Subscribe to RSS
DOI: 10.1055/s-0042-1749343
Evaluation of Bone Metabolism in Children Using Antiseizure Drugs: A Single-Center Experience and Review of the Literature
Abstract
The effect of anti-seizure drugs (ASDs) on bone mineral density (BMD) is a controversial topic. This study investigated the effect of monotherapy and polytherapy drugs separately. Patients with a history of epilepsy treated with the same ASDs for more than 6 months were included in the study. Data regarding patient demographics, biochemical markers related to bone metabolism (calcium, phosphorus, alkaline phosphatase, parathyroid hormone, vitamin D), and BMD with dual-energy X-ray absorptiometry (DXA) were collected and compared. In total, 104 children with epilepsy using valproic acid (VPA), levetiracetam (LEV), carbamazepine (CBZ) alone or in combination and 22 healthy controls were evaluated. The ages of the children (64 boys, 62 girls) ranged between 2 and 17, with a mean of 9.50 ± 4.03 years. BMD or Z-scores did not differ among the monotherapy groups or between them and the polytherapy group. The lowest mean Z-score was in the VPA group but without statistical significance. Alkaline phosphatase levels were significantly higher in the group using CBZ. Calcium levels significantly differed between the groups (p = 0.001). The CBZ and LEV groups had the lowest calcium levels. However, phosphorus and vitamin D measurements did not significantly differ by ASDs used. Unfortunately, low vitamin D levels were evident in all children with epilepsy and even among controls. Physical activity, sun exposure, and calcium intake might be recommended in children treated with ACDs and in combination with additional risk factors monitoring via DXA should be considered. Further studies in a large population are necessary to judge which ASDs are more at risk to reduce bone mineralization than others.
#
Keywords
bone mineralization - bone mineral density - dual-energy X-ray absorptiometry - epilepsy - vitamin DIntroduction
Epilepsy is one of the most common diseases for which children are referred to pediatric neurology outpatient clinics. International League Against Epilepsy defines epilepsy as two or more seizures occurring more than 24 hours apart. The first-line treatment of the disease is medical therapy with anti-seizure drugs (ASDs), first with monotherapy. If monotherapy is not sufficient, then polytherapy may be used according to the patient's age, seizure type, or epileptic syndrome. Other modalities, such as ketogenic diet, vagus nerve stimulation, and epileptic surgery, are preferred in refractory seizures.[1]
Various reports are available on bone mineralization of children with epilepsy. These generally recommend considering vitamin D and plasma calcium (Ca) status. In addition, bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA) may be considered if immobilization, polytherapy, or other severe comorbidity exist since these children are at risk of low BMD.[2] [3] Low bone mineral mass or BMD is the preferred term for pediatric DXA reports when BMD Z-scores are less than or equal to −2.0 SD.[4]
The pathogenesis of the negative effects of ASDs on bone mineralization is not clear, especially for the new generation ASDs. Liver cytochrome c activation and the degradation of vitamin D by enzyme-inducing drugs and the disruption of Ca, phosphorus (P), and parathyroid hormone (PTH) metabolism may be responsible.[3] [5]
The most common and reliable method for evaluating bone health is DXA which uses X-ray beams.[6] [7] The use of T-score (SD score compared with young adults) is inappropriate for children. The Z-score (SD compared with persons of the same age), calculated according to normative data from children of the same chronological age, sex, and ethnicity, is more useful.[8]
The present study investigates the relationship between low bone mineralization and epilepsy in children. In addition, we consider whether there are differences between the drugs used as monotherapy and ASDs used as polytherapy. We also present a review of the current literature in Turkey and the world related to this topic.
