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The aim of this study is to assess bone mineral status in children with epilepsy, on different antiepileptic drugs (AEDs) regimen, using dual-energy X-ray absorptiometry (DXA) and routine biochemical bone markers.
This is observational prospective controlled cohort study, conducted at Mansoura University Children Hospital, from January 2014 to June 2015. In this study, we had 152 participants with ages 3–13 years, 70 children diagnosed with epilepsy and 82 were controls. Children classified into two groups according to the duration of treatment, Group 1 children maintained on AEDs for 6–24 months, Group 2 children ≥24 months. Bone mineral density (BMD) measured by DXA and biochemical markers includes serum calcium, phosphorus, alkaline phosphatase (ALP), and parathyroid hormone (PTH).
In this study, we found that the serum level of calcium and phosphate were significantly low (P > 0.05) in total cases versus control. We found that the serum level of and ALP and PTH were significantly high (P > 0.05) in total cases versus control. Regarding the DXA markers, there was a significant decrease of BMD and Z-score for the total body and lumbar area in the total cases versus control (P > 0.05).
The present study showed that all AEDs (new and old) affect bone mineral status in children receiving therapy for more than 6 months, altering both biochemical markers (serum calcium, phosphorus, ALP, and PTH) and radiologic markers (BMD assessed using DXA). Children on AEDs for a longer duration (≥2 years) showed more severe side effects on BMD. Children receiving multiple AEDs are more prone to altered bone mineral status, especially with long duration of therapy. The study also highlights the role of DXA as a safe noninvasive method to assess BMD in children on long-term AEDs.
Epilepsy is the most common serious neurological disorder worldwide, affecting about 50 million people. The cumulative lifetime incidence of epilepsy is 3% and more than half of these cases begin in childhood. Long-term antiepileptic medications have long been known to increase bone turnover and reduce bone mass. Among epileptic children, the effect of older antiepileptic drugs (AEDs) such as phenobarbital, phenytoin, carbamazepine (CBZ), and valproic acid (VPA) on bone mineral status have been examined.[4,5,6,7] However, the effect of new AEDs, including oxcarbazepine (OXC), topiramate (TPM), lamotrigine (LMT), and levetiracetam (LEV) on bone metabolism in epileptic children have not been well established.[8,9]
The aim of this study is to assess bone mineral status in children with epilepsy receiving different regimens of AEDs through evaluation of routine biochemical parameters of bone metabolism and bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry (DXA) technology.
This is observational prospective controlled cohort study. The study included 70 children who had an established diagnosis of epilepsy with age range between 3 and 13 years (mean age 7.7 ± 3.2 years), 41 male. Compared to control group of 82 healthy children who were recruited from general out-patient clinics coming for routine checking or minor illnesses. They were age-, sex-, and socioeconomic status matched to epileptic children. The diagnosis of epilepsy was based on the clinical history and electroencephalography (EEG). Seizure types were described according to the International League Against Epilepsy criteria.
Patients were recruited from the pediatric neurology outpatient clinic of Mansoura University Children Hospital, Mansoura, Egypt, during the period between January 2014 and June 2015. We included in this study, subjects who were already on one or more AED for at least 6 months. Table 1 shows the demographical and clinical features of the studied patients.
All children included in the study having the average diet guided by their socio-economic status, children on special diet were excluded from the study. In addition, we exclude children with a history of the medical disorder, which likely affect bone metabolism (e.g., endocrinal, hepatic, renal, hematological, rheumatologic, and gastrointestinal diseases). In addition, children on medications known to affect bone metabolism (e.g., steroids, diuretics, Vitamin D, and calcium supplements), history of fractures or a known bone disorder, and the presence of physical impairments or neurological deficits that interfere with normal age appropriate activity.
Based on the utilized AEDs regimen, patients were divided into five different drug groups: 21 patients were on valproate (VLP), 10 patients on TPM, 10 patients on OXC and 9 patients on LEV monotherapy and 20 patients were on polytherapy.
