Effect of Carbamazepine Therapy on Vitamin D and Parathormone in Epileptic Children

doi:10.1016/j.pediatrneurol.2010.05.013

Pediatric Neurology

Volume 43, Issue 5, November 2010, Pages 320-324

https://doi.org/10.1016/j.pediatrneurol.2010.05.013 Get rights and content

Evidence suggests that carbamazepine affects bone metabolism by altering vitamin D status. We prospectively compared 25-hydroxyvitamin D, parathormone, calcium, phosphorus, and alkaline phosphatase levels at initiation and 6 months of carbamazepine therapy in children, and correlated them with carbamazepine levels. We included 47 children newly diagnosed with partial epilepsy, initiated on carbamazepine therapy. Of these, 32 were studied for 6 months. Children were managed according to standard protocol. Various parameters were measured at initiation and at 6 months. Carbamazepine levels were estimated after 6 months. Mean age was 6.72 ± 2.22 years S.D. Mean 25-hydroxyvitamin D was 14.45 ± 9.77 ng/mL S.D. and 11.31 ± 9.15 ng/mL S.D. at baseline and 6 months (P = 0.023), respectively (21.7% decline). Mean parathormone increased from 34.24 ± 21.38 pg/mL S.D. to 45.01 ± 24.46 pg/mL S.D. (P = 0.001). Change in vitamin D correlated negatively with change in parathormone (r = −0.404, P = 0.022). Serum alkaline phosphatase increased from 283.50 ± 100.10 IU/L S.D. to 364.25 ± 126.98 IU/L S.D. (P < 0.001). Changes in vitamin D and parathormone did not correlate significantly with carbamazepine level. Carbamazepine therapy decreased levels of vitamin D. Hence vitamin D monitoring and supplementation may help prevent alterations in bone metabolism.

Introduction

The cumulative lifetime incidence of epilepsy is 3%, and more than half of these cases begin in childhood. Partial seizures account for up to 40% of childhood seizures [1]. Carbamazepine is the most commonly used drug in the management of epilepsy in India [1]. Long term antiepileptic therapy is known to alter bone metabolism in children, and vitamin D deficiency is frequently cited as a cause of decrease in bone mineral density in these patients. Carbamazepine, which induces a liver enzyme (CYP 450), has the potential to affect bone metabolism and vitamin D status. Reports of hypovitaminosis D associated with carbamazepine in children have been conflicting. Various studies indicated that carbamazepine therapy can cause hypovitaminosis D [2], [3], [4], [5], whereas a few studies reported that carbamazepine therapy is not associated with alterations in bone mineral metabolism and hypovitaminosis D [6], [7], [8], [9]. Most of these studies were conducted in a mixed population of epileptic children. Hence, this study prospectively evaluated changes in vitamin D level and other biochemical markers of bone mineralization (calcium, phosphorus, alkaline phosphatase, and parathyroid hormone) in ambulatory children with partial epilepsy, receiving carbamazepine monotherapy.

Section snippets

Materials and Methods

This prospective study was performed in a tertiary care referral hospital. Children aged 2-12 years, and presenting with partial seizures and motor signs at pediatric emergency departments, were enrolled in the study and followed for 6 months. This study was approved by the Ethics Committee of the University College of Medical Sciences.

After obtaining written consent from patients' parents or guardians, we collected detailed histories regarding types of seizure, any previous drug intake, any

Results

Of 47 children, the comparative data of 32 children (18 boys and 14 girls) followed for 6 months were analyzed. Fifteen children were excluded, 11 children were lost to follow-up, one child died in a traffic accident, two children developed drug reactions and shifted to valproate, and one child was diagnosed with tuberculoma and commenced antitubercular therapy.

