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Objective: This
research aimed to determine the difference between levels of serum calcium,
alkaline phosphatase and bone mineral density based on the treatment duration
of anti-epilepsy drugs in epilepsy children.
Materials
and methods: A cross sectional study was done in pediatric
neurology outpatient department of Sanglah Hospital from May until July 2017.
Forty-three samples were eligible in this study with the inclusion criteria
being 1-11 years old epileptic patient, who were on first line of anti-epilepsy
medicines (carbamazepine, phenobarbital, phenytoin, valproic acid) for 6 months
or more regularly and agreed to join the research. Blood sample for calcium,
ALP level and bone mineral density (BMD) were taken on each sample. Data was
analysed by one way ANOVA for normal distribution variables and Kruskal-Wallis
for abnormal distribution variables.
Results:
Bivariate analysis of one way ANOVA has revealed a significant difference of
calcium levels based on duration of treatment (P=0.028). Post Hoc test showed
the differences of the mean of calcium levels based on duration of treatment
0.28 (P=0.008; IK 95% 0.078-0.481). There were no significant difference of
bone density (P=0.463) and serum ALP (P=0.087) based on duration of treatment.
Conclusion: Long
term antiepileptic treatment may reduce the serum calcium level significantly
without inducing the severe hypocalcemia. Calcium and vitamin D supplementation
should be considered for epileptic patient who are on long duration of
treatment.
Keywords: Alkaline
phosphatase, Anti-epilepsy, Bone mineral density, Calcium, Children
INTRODUCTION
Epileptic patients will need to take anti-epilepsy medication for long
period and have serious risk of any side effects such as the disturbances of
mineral and bone metabolism [1,2]. Epilepsy has strong correlation with
fracture. Some of them are caused by seizure or fall. Side effects of
anti-epilepsy medication (bone metabolism) have been reported since four
decades ago and identified as risk factor of less bone density and calcium
metabolism abnormality [3]. First line anti-epilepsy medicine that related to
bone metabolism disturbance is the enzyme inducer such as carbamazepine,
phenytoin and phenobarbital [4-6]. They induce microsomal enzyme of the liver
and increase catabolism and inactivation of vitamin D. Other drug which is
non-enzyme inducer or enzyme sparing drugs such as valproic acid may have
direct effect on bone by recruiting osteoclast and altering renal function
[4,6,7].
Alkaline phosphatase is a marker of bone forming processed and osteoblast activity. This enzyme is a glycoprotein that is found on the surface of plasma membrane of osteoblast which can be used to predict disturbances of any bone mineralization diseases and disorders [9]. Data of any changes in calcium serum level, alkaline phosphatase level, and bone density in long-term AED treatment was still controversial. Data about the side effects of AED treatment calcium serum level, alkali phosphatase level and bone density in epilepsy children in Indonesia, especially Bali has never been reported. This research aimed to determine the difference between level of serum calcium, alkaline phosphatase and bone density based on the treatment duration of anti-epilepsy drugs in epileptic children.
MATERIALS AND METHODS
This was a cross sectional study performed in
pediatric neurology outpatient department of Sanglah Hospital from May until
July 2017. Inclusion criteria included 1-11 years old epileptic patient, who
were on first line anti-epilepsy medicines (carbamazepine, phenobarbital,
phenytoin, valproic acid) for 6 months or more regularly and agree to join the
research. Exclusion criteria were epileptic patient with severe neurological
deficit, consume regular calcium and vitamin D supplementation during treatment
and received other anti-epilepsy medication, already in puberty period (Tanner
stage 3), under-nourished, had metabolic illness that might affect bone
metabolism such as liver disorder, kidney, hematology, parathyroid,
gastrointestinal, malignancy and consume medication that affect bone metabolism
such as glucocorticoid, bisphosphonate, thiazide, anticoagulant and steroid.
Data recorded include age, gender, body weight, height, number of anti-epilepsy
medication, and duration. The blood samples were taken for calcium and ALP
level and bone mineral density (BMD) in the same day. Serum calcium level
measured by immuno-radiometric assay Roche/Hitachi cobas c 311/501 analyzer.
The ALP level was measured by calorimetric method to determine ortho-phosphoric
monoester phospho-hydrolase at the serum. The BMD was checked by trained
radiographer with scan dual-energy X-ray (C.B.D. DEXA) GE Healthcare en CORE
2007. All of the measurements were done in Pathology clinic lab and radiology
department of Sanglah Hospital Bali. All of the data gathered were analysed
using SPSS 22.0 software. Normality data test using Shapiro-Wilk followed by
one way ANOVA for normal distribution variables and Kruskal-Wallis for abnormal
distribution variables. This research has been approved by Ethical Commission
of FK UNUD/RSUP Sanglah Denpasar Bali.