In addition, according to the duration of AED therapy, children with epilepsy were divided into two groups; Group 1, children with therapy duration 6–24 months and Group 2, children with therapy duration >24 months.
All patients and healthy control subjects underwent the same research protocol. Informed consent was obtained from parents of all study participants before enrollment. The Local Ethics Committee approved the study protocol.
Data collection included age, sex, weight, height, and body mass index calculation (weight in kg divided by height squared in m2). Seizure-related variables recorded were age at onset, duration of treatment, type and frequency of seizure, type of utilized AED(s) (monotherapy or polytherapy), the degree of patients' control on AED(s), and obvious side effects from medications. Regarding the degree of control on AEDs, patients were considered controlled on AEDs, when seizure free for the past 6 months.
BMD at the lumbar spine (L2–L4) and total body (TB) were measured using dual photon X-ray absorptiometry (DXA; Lunar DPX IQ-USA, software version 4.5, DPX Series YZB/USA 2099). All scans were performed at Endocrinology and Diabetes Unit, MUCH by the same technologist.
Results for BMD were expressed as absolute values (g/cm2), then BMD Z-score was calculated (number of standard deviation [SD] score from mean BMD of 352 healthy age- and sex-matched Egyptian controls).[11,12,13]
Biochemical parameters used for evaluation of bone metabolism included; serum levels of calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and parathyroid hormone (PTH) at the time of examination.
Statistical analysis conducted using SPSS 17. Values are described as mean ± SD. Comparison between the control groups and the different therapy groups and between polytherapy and different monotherapy regimens using one-way ANOVA with least significant difference post hoc test with significance described as P < 0.05.
In this study, we had 152 participants, 70 of these children were diagnosed with epilepsy based on the clinical history and EEG. They were on different regimens of AED therapy, the mean age (7.7 ± 3.2 years), 41 male. There were 43 children diagnosed with a generalized seizure, whereas the other 27 children had partial seizures. According to drug therapy, there were 21 children on VLP monotherapy, 10 children on TPM,10 children on OXC, 9 children on LEV and 20 children were on polytherapy (more than one AED). The other 82 were normal children as control group [Table 1].
In this study, the biochemical and DXA markers were studied for total cases versus control group, and we found that the serum level of calcium and phosphate were significantly low (P > 0.05) in total cases versus control. We found that the serum level of ALP and PTH were significantly high (P > 0.05) in total cases versus control. Regarding the DXA markers, there was significant decrease of BMD and Z-score for the TB and lumber area in the total cases versus control (P > 0.05) [Table 2].
In this study, we classify patients into different groups according to the type of AEDs, we found that the lowest serum calcium, phosphorus, and ALP were for patients receiving TPM monotherapy, whereas there were significantly high PTH for patients receiving LEV. On regards to DXA, we found statically significant decrease on BMD and Z-score for children receiving both TPM and LEV on comparison to other groups [Table 3].
In this study, regarding the biochemical profile, we found that there were the statistically significant difference (low Ca, P, ALP, and high PTH) for children receiving AEDs more than 24 months in comparison to those receiving treatment <24 months. The most significant changes were for children receiving polytherapy >24 months [Table 4].
Regarding DXA study, we found that significant differences (less lumber and total Z-score) between children receiving AEDs for periods <24 months and those receiving treatment equal to or more than 24 months.
The bone diseases associated with the use of AEDs are emerging as serious health threat for millions of people, especially in childhood, which is the most important period for bone development. Studies have reported variable changes in BMD and variable changes of different biochemical markers in children taking AEDs.[15,16,17,18]
In this study, we found that the serum level of calcium and phosphate were significantly low (P > 0.05) in total cases versus control, whereas the serum level of ALP and PTH were significantly high (P > 0.05) in total cases of epileptic children versus control. Regarding the DXA markers, there were significant decrease of BMD and Z-score for the TB and lumber area in the total cases versus control (P > 0.05), which means that all children receiving AEDs for periods of 6 months or more have significant alteration of biochemical and radiologic markers regardless the type and number of AEDs.