The weight, height, and body mass index of all patients fell between the 10th and 90th percentiles. The clinical characteristics of the

Discussion

With current estimates of 50 million people worldwide manifesting epilepsy, together with a rapid increase in the use of antiepileptic medications for other indications, the bone disease associated with the use of antiepileptic medications is emerging as a serious health threat for millions of people, especially in childhood, which is the most critical period of bone development [11]. Both parathormone and vitamin D play important roles in the development and maintenance of bone mass by

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Cited by (43)

Sex differences in side effects of antiseizure medications in pediatric patients with epilepsy: A systematic review
2022, Seizure
Citation Excerpt :
Thirty-two patients (18 males and 14 females) were enrolled. It was reported that CBZ treatment negatively affects vitamin D levels, in particular, this change was significantly more pronounced in female subjects (p = 0.03) [54]. Two studies evaluated the occurrence of kidney stones in patients treated with TPM [56,57].
To perform a systematic review searching for differences in the side effects of antiseizure medications (ASMs) with respect to sex in pediatric patients with epilepsy.
We carried out a comprehensive literature search of the PubMed database and all results up to April 2020 were included. Titles, abstracts, and full texts of the articles were screened by two independent reviewers. We included all studies evaluating the side effects of ASMs in patients with epilepsy younger than 18 years, with reference to the two sexes. Studies on ASMs used for indications other than epilepsy were excluded.
A total of 5164 studies were identified. Sixty-seven studies were finally included, 5 of them also including adult patients in the sample. Sixteen studies revealed sex-related differences in side effects of ASMs, disclosing a higher frequency of general side effects in girls: a higher risk of overweight, hyperammonaemia, high leptin levels, and carnitine deficiency in girls on valproic acid; a lower height increase, an increased risk of weight loss, the anecdotical occurrence of acute psychosis in girls on topiramate; a higher risk of retinal toxicity in boys on vigabatrin.
The effect of sex on susceptibility to side effects of ASMs is poorly investigated with sparse results, and it could be underestimated. The findings of our study point to the presence of sex differences which should be thoroughly investigated to be confirmed, highlighting the need for a systematic evaluation of sex as a determinant variable influencing the response to medications in clinical research.
Impact of carbamazepine on vitamin D levels: A meta-analysis
2021, Epilepsy Research
Citation Excerpt :
A host of cross-sectional studies have been done, with most, but not all, showing reduced 25OHD levels in CBZ-treated patients. A study on healthy male volunteers showed no change in 25OHD levels or other markers of bone metabolism over the course of 10 weeks treatment (Bramswig et al., 2003), and no decrease in 25OHD levels was found when 32 children were studied after six months of CBZ treatment (Misra et al., 2010). To definitively assess what current data reflect regarding this issue, we performed a meta-analysis of controlled studies in which 25OHD levels were measured in epilepsy patients treated with CBZ.
There are longstanding concerns about the impact of enzyme-inducing anti-seizure medications (ASMs) on vitamin D, an important molecule in both bone metabolism and inflammation pathways. The relationship between chronic use of carbamazepine and vitamin D levels has been studied, but no comprehensive review to inform practitioners and policymakers is currently available. We performed a meta-analysis on studies that measured 25-hydroxyvitamin D (25OHD) levels in persons taking carbamazepine to determine whether this drug significantly reduces circulating 25OHD.
From a literature search of the terms “carbamazepine” and “vitamin D”, we identified 12 studies that measured 25OHD levels in persons on carbamazepine monotherapy groups and controls. Persons taking carbamazepine had significantly lower 25OHD levels than persons not taking carbamazepine. The average 25OHD levels of carbamazepine-treated patients across all studies was 21.8 ng/mL (IQR 15.4,26.0) whereas 25OHD levels of control subjects was 28.0 ng/mL (IQR 20.8,30.4). The weighted difference of means was 4.00 ng/mL of 25OHD. Neither age nor sex nor duration of carbamazepine therapy had a significant impact on this finding. The effect was similar irrespective of whether the comparator group consisted of healthy controls or epilepsy patients taking non-inducing medications.