#
Materials and Methods
The study was performed at the Pediatric Neurology Outpatient Clinic, Van Training and Research Hospital, Turkey, between August 2016 and June 2018. Children using the same anti-seizure medication/medications (mono/polytherapy) for more than 6 months were included in the study. The patients were divided into four groups according to the therapy administered as valproic acid (VPA), levetiracetam (LEV), and carbamazepine (CBZ), the three monotherapy groups, and VPA combined with levetiracetam (VPA + LEV), the only polytherapy group. Combinations like CBZ + VPA or LEV + CBZ are not commonly used, so these groups were not evaluated. The healthy control group consisted of patients presenting to the pediatric neurology outpatient clinic with a headache. These children had no bone pathology or systemic disease. Our analysis covered subject data regarding epilepsy assessed with DXA scan, biochemical parameters, and demographic variables in all groups (VPA, CBZ, LEV, VPA + LEV, and control).
All subjects were ambulatory, none having significant comorbidities such as cerebral palsy or severe psychiatric problems. There was no known history of fractures in any of the patients. Also, none of them were sedentary or involved in any extra sporting activities.
We compared demographic variables (age, gender, weight, height, body mass index), epilepsy type, cranial magnetic resonance imaging (MRI) results, and biochemical parameters, such as Ca, P, alkaline phosphatase (ALP), vitamin D, PTH, between the monotherapy, polytherapy, and control groups. BMD was measured by DXA scanning (Stratos-DR, DMS, France) of the lumbar spine. DXA was only studied in children with epilepsy and therefore compared among the monotherapy groups and between the monotherapy and polytherapy groups due to ethical reasons.
BMD Z-score values of the patient: aBMD (areal BMD) of their total L1-L4 vertebrae was calculated by subtracting their age-appropriate reference value and dividing by the standard deviation of that age. Since the DXA value may be much lower in cases with short stature, aBMD values were determined according to height age-appropriate references. The DXA Z-score data determined for Turkish children is taken as the source.[9]
Statistical Analysis
Descriptive statistical methods (mean, standard deviation, median, frequency, percentage, minimum, and maximum) were used in the data analysis. The conformity of quantitative data to normal distribution was tested by the Shapiro-Wilk test and graphical examinations. The Student's t-test was used to compare normally distributed quantitative variables between two groups, and the Mann-Whitney U test to compare non-normally distributed quantitative variables. Besides, the one-way analysis of variance (ANOVA) was used in comparisons of three or more groups with normal distribution and the Bonferroni test in binary comparisons. Furthermore, we conducted the Kruskal–Wallis test to compare three or more groups without normal distribution and the Bonferroni-Dunn's test for binary comparisons. Moreover, the Pearson's Chi-square and the Fisher-Freeman-Halton tests were performed to compare qualitative data. Statistical significance was accepted as p <0.05. NCSS (Number Cruncher Statistical System) 2007 (Kaysville, Utah, United States) program was used for statistical analysis.
#
Ethical Issues
Informed consent was obtained from all individual participants included in the study. All procedures performed in this study were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Ethics Committee. (Date and no:November 07, 2019/11)
#
#
Results
The study included 126 children (104 with epilepsy and 22 controls), and 62 (49%) were girls. The ages of the children ranged between 2 and 17, with a mean of 9.50 ± 4.03 years. [Table 1] shows the electroencephalography and MRI findings, and ASDs used. Medication dosages per kilogram were similar for each group. [Table 2] shows the demographic variables and comparison of biochemical parameters between the groups.
Abbreviations: ASD, anti-seizure drug; CBZ, carbamazepine; EEG, electroencephalography; LEV, levetiracetam; MRI, magnetic resonance imaging; VPA, valproic acid.