RESULTS
There were 68
epileptic children who came to pediatric neurology outpatient department of
Sanglah Hospital. Ten subjects had severe cerebral palsy, five subjects had
congenital hypothyroidism, five subjects had just started treatment, three
subjects had puberty (Tanner 3 stage), two subjects had refused to join the
study. At the end, there were 43 subjects
fulfilled the inclusion criteria. Twenty-seven (56.2%) subjects were male
(mean, 6.7 years old). Out of 43 subjects, 14 subjects were on antiepileptic
drugs for 6 months – 1 year duration of treatment, 13 subjects for 1-2 years,
and 16 subjects for more than 2 years. Median of treatment duration was 20.1
months. Most of them (60.4%) took non-inducer AED (anti-epilepsy drug) and 17
patients (39.6%) took inducer AED. As many as 37 (86%) subjects only took one
medication (monotherapy). Subject characteristic described in (Table 1).
Bivariate
analysis of one way ANOVA revealed the significant differences of calcium level
based on duration of treatment (p=0.009). Post Hoc test showed significant
differences of the mean of calcium level based on duration of treatment between
6 months to 1 year of treatment with >2 years AED treatment (p=0.003; CI 95%
0.12-0.53). There was no significant difference of bone density (p=0.463) and
serum ALP (p=0.087) based on duration of treatment (Table 2).
DISCUSSION
Bone and mineral metabolism disturbances
caused by side effect of AED threatened millions of epileptic patient
especially in children who have growth spurt [10]. Antiepileptic medicines such
as carbamazepine induce cytochrome P450 enzyme in liver to increase vitamin D
conversion into inactive metabolite. This may decrease calcium absorption in
intestine that leads to hypocalcemia and high level of parathyroid hormone.
Secondary hyperparathyroidism can be detected by low serum calcium and
phosphorus and high level of alkaline phosphatase [8].
This study revealed significant differences
of serum calcium level based on duration of treatment. Children who took more
than 2 years of AED, significantly had lower calcium level (0.28 mg/dl) than
those who took 6 months to 1 year treatment. The mean serum of calcium level
(8.8-10.8 mg/dl) showed descending trend as treatment progressed, however it
was still in normal range in children who were 1-12 years old. These results
are statistically significant but not in clinical. This research is correlated
with previous studies that reported hypocalcemia in epileptic patient with long
duration of treatment with incidence of 3-30% [11-13].
This study revealed decreased level of
calcium after 2 years of treatment without induced hypocalcemia. Human body has
compensation mechanism to keep calcium homeostasis in serum, by calcium in food
or bone resorption [13]. Several previous studies found bone metabolism
disturbance after long duration of treatment especially after non-inducer AED
usage [14,15]. A meta-analysis study by Zhang et al showed long term effect of
anti-epilepsy medication to lumbal, trochanter, femoral neck and overall bone
density [16]. It is suspected in enzyme inducer (activation of cytochrome P450)
cause lower level of vitamin D [8]. In non-inducer AED such as valproic acid,
there is an activation of pregnane X receptor which promotes gene expression of
vitamin D [17]. Anti-epilepsy drugs also reduce calcium absorption and vitamin
D activation in intestine [7]. The subjects of this study mostly used non
enzyme inducer monotherapy with 20 months’ median duration of treatment [18].
Serum alkaline phosphatase can be used as
biochemical marker of bone mineralization. A meta-analysis study showed that
children who consumed AED had increased level of ALP, but only those who
consumed carbamazepine and newer class of AED. ALP might show liver metabolism
more than bone metabolism [16]. Voudris et al. [19] suggested isoenzyme of ALP
measurement because higher sensitivity and specificity. This study did not find
any significant differences of serum ALP and duration of treatment. This study
has several limitations. We did not calculate the number of calcium intake,
vitamin D level, parathyroid hormone level, sunlight exposure, that also affect
bone metabolism. We also did not measure the liver function test that might
affect serum ALP. This was a cross sectional study which was unable to prove
the causal relationship and natural history of illness.
CONCLUSION
Long term antiepileptic treatment may reduce
the serum calcium level significantly without inducing the severe hypocalcemia.
Calcium and vitamin D supplementation should be considered for epileptic
patient on long duration of treatment. We confirm that we have read the
Journal’s position on issues involved in ethical publication and affirm that
this report is consistent with those guidelines.
DISCLOSURE
Neither of the authors has any conflict of
interest to disclose.
KEY POINTS
·
Epileptic
patients will need to take anti-epilepsy medication for long period and have
serious risk of any side effects such as the disturbances of mineral and bone
metabolism.
·
First
line anti-epilepsy medicine that related to bone metabolism disturbance is the
enzyme inducer such as carbamazepine, phenytoin and phenobarbital.
·
Those
induce microsomal enzyme of the liver and increase catabolism and inactivation
of vitamin D, others may have direct effect on bone by recruiting osteoclast
and altering renal function.
·
Long
term antiepileptic treatment may reduce the serum calcium level significantly
without induced the severe hypocalcemia.
·
Calcium
and vitamin D supplementation is considered for epileptic patient with long
duration of treatment.
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377-383.
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levels and bone turnover in epilepsy patients taking carbamazepine or
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