Correlation Between Calcium Serum Levels and Bone Mineral Density with Duration of Antiepileptic Drugs Uses in Children with Epilepsy I

Published by Oriental Scientific Publishing Company © 2018 This is an Open Access article licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License (https://creativecommons.org/licenses/by-nc-sa/4.0/ ), which permits unrestricted Non Commercial use, distribution and reproduction in any medium, provided the original work is properly cited. Correlation Between Calcium Serum Levels and Bone Mineral Density with Duration of Antiepileptic Drugs Uses in Children with Epilepsy

Antiepileptic drugs (AEDs) include sodium valproate (VPA), phenobarbitone (PB), phenytoin (DPH), and carbamazepine (CBZ) is widely used to control seizure in epilepsy.These drugs are commonly used for a long time.Recently, the longer uses of AEDs are related to mineral and bone metabolism disorders.][3] The drugs such as CBZ, DPH, and PB are known for inducing the activity of hepatic oxidase throughout the enzyme microsomal (P450).5][6] This VDD inhibit intestinal calcium transport and absorption, that causing hypocalcaemia. 7The other mechanism of the AEDs is act directly on bone cells that influence bone formation and resorption.][9][10] Other AEDs such as VPA that is descriptively termed as hepatic noninducers affect bone metabolism by unclear mechanism.
In our pediatric department the most common use of AEDs are VPA, CBZ, DPH, and PB as a single or multiple therapies to control seizure in pediatric epilepsy.Until now, there is no routine investigation of most common abnormalities of laboratory in relation to chronic use of AEDs such as hypocalcaemia, hypophosphatemia, increased of alkaline phosphatase (AP), increased parathyroid hormone (PTH), and decreased 25-hydroxy vitamin D (25OHD) in our department.The study evaluates the correlation of long-term uses of AEDs with calcium serum levels and BMD in epileptic children.

MATERIAL AND METHODS
This correlative study was done to analyses 30 children aged 1-10 years old with epilepsy who were controlled in outpatient Pediatric Neurologic Clinic of Sanglah Hospital Denpasar Bali, between July and September 2016.Ethic Committee of Udayana University -Sanglah Hospital Denpasar Bali, approved this study and all subjects were signed in the informed consent.
Inclusion criteria were children aged 1-10 years old; use of first line AEDs (VPA, CBZ, DPH or PB) for 6 months or more; and agreed participating in this study.Exclusion criteria were epileptic children with cerebral palsy; receive calcium and vitamin D supplementation during therapy; severe malnutrition; and suffer from the illness that were known affecting bone metabolism including hepatic, hematologic, rheumatologic, renal, parathyroid, musculo-skeletal, thyroid, and gastrointestinal disorders or using medications that were known affecting bone turnover such as glucocorticoids, bisphosphonates, thiazides, anticoagulants, or steroids.
Demographic data of all subjects such as age, body weight, body height, gender, and history of the disease previously, history of the drugs consumption, history of the epilepsy and its therapy were collected from medical record.Nutritional status was determined using the WHO growth standard.Severe malnutrition was defined if weight-for height z scores less than -3SD.On the same day, blood samples and radiologic imaging were evaluated for measurement of calcium levels and bone mineral density.Levels of calcium serum was measured using immunoradiometric assay Roche/Hitachi Cobas c 311/501 analyzer and scan dual-energy X-ray (C.B.D.DEXA) GE Healthcare en CORE 2007 for measurement bone mineral density.Both laboratory and imaging measurement were done in Clinical Pathology and Radiology Department of Sanglah General Hospital Denpasar Bali.
The data were analyzed using SPSS 20.The variables of duration of AEDs used, calcium serum levels, and bone mineral density were analyzed initially by normality test of Shapiro Wilk.The Pearson correlation test was done between two continuous variables with normal distribution of the data.Significantly suggested if P value < 0.05.

Fifty-five children with epilepsy came to outpatient of Pediatric Neurology Clinic Sanglah
Hospital during study period.Twenty-five children were excluded.Among of them, ten children had cerebral palsy, five children had hypothyroid congenital, three children had puberty, five children used AEDs less than 6 months, and two children refused to participate.The characteristics of subjects are showed in Table 1.
Figure 1a and Figure 1b showed the correlation between duration use of AEDs and calcium serum levels and BMD.Duration use of AEDs showed moderate negative correlation with calcium serum levels (r = -0.493;P = 0.006), while

DISCUSSION
We have evaluated 30 children (18 boys and 12 girls) with epilepsy with their mean of age were 8.5 years old.Most of subjects used single AEDs, especially enzyme inducers AEDs such as CBZ, DPH, and PB.Its mean that first line AEDs that is classified as an enzyme inducer is commonly used in our department.These results were similar with another study that commonly used enzyme inducer AEDs for the epileptic patients, but mostly on multiple drugs regimens. 11In our department, multidrug AEDs are used if single AEDs cannot control the seizures during three months period of the treatment.In this study only six of 30 subjects received multidrug AEDs.The combination is commonly among enzyme inducer AEDs such as CBZ combine with PB or between enzyme inducer combine with non-enzyme inducer such as CBZ combine with VPA.
Both of enzyme inducer and noninducer AEDs causing abnormalities of vitamin D metabolism.5][6] Vitamin D is a pro-hormone that is metabolized in the liver and kidney to become an active metabolite. 12Enzyme inducer of AEDs inhibit the conversion of D vitamin in liver cells.1]13 This study found that chronic use of AEDs was significantly having a moderate negative correlation with concentration of calcium serum.It means that the longer use of AEDs the lower levels of calcium serum.5][16] The possible mechanisms of AEDs causing hypocalcaemia are stimulate catabolism of D vitamin, inhibits parathyroid hormone to induce calcium mobilization, and decrease dietary calcium absorption. 16alcium and also D vitamin are an important micronutrient in developing and also maintaining bone health.2][13] The enzyme inducer AEDs stimulate hepatic cytochrome P450 to inactivated vitamin D. Inactivated vitamin D decrease calcium absorption in intestinal tract, and causing hypocalcaemia and increase circulating of parathyroid hormone.Parathyroid hormone increase mobilization of calcium from the bone that causing low BMD. 14nfortunately, our study showed weak negative correlation between duration of the AEDs treatment and bone mineral density and statistically not significant.Our study mostly uses enzyme inducer AEDs, mono-therapy, and median duration of the AEDs treatment is 20.5 months.So the possibility reasoning of these results are mostly mono-therapy and less than 2 years of the AEDs uses.

CONCLUSION
It could be concluded that chronic use of AEDs having a moderate negative correlation with concentration of calcium serum and weak negative correlation with BMD.

Table 1 .
Characteristics subjects