Indian J Pediatr DOI 10.1007/s12098-014-1518-0
ORIGINAL ARTICLE
Bone Mineral Density in Ambulatory Children with Epilepsy Omid Yaghini & Seyed Hasan Tonekaboni & Seyed Mohammad Amir Shahkarami & Farzad Ahmad Abadi & Fakhredin Shariat & Fatemeh Abdollah Gorji
Received: 8 December 2013 / Accepted: 12 June 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Objective To elucidate the effects of antiepileptic drugs (AEDs) on bone health status of ambulatory epileptic children. Methods A total of 120 epileptic children aged 2–15 y were enrolled in three groups. The first group was on therapy with carbamazepine, phenobarbital or primidone. The second was treated with valproic acid and the third group was untreated. Serum calcium, phosphorous, total alkaline phosphatase, and parathyroid hormone levels were compared between groups. Bone mineral density tests were also performed at four sites of the lumbar spine and three sites of femoral neck and results were compared between the groups.
Results Of all enrolled subjects, 67 patients (55.8 %) were vitamin D deficient. The three groups were not significantly different in terms of vitamin D, calcium, phosphorus, total alkaline phosphatase, and parathyroid hormone levels. While patients in first group had lower Z-score of femoral neck and lumbar spine compared to those on valproic acid, these values were also significantly different than that of the third group. Conclusions It can be concluded that both enzyme-inducing AEDs and non enzyme-inducing AEDs decrease bone mineral density (BMD). Also alkaline phosphatase (ALP) is affected in ambulatory epileptic children on enzyme-inducing AEDs. Nevertheless, valproic acid (a non-enzyme-inducing agent) does not have the mentioned side effects.
O. Yaghini Pediatric Neurology Unit, Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran
Keywords Antiepileptic drugs . Bone mineral density . Vitamin D . Epilepsy . Children
S. H. Tonekaboni Pediatric Neurology Unit, Department of Pediatrics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Introduction
S. M. Amir Shahkarami Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran O. Yaghini : S. M. Amir Shahkarami Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran F. Ahmad Abadi Pediatric Neurology Unit, Department of Pediatrics, Ardabil University of Medical Sciences, Ardabil, Iran F. Shariat Pediatric Neurology Unit, Department of Pediatrics, Arak University of Medical Sciences, Arak, Iran F. Abdollah Gorji Department of Statistics, Shahid Beheshti University of Medical Sciences, Tehran, Iran S. H. Tonekaboni (*) Department of Pediatric Neurology, Mofid Children Hospital, Dr.Shariati Ave., Tehran, Iran e-mail:
[email protected]
About one percent of children worldwide suffer from various types of epilepsy and usually require long-term treatment with antiepileptic drugs (AEDs) [1]. The association of skeletal abnormalities with chronic antiepileptic therapy was first described about three decades ago and most of the available data is from adults [2]. AEDs associated osteopathy includes decreased bone mineral density (BMD), increased fracture risk, and overt osteomalacia [2]. Although the skeletal consequences of antiepileptic drugs may vary, the AEDs, especially enzyme-inducing drugs such as phenobarbital, primidone, phenytoin, and carbamazepine are generally known to alter bone metabolism [3, 4]. Subjects on enzyme-inducing AEDs are expected to have lower BMD compared to those on non-enzyme-inducing medicines such as valproic acid in which the hepatic cytochrome P450 enzyme system remains intact [3, 4]. Unpleasant side effects of AEDs on calcium metabolism and bone density were primarily reported in institutionalized
Indian J Pediatr
patients [5]. It is difficult to separate the effects of AEDs from numerous confounding variables in institutionalized patients, including inadequate diet, exercise, and sunlight exposure. As the AEDs effects are confounded with other many variables in different groups of patients, bone and mineral metabolism in ambulatory subjects with epilepsy (i.e., subjects who are able to walk) raises more questions and is the main focus of studies in this field. Consequently, BMD in an adult ambulatory outpatient population receiving AEDs was assessed in other studies. It was shown that bone changes occur not only in institutionalized patients, but also in ambulatory adult subjects [6, 7]. However, the majority of studies have mainly assessed adult patients and changes in calcium metabolism among children receiving AEDs are not fully clear. The present study was designed to determine the effects of various types of AEDs on bone and calcium metabolism in ambulatory children. Therefore, ambulatory epileptic children on various anticonvulsants were selected to elucidate the effects of AEDs on bone health status in an Iranian child population.