Carbamazepine use is associated with a reduction of 25OHD levels. In combination with other literature establishing the problematic metabolic effects of carbamazepine, this meta-analysis provides additional evidence in favor of the use of alternative ASMs as first-line agents. At minimum, vitamin D supplementation should be strongly considered for patients prescribed carbamazepine.
A vitamin D enriched diet attenuates sex-specific behavioral deficits, increases the lifespan, but does not rescue bone abnormalities in a mouse model of cortical dysplasia
2021, Epilepsy and Behavior
Individuals who experience recurrent spontaneous seizures often show behavioral and physiological comorbidities. Those with epilepsy are at a high risk of bone fractures (independent of seizure-related falls) and show a higher rate of a diagnosis of Autism Spectrum Disorder. The neural subset-specific (NS) Pten knockout (KO) mouse has an epilepsy phenotype, has been characterized to show autistic-like deficits, and has an osteoporosis phenotype. The current study examined the effect of a vitamin D enriched diet (20,000 IU VD) in the NS-Pten KO and wildtype mice. Mice were placed onto a vitamin D enriched diet at 4 weeks of age and maintained on that diet throughout testing. Behavioral testing began at 6 weeks of age and included tests for general activity, anxiety, repetitive behaviors, social behaviors, and memory. Results indicated that a vitamin D diet attenuated hypoactivity levels in male KO mice (p < 0.05). In a social partition task, vitamin D increased sociability in male wildtype mice, (p < 0.05). Most significantly, vitamin D fortified diet increased percent survival in KO animals and decreased the level of microglia marker IBA-1 and mTOR (mammalian target of rapamycin) downstream targets pS6 and pAKT. A high vitamin D diet did not reverse bone deficits in male or female KO mice. Overall, these findings suggest that a vitamin D enriched diet had a significant impact on the behavioral phenotype of NS-Pten KO mice, suggesting that dietary manipulations could be a potential therapeutic option for autistic-like behavior.
Vitamin D deficiency in pediatric patients using antiepileptic drugs: systematic review with meta-analysis
2020, Jornal de Pediatria
To measure the prevalence of vitamin D deficiency (through the 25-hydroxyvitamin D metabolite) in pediatric patients using antiepileptic drugs.
Meta-analysis of studies identified through search in the PubMed, Embase, LILACS, and Cochrane Library databases, on February 19, 2019.
A total of 748 articles were identified, 29 of which were relevant to the objectives of this study. The prevalence of vitamin D deficiency found was 0.32 (95% CI = 0.25–0.41; I² = 92%, p < 0.01). In the subgroup analyses, the most significant results were observed in the group of patients using cytochrome P450-inducing antiepileptic drugs, with a prevalence of 0.33 (95% CI = 0.21–0.47; I² = 86%, p < 0.01) and, considering the study design, in the subgroup of cohort studies, with a prevalence of 0.52 (95% CI = 0.40–0.64; I² = 76%, p < 0.01).
Taking into account the deleterious effects of vitamin D deficiency on the bone health of individuals using antiepileptic drugs, it is suggested to include in their care 25-hydroxyvitamin D monitoring, cholecalciferol supplementation, and treatment of the deficiency, when present.
Mensurar a prevalência de deficiência de vitamina D (através do metabólito 25-hidroxivitamina D) em pacientes pediátricos em uso de fármacos antiepilépticos.
Metanálise de estudos identificados por meio de pesquisa nas bases de dados Pubmed, Embase, LILACS e Cochrane em 19 de fevereiro de 2019.
Foram identificados 748 artigos, dos quais 29 mostraram-se relevantes aos objetivos deste estudo. A prevalência de deficiência de vitamina D encontrada foi de 0,32 (IC 95% = 0,25 – 0,41) (I² = 92%, p < 0,01). Nas análises por subgrupos, os resultados mais expressivos foram observados no grupo de pacientes em uso de fármacos antiepilépticos indutores do citocromo P450, que apresentou prevalência de 0,33 (IC 95% = 0,21 – 0,47) (I² = 86%, p < 0,01). Considerou-se o delineamento dos estudos, no subgrupo de estudos de coorte, com prevalência de 0,52 (IC 95% = 0,40 – 0,64) (I² = 76%, p < 0,01).
Levando-se em consideração os efeitos deletérios da deficiência de vitamina D na saúde óssea dos sujeitos em uso de fármacos antiepilépticos, sugere-se incluir em seu atendimento, o monitoramento de 25-hidroxivitamina D, suplementação com colecalciferol e tratamento de deficiência quando existente.
Effects of vitamin D on drugs: Response and disposal
2020, Nutrition
Citation Excerpt :
VD supplementation was found to have significant protective effects on the formation of hepatic nodules, antioxidant enzymes, and DNA damage induced in rats with hepatocellular carcinoma [86]. VD supplementation also improved the development and behavior of autism-like behaviors in rats induced by valproic acid [87], which may be because antiepileptic drugs could lower VD levels in the body and VD supplementation may help improve symptoms caused by VD deficiency [88,89]. Furthermore, cell experiments have shown that calcitriol significantly reduced the activity and proliferation of levodopa (anti-Parkinson drug) on neural stem cells by activating the PI3K signaling pathway and reducing oxidative stress [90].
Vitamin D supplementation and vitamin D deficiency are common in clinical experience and in daily life. Vitamin D not only promotes calcium absorption and immune regulation, but also changes drug effects (pharmacodynamics and adverse reactions) and drug disposal in vivo when combined with various commonly used clinical drugs. The extensive physiological effects of vitamin D may cause synergism effects or alleviation of adverse reactions, and vitamin D's affect on drugs in vivo disposal through drug transporters or metabolic enzymes may also lead to changes in drug effects. Herein, the effects of vitamin D combined with commonly used drugs were reviewed from the perspective of drug efficacy and adverse reactions. The effects of vitamin D on drug transport and metabolism were summarized and analyzed. Hopefully, more attention will be paid to vitamin D supplementation and deficiency in clinical treatment and drug research and development.
Effects of enzyme-inducing antiseizure medication on vitamin D dosing in adult veterans with epilepsy
2020, Epilepsy Research
The association of antiseizure medication (ASM) and bone density abnormalities has long been recognized; however, there remains a lack of consensus on efficacy and optimal vitamin D dosing in patients receiving enzyme inducing and non-inducing ASMs. The objective was to explore the relationship between ASMs and vitamin D supplementation requirements in a population of adult patients with epilepsy.
Patients with a diagnosis of epilepsy receiving supplemental vitamin D were included in this retrospective chart review. All instances of 25-hydroxyvitamin D₃ (25−OHD) measured among those patients were compared between patients taking an enzyme inducing antiseizure medication (EIASM) to patients receiving ASM regimens only containing non-enzyme inducing antiseizure medications (NIASM). ASM use, prescription and over the counter (OTC) vitamin D use, 25-OHD plasma concentration, presence of chronic kidney disease (CKD), age, gender, and ethnicity were collected. Multiple linear regression was used to adjust for potentially confounding variables; the model included a cluster by participant term to account for repeated patients in the dataset.
There were 542 vitamin D levels evaluated from 172 unique patients. There was an 11.5 % higher absolute percent increase in patients who achieved a 25-OHD level over 30 ng/mL in the NIASM (p = 0.012). Patients on EIASMs were supplemented with an additional 508 units of vitamin D daily (95 %CI 136–878, p = 0.007). When adjusted for CKD, OTC vitamin D use, OTC multivitamin use, age, gender, and ethnicity, patients on EIASMs were supplemented with an additional 445 units of vitamin D (95 %CI -69 to 960, p = 0.089) compared to NIASM use.
Patients taking EIASMs had an increase in vitamin D deficiency and vitamin D supplementation suggesting that EIASMs impact vitamin D metabolism. Closer monitoring of vitamin D status in patients with epilepsy, especially those on EIASMs, is warranted. This evaluation suggests that for patients taking ASM, use of a lower dose OTC requires closer monitoring of vitamin D status in patients with epilepsy, especially those on EIASMs, is warranted. vitamin D agent may not be adequate.

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Original ArticleEffect of Carbamazepine Therapy on Vitamin D and Parathormone in Epileptic Children

Introduction

Section snippets

Materials and Methods

Results

Discussion

Epilepsy Behav

Pediatr Neurol

Eur J Pharmacol

Seizures in childhood

Bone mineral status in pediatric outpatients on antiepileptic drug monotherapy

J Child Neurol

Effects of anticonvulsants therapy on vitamin D status in children: Prospective monitoring study

J Child Neurol

Does carbamazepine treatment lead to a need of extra vitamin D in some mentally retarded children?

Acta Paediatr Scand

Increased bone turnover in pre-pubertal, pubertal and post-pubertal patients receiving carbamazepine

Epilepsia

Long term anticonvulsant therapy and vitamin D metabolism in ambulatory pubertal children

Neuropediatrics

Effect of vitamin D2 and D3 on bone mineral content in carbamazepine treated epileptic patients

Acta Neurol Scand

Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbamazepine

Epilepsia

Original Article
Effect of Carbamazepine Therapy on Vitamin D and Parathormone in Epileptic Children