of osteoporosis trace back to youth. Physiologically, bone mineral density increases through childhood and adolescence until it peaks at age 20 years 3. Peak bone mass is then maintained at a steady plateau to age 40 years, after which there is a steady decline in bone density until fractures manifest in the elderly. Heritable factors account for 80% of the variability of bone density, such that white women are at the highest risk, whereas African Americans have the lowest osteoporotic fracture rates. Pathologically, osteoporosis results from either high turnover osteoporosis or from induced vitamin D osteomalacia. These factors either lower peak bone mass attained at the end of adolescence, induce loss during the plateau years or accelerate bone loss after age 40 years. Sedentary life styles, lack of weight-bearing exercise, smoking, chronic disease, and concomitant medications all increase the likelihood of osteoporosis. In epilepsy, two dominant factors influence bone health. First, limitations to physical activity that result from focal neurologic deficits or cerebral palsy underlying the symptomatic epilepsies and the resultant disuse can adversely affect bone mineralization 4. Frequently patients with hemiparesis acquired early in life have smaller limbs and reduced density on the afflicted side. General recommendations that patients limit certain activities (such as swimming, contact sport, etc.) may further contribute to impaired bone mineralization, although the impact of these restrictions has yet to be examined. Furthermore, the psychiatric depression that frequently accompanies epilepsy, with its attendant hypomotor states, also may contribute adversely. This combination of inherent limitations and disuse or imposed restrictions may accentuate osteoporosis in epilepsy. Second, AEDs can adversely influence bone health 5. The association between AEDs and bone disease has been known for >30 years. It is estimated that AED treatment for ≥5 years places patients aged 50 years or older at twice the risk for osteoporotic fractures. Rickets and fractures with qualitative radiographic evidence of osteoporosis have been associated with long-term phenytoin (PHT) and phenobarbital (PB) treatment. AEDs that induce P450 enzymes accelerate vitamin D catabolism. Reduced vitamin D levels cause a compensatory secondary hyperparathyroidism. This results in increased bone turnover and loss of cortical bone that in severe cases causes rickets and painful osteomalacia. The secondary hyperparathyroidism is usually subtle and may be detected by assessing serum calcium, phosphorus and alkaline phosphatase, and urinary calcium. Measurement of bone mineral density by dual energy x-ray absorptiometry (DEXA) at the hip, spine, and radius also can help to suggest secondary hyperparathyroidism. Patients at <1–2.5 standard deviations below normal are considered to have osteopenia, whereas patients 2.5 standard deviations below normal have osteoporosis. Reductions in bone density have been shown for a number of enzyme-inducing AEDs. These AEDs induce the P450 enzyme system, which results in increased catabolism of vitamin D. Lowered vitamin D levels results in secondary hypoparathyroidism, which increases bone turnover and results in lowered bone density. Non–enzyme-inducing AEDs, however, also can result in osteopenia. Early observations of reduced density in patients with primary generalized idiopathic epilepsy were made after valproate (VPA) treatment 5. Furthermore, recent cross-sectional studies in patients taking enzyme-inducing AEDs found reduction in bone density in the absence of vitamin D deficiency 6, 7. Calcium and vitamin D supplementation alone, although necessary to meet normal nutritional guidelines, may be inadequate in preventing bone loss in epilepsy. Bone loss associated with other chronic diseases and other bone-depleting medication has prompted a search for more aggressive therapeutic interventions 4. Osteoporosis can be effectively treated with the bisphosphonates 4. These agents disrupt osteoclastic bone resorption by causing apoptosis of osteoclasts. Oral bisphosphonates are typically administered daily. Third-generation intravenous agents, such as zoledronic acid, can be just as effective when administered once annually. Potential therapeutic interventions, however, clearly require randomized prospective studies. Variables that might be addressed in such trials include (a) the impact of AED monotherapy and polytherapy on the attainment of peak bone mass in adolescence and subsequently during the plateau years; (b) bone health in women, a group that experience the largest fracture rates; (c) characterization of the impact of limitations in physical activity on bone density in patients with epilepsy who have cerebral palsy or those with developmental disabilities/mental retardation; (d) the effect of newer AEDs, some with potentially favorable bone health profiles, on bone metabolism; (e) standardization to include measures of bone density in addition to markers of bone turnover; and (f) the effectiveness of current recommendations for supplementation with calcium and vitamin D. It is not often in our treatment of epilepsy that we think about bone health, although as is increasingly recognized, there is good reason to. Two approaches appear essential. Exploration of effective therapeutic strategies to help maintain bone health in the young and prevent bone loss in the elderly are required. Equally essential, however, is the pressing need to increase awareness of the importance of bone health in epilepsy.