Material and Methods A total of 120 Iranian children with epilepsy (age: 2–15 y) who were referred to authors’ neurology outpatient clinic during January-March 2011 were enrolled in this retrospective study. The patients were categorized to three distinct groups. The first group included subjects who had received at least 6 mo of enzyme-inducing AEDs i.e., carbamazepine (CBZ), phenobarbital (PB) or primidone (PRM) and in the second group the patients on therapy with a non-enzyme-inducing AED; valproic acid (VPA) were categorized. Patients who received both enzyme-inducing and non-enzyme-inducing agents were considered in the first group. Epileptic children who had not been treated with any kind of AEDs before the study were allocated to the third group (control group). Various reasons had caused these epileptic patients in the third group to remain untreated. Some of these patients had new onset epilepsy and some others were untreated due to non-compliance to treatment with AEDs or delayed diagnosis. It must be noted that the present study was retrospectively designed and patients in 3 groups were categorized according to their past drug history until the time of referring to authors’ neurology outpatient clinic and entrance to the study. The time-point in which the patients had a blood draw or other lab studies, was at presentation and entrance to the study. For example, at the time entrance to the present study (at the time of blood draw), patients in group 3 would have been on an AED for at least 6 mo. All subjects were on regular diet and those with evidence of malnutrition or failure to thrive were excluded. Moreover, individuals with Tanner stage 3 or higher were excluded.
Subjects with any renal, hepatic, endocrine, and boneaffecting metabolic diseases were not included. All patients were able to walk normally without any supportive devices but none had athletic or professional levels of physical activity. In addition, the patients were enquired about the medications they had used during the past 6 mo. Children with known risk factors of decreased bone density, namely diseases or medications proven to affect calcium metabolism or bone mass, and those who had received any form of calcium and vitamin D either as a part of treatment or as supplements were not enrolled in the study. The parents were completely informed about the details of the study and written informed consent was obtained at the beginning of the study. The study protocol was reviewed and approved by the Ethical Committee of Shahid Beheshti University of Medical Sciences (Tehran, Iran). For all patients, BMD of lumbar spine (L1, L2, L3 and L4) and femoral neck was assessed using a dual-energy Xray absorptiometer (DEXA). All BMD measurements were made by a single machine using fast scan mode (C.B.D. DEXA) with strict adherence to the procedures and instructions in the operator’s manual. In this study Z-score for each patient was calculated using the mean and standard deviation (SD) of the peak bone mass in European children and the values were compared between the three groups. After obtaining venous blood samples from all patients, serum was separated and frozen until the time of biochemical analysis. Since the changes in bone metabolism occur as a time dependent function of AED use [8], treatment duration was determined atleast 6 mo at the time that all blood samples were obtained. Calcium (Ca), phosphorous (P), total alkaline phosphatase (ALP), and albumin were measured by standard automated equipment. Total Ca was corrected for serum albumin. Parathyroid hormone (PTH) and serum 25-hydroxy vitamin D were determined using an immunoradiometric assay (DiaSorin Inc., Stillwater, MN; normal range, 13–54 pg/ml) and radioimmunoassay (Biosource, Belgium), respectively. Vitamin D deficiency was defined as vitamin D less than 10 ng/ml in this study [9]. The patients’ body mass index (BMI) was also computed as weight divided by height squared. The anthropometric and BMD data was expressed as the mean and SD. Quantitative values (BMD, age, BMI, and laboratory values) of the three groups were compared using one way analysis of variance (ANOVA). Chi-squared test was employed for comparing qualitative values. All statistical analyses were performed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA). In all analyses, P values of less than 0.05 were considered significant.
Indian J Pediatr Table 1 Comparison of vitamin D status between the epileptic children receiving phenobarbital, carbamazepine, and primidone (the first group), valproic acid (the second group), and the control group
Normal vitamin D (≥10 ng/ml) Vitamin D deficiency (