Descriptive properties and biochemical parameters |
Control (n: 22) |
Patients with epilepsy (n = 104) |
p-Value |
||||
---|---|---|---|---|---|---|---|
VPA (n = 37) |
CBZ (n = 19) |
LEV (n = 29) |
VPA + LEV (n = 19) |
||||
Age (year) |
Mean ± SD |
10.41 ± 3.54 |
9.86 ± 3.89 |
9.26 ± 3.71 |
7.97 ± 5.01 |
10.32 ± 3.04 |
0.240 [d] |
Gender; n (%) |
Girl Boy |
16 (72.7) 6 (27.3 |
23 (62.2) 14 (37.8) |
6 (31.6) 13 (68.4) |
12 (41.4) 17 (58.6) |
5 (26.3) 14 (73.7) |
|
Height (cm) |
Median (IQR) |
133 (123–150) |
136 (119–156) |
130 (120–150) |
117 (100–155) |
140 (121–151) |
0.301 [d] |
Weight (kg) |
Median (IQR) |
33 (23–43) |
34 (21–48) |
30 (21–38) |
22 (15.5–49.5) |
35 (22–40) |
0.194 [e] |
BMI (kg/m2) |
Median (IQR) |
17.22 (15.80–21.36) |
17.36 (15.65–19.28) |
16.29 (15.13–18.13) |
16.29 (14.98–18.14) |
17.26 (14.92–18.66) |
0.412 [e] |
BMD |
Median (IQR) |
0.66 (0.46–0.80) |
0.5 (0.4–0.6) |
0.47 (0.42–0.76) |
0.59 (0.51–0.75) |
0.106 [e] |
|
Z-score |
Median (IQR) |
−0.51 (−1,65–0,45) |
−1.3 (−2.1 to −0.6) |
−0.73 (−1.57 to −0.27) |
−1.06 (−1.38 to 0.43) |
0.394 [d] |
|
Z-score |
< − 2SD (n) > − 2SD (n) |
5 32 |
5 14 |
4 25 |
2 17 |
||
ALP (U/l) (n = 124) |
Median (IQR) |
225 (181–238) |
181 (150–269) |
260 (217–371) |
222 (166–282) |
205 (157–269) |
|
PTH (pg/mL) (n = 121) |
Median (IQR) |
34 (29–50) |
43 (30–70) |
46.5 (34–88) |
36 (24.5–51) |
37.5 (25.7–51) |
0.098 [e] |
Ca (mg/dL) (n = 124) |
Median (IQR) |
9.8 (9,4–10) |
9.8 (9.6–10) |
9.2 (9–9,5) |
9.3 (9–9.6) |
9.5 (9.2–10.1) |
|
P (mg/dL) (n = 124) |
Median (IQR) |
4.4 (4–4.9) |
4.7 (4.1–5.1) |
4.8 (4.5–5.3) |
5 (4.2–5.2) |
4.4 (4–5) |
0.417 [d] |
Vitamin D (ng/dL) (n = 122) |
Median (IQR) |
15 (11–25) |
15 (9–22) |
13 (10–15) |
16 (11–21) |
15 (11–25) |
0.455 [e] |
Abbreviations: CBZ, carbamazepine; IQR, interquartile range; LEV, levetiracetam; VPA, valproate.
a p <0.05.
b p <0.01.
c Pearson Chi-square test.
d One-way ANOVA test.
e Kruskal–Wallis test.
There was no significant difference between the groups by age, weight, height, or BMI. We also observed no difference between the groups by lifestyle and physical activity. However, there were differences regarding gender, and girls were dominant in the VPA group, whereas boys in the other groups. Nevertheless, BMD or Z-scores did not differ among the monotherapy groups or between them and the polytherapy group. The lowest mean Z-score was in the VPA group but without statistical significance.
We observed a statistically significant difference between the ASD groups in terms of ALP (p = 0.045). Relevant binary comparisons revealed the significance originated from the CBZ group, which had higher ALP measurements than the VPA group (p = 0.022). No further significance was detected in the other binary comparisons. However, when we look at the ALP Z-score described by Turan et al,[10] we found that none of the epilepsy patients or healthy children had an ALP value above 2SD. ALP values were close to the mean in 32 of 104 epilepsy patients and in five healthy children, and were below −2SD in all other children. This situation was attributed to nutritional deficiency in children.