In the study of Rauchenzauner et al., they found that AED monotherapy does not lead to Vitamin D deficiency in otherwise healthy children treated with nonenzyme inducing AEDs (VPA, LMT) or minimal enzyme-inducing AED (OXC). In spite of this, they found altered bone profile (increased PTH) and bone metabolism in children treated with VPA monotherapy for duration longer than 6 months. Shellhaas et al. found that Vitamin D insufficiency was highly prevalent in unselected population of children with epilepsy included in their study, regardless the type of AED. In this study, newer AEDs (LEV, TPM) significantly alter both biochemical and DXA Markers, this observation gives us attention about bone mineral status in children on newer AEDs, as most of the studies lacking new AEDs. Meta-analysis study performed by Zhang et al., suggests that treatment with AEDs may be associated with decreased BMD in epileptic children. In this study, as we found that the longer the duration (≥2 years) of AEDs, the more severe effects on BMD, assessed by both biochemical markers (low Ca, P, and high ALP, PTH) and confirmed by DXA markers (low lumber and total Z-score). Furthermore, more side effects appear especially for children on multiple AEDs for long duration ≥2 years. Zhang et al. suggest AEDs affect bone metabolism by reducing 25-hydroxyvitamin D. Low 25-hydroxyvitamin D concentration results in secondary hyperparathyroidism and accelerated bone loss, influencing the absorption of calcium and phosphorus. This suggestion is strengthened by our results that confirmed lower serum calcium increased ALP and PTH in children receiving AEDs for more than 6 months.
While total ALP is considered a reliable marker of bone formation. Zhang et al. found increased serum ALP is associated with the use of CBZ and new AEDs and not with VPA, indicating that total ALP is inadequate marker of bone metabolism. Other studies consider ALP isoenzyme more sensitive and specific to bone metabolism.[20,21] The relationship between Vitamin D status and bone density in epileptic children still unclear. Some studies suggest positive relation; others found no direct relation between high- and low-dose supplementations of Vitamin D to epileptic children compared to healthy controls.[22,23]
In the recent longitudinal study by Lee et al., of 143 epileptic children exposed to AEDs for 2 years, they conclude that a high proportion of these children on AEDs had hypovitaminosis D and a significant decrease between the initial and the last follow-up. Polytherapy and longer duration of AEDs, tube feeding and overweight were independently associated with a longitudinally significant decrease of 25-hydroxy Vitamin D. The underlying pathophysiologic mechanisms are poorly understood, but are probably multifactorial. Old AEDs (e.g., CBZ) are cytochrome P450 enzyme inducer, thereby alter Vitamin D metabolism, whereas VPA and new AEDs are nonenzyme inducers or minimal enzyme inducers.
Thus, other mechanisms are suggested for altered BMD in children receiving nonenzyme inducing AEDs which needs future researchers.
This study showed that all AEDs (new and old) affect bone mineral status in children receiving therapy more than 6 months, altering both biochemical markers (Ca, P, ALP, and PTH) and BMD assessed by DXA. Children on AEDs for a longer duration (≥2 years) showed more severe side effects on BMD. Children receiving multiple AEDs are more prone to altered bone mineral status, especially with long duration of therapy. The routine biochemical markers (Ca, P, ALP, and PTH) seem to be less sensitive and less specific. New bone markers, which are more sensitive and specific, could be considered in future researches. DXA scan, which is sensitive and specific tool to assess BMD, can be used in selected high-risk children on AEDs. We recommend, assessing bone mineral status in all children on AEDs for duration ± 6 months therapy, with more attention to children on AEDs ≥2 years, especially those on multiple AEDs.
The numbers of children included in each subgroup limits this study, and we recommend that larger scale study with long-term follow-up for more accuracy.
There are no conflicts of interest.