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
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)
- et al.
Management of epilepsy in adolescents and adults
Lancet
(2000) - et al.
Epilepsy after the first drug fails: substitution or add-on
Seizure
(2000) - et al.
Predictors of bone density in ambulatory patients on antiepileptic drugs
Bone
(2008) Fractures in epilepsy children
Seizure
(2010)- et al.
Longitudinal change of vitamin D status in children with epilepsy on antiepileptic drugs: prevalence and risk factors
Ped Neurol
(2015) - et al.
Bone mineral density evaluation of epileptic children on anti-epileptic medications
Egypt J Radiol Nuclear Med
(2017) - et al.
Determinants of low bone mineral density in children with epilepsy
Eur J Paediatr Neur
(2018) - et al.
Bone disease during chronic antiepileptic drug therapy: General versus specific risk factors. Review
J Neurol Sci
(2013) - et al.
The effect of levetiracetam on rat bone mass, structure and metabolism
Epilepsy Res.
(2013) - et al.
Bone mineral density in adult patients treated with various antiepileptic drugs
Seizure
(2012)