Although there was no statistically significant difference between the PTH measurements of the VPA, LEV, CBZ, VPA + LEV, and control groups (p = 0.068), the PTH levels were notably high in the CBZ group. Besides, Ca levels significantly differed between the groups (p = 0.001). The CBZ and LEV groups had the lowest Ca levels. However, P and vitamin D measurements did not significantly differ by ASDs used. Unfortunately, low vitamin D levels were evident in all children with epilepsy and even among controls.
Furthermore, there was no significant relationship among PTH, ALP, and Z-scores. However, vitamin D was found low (10.45 ± 5.20 ng/mL) in the group with high PTH (>65 pg/mL) with a significant difference (p = 0.001).
Moreover, among the children with epilepsy, 16 patients had low BMD, of which five were using VPA, five were using CBZ, four were using LEV, and two were using VPA +LEV. The patient with the lowest Z-score (−7,2) used VPA, with an 8 ng/mL vitamin D level. This patient was thought to have a defect in the bone mineralization.
All patients with low bone density had low vitamin D levels. Then we opted for correlation analysis to look for whether the BMI (anthropometry) or vitamin D deficiency do more than ASDs. There was no correlation between vitamin D and Z-score, but a significant statistical correlation was found between BMI and Z-score (p: 0.015). It was determined that the formulation as BMI × 0.1–2.6 = Z-score was valid for 57% of the patients.
No significance was found between vitamin D and Z-score by linear regression model. A low level of positive significant correlation was detected between BMI and Z-score (regression value: 0.23).
#
Discussion
BMD measurements have always been relevant for physicians prescribing ASDs. The present study aims to review the literature by summarizing the research done since the late 1900s. We present the articles chronologically, mainly including the studies conducted in Turkey. [Table 3] summarizes the studies with their respective significance.[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] As seen in the Table, some studies report lower BMDs due to ASDs, while others indicate no significant difference. Unfortunately, the available body of work does not allow an objective evaluation due to the nonequivalent formation of groups (e.g., regarding BMD assessment from different areas), the generally low vitamin D levels of children, the heterogeneity of some groups (e.g., including patients with comorbidities or non-ambulatory status), and the absence of information on eating habits.
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ASDs, anti-seizure drugs; AST, aspartate aminotransferase; Ca, calcium; CBC, complete blood count; CBZ, carbamazepine; CLB, clobazam; DPH, diphenylhydantoin; EIASD, enzyme inducing ASDs; ETX, ethosuximide; GBP, gabapentin; GGT, c-glutamyl transpeptidase; LEV, levetiracetam; LTG, lamotrigine; NS, non-significant; OXC, oxcarbazepine; P, phosphate; PB, phenobarbital; PRM, primidone; PTH, parathormone; VGB, vigabatrin; VPA, valproate; ZON, zonisamide.
Studies mostly report adversely affected BMD as a result of polytherapy and the duration of epilepsy. However, these studies typically did not have homogenous polytherapy groups, included patients using two or more ASDs, and did not specify the drugs used. In the present study, we specifically indicated the polytherapy group as VPA + LEV but could not do the same for the other groups due to the low number of drug combinations. Our evaluation of the drugs in the monotherapy groups among themselves and with the polytherapy group yielded no difference in terms of BMD.
DXA was generally measured from the lumbar vertebral region in the literature, but some studies used the femoral neck and forearm, obtaining lower BMDs. Nevertheless, this result should not be considered significant since the lumbar region is the most proper for BMD measurement in children.[4] [8]
We also reviewed studies on biochemical markers related to BMD and biomarkers related to bone metabolism. McNamara et al[27] investigated the metabolic abnormalities caused by ASDs and reported decline in BMD with PB, phenytoin, VPA, CBZ, OXC, gabapentin, TOP, and clonazepam, but mixed results with LEV and LTG.[27]
In another study, Durá-Travé et al[28] compared the biochemical parameters between VPA (n:59), LEV (n:31) monotherapy groups, and healthy controls (n:244) in Spain. They indicated that the Ca and P levels in the monotherapy groups were within the normal range but significantly lower than the controls. Besides, they found no significant difference between the groