Elsevier

Epilepsy & Behavior

Volume 115, February 2021, 107708
Epilepsy & Behavior

Effects of long-term antiepileptic polytherapy on bone biochemical markers in ambulatory children and adolescents and possible benefits of vitamin D supplementation: a prospective interventional study

https://doi.org/10.1016/j.yebeh.2020.107708Get rights and content

Highlights

  • Young individuals on therapy with more than one antiepileptic drug represent an important part of epilepsy-treated patients.

  • Long-term polytherapy seems to have an adverse effect on bone biochemical markers.

  • Vitamin D supplementation even at the dose of 400 IU/d has some beneficial effect on bone biochemical markers.

  • All routine biochemical markers do not seem to be reliable for assessing bone metabolism in children with epilepsy on therapy and even more on polytherapy.

Abstract

Purpose

Our aim was to investigate any adverse effects of long-term polytherapy (VPA and add-on-therapy) on bone biochemical markers in ambulatory children and adolescents with epilepsy and the possible benefits of vitamin D supplementation on the same markers.

Methods

In this prospective interventional study, the levels of 25(OH)D and the bone turnover markers of CrossLaps (CTX), total alkaline phosphatase (tALP), osteoprotegerin (OPG), and the receptor activator for nuclear factor kB (RANK) ligand (sRANKL) were determined in forty-two ambulatory children with epilepsy on polytherapy (valproic acid + one or more other from levetiracetam, topiramate, lamotrigine, or rufinamide). The same markers were assessed after a year’s supplementation of vitamin D (400 IU/d) and were compared with those of clinically healthy controls. The respective mean (±SD) ages were 11.9 ± 4.6 and 11.4 ± 4.4 yrs.

Results

The basal mean 25(OH)D levels in the patients did not differ from controls (23.9 ± 11.5 vs 27.4 ± 13.3 ng/ml), but increased significantly after the vitamin D intake (31.1 ± 13.3 ng/ml, p < 0.01). In parallel, basal serum CTX levels were found to be significantly lower in the patients than controls (0.89 ± 0.63 vs 1.22 ± 0.58 ng/ml, p < 0.02), but not tALP. Osteoprotegerin was higher in the patients (5.7 ± 7.7 pmol/L vs 2.6 ± 1.0 pmol/L, p < 0.03), while sRANKL did not differ. After vitamin D, the CTX levels increased to comparable levels in controls (0.99 ± 0.57 ng/ml), and those of OPG decreased to levels that did not differ from controls (4.9 ± 5.1 pmol/L). The ratio of OPG/sRANKL was higher in patients than controls before treatment (0.030 ± 0.045 vs 0.009 ± 0.005, p < 0.03), but decreased (0.026 ± 0.038) to comparable values in controls later.

Conclusions

These findings imply a lower bone turnover in the young patients on long-term polytherapy (VPA and add-on-therapy), but after one year’s vitamin D intake, bone biochemical markers improved.

Introduction

Even though monotherapy is the ideal pharmacotherapeutic option for epilepsy, there are a considerable number of patients whose seizures cannot be controlled on monotherapy.

It is estimated that seizures in 30–40% of patients remain uncontrolled on a single antiepileptic drug (AED) [1]. Hence, if the first drug has partial efficacy and is well tolerated, then another drug in combination is tried and add-on therapy appears to be more effective when started immediately after first-drug failure [2], [3]. Also, there are the second- and third-generation AEDs which are believed to be of equivalent efficacy and safer than the older ones, having several significant advantages including reduced drug–drug interactions, less life-threatening adverse events, and less negative impact on cognitive functions [4]. However, despite improved efficacy and tolerability, the second- and third-generation AEDs are still far from ideal to fully control seizures without significant impact on the life quality of patients [5]. Children with generalized and secondary generalized epilepsy very often take VPA as the first-line therapy in monotherapy and then they are put on other drugs as add-on-therapy. Treatment with more than one AED is thought to have an increased bone-destructing influence compared with monotherapy. However, from the few studies available, polypharmacy seems to be an independent predictor of low bone mass and bone formation in children as well as of vitamin D insufficiency/deficiency [6], [7], [8], [9].

The aim of the present study was to explore the possible adverse effects on new and old bone biochemical markers of long-term polytherapy in children and adolescents with epilepsy and also to investigate any possible beneficial effects of vitamin D supplementation on the same markers. For this goal, we determined serum markers of bone turnover including proteins of the receptor activator for nuclear factor kB (RANK)/RANKL/osteoprotegerin (OPG) system, tALP, and CrossLaps (CTX) in children up to 18 years of age before and one year after vitamin D intake (400 IU/d) who were on long-term polytherapy with VPA as one of the AEDs.

Section snippets

Study design-subjects

This was a prospective interventional study. Patients were recruited from the Epilepsy Pediatrics Clinic of the University Hospital of Ioannina. Forty-two ambulatory children 3–20 years of age (mean 11.9 ± 4.6 years, median 11.3) monitored for epilepsy and treated with VPA (10–35 mg/kg/d and one or more including levetiracetam (10–60 mg/kg/d, n = 16), lamotrigine (1–5 mg/kg/d, n = 6), rufinamide (10–45 mg/kg/d, n = 6), clobazam (10–20 mg/kg/d, n = 6) or topiramate (5–9 mg/kg/d, n = 8) for over

Results

The years of antiepileptic treatment of the patients was 4.5 ± 1.5 years (median 5.0). As shown in Table 1 the ages of patients and controls were comparable and so were their BMIs. Before vitamin D supplementation, serum 25(OH)D levels did not differ between patients and controls (23.9 ± 11.5 vs 27.4 ± 13.3 ng/ml). Also, the numbers of patients having 25(OH)D levels lower than 20 ng/ml were not significantly different than those of controls (43.2% vs 27.6% respectively). One year after D

Discussion

As is well known, bone density increases up to the end of adolescence when it reaches its peak [11]. Hence, whatever circumstances may interfere with the process during this timeperiod may have impact on later life. Polytherapy as well as its duration have been implicated in lowering BMD in these patients [12], [13]. Coppola et al. reported that a significant percentage (64.1%) of children and young adults on polytherapy with valproate included had lower bone mineral density (BMD) vs 36.9% who

Conclusion

In conclusion, long-term polytherapy seems to have an adverse effect on bone biochemical markers, and vitamin D supplementation even at the dose of 400 IU/d has some beneficial effect. Probably,a longer duration of vitamin D might show more definitive results. However, as other authors also point out, intervention should start in parallel to the AED therapy when the 25(OH)D levels are abnormal and continue to maintain the levels >30 ng/ml irrespective of mono- or polytherapy. Also, as it seems

Acknowledgments

Thanks to Afroditi Papaghianni for her technical assistance.

Author contributions

MP, IN, ES, VC, and AC made the diagnosis, collected, made the biochemical analysis, and analyzed the data; MT read, edited, and approved the final manuscript.

Declaration of conflicting of interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This study was funded in part by InterMED Pharmaceutical Laboratories S.A., Greece.

Ethical approval

Approval was obtained by the Institutional Review Board of the University Hospital of Ioannina, Greece.

References (31)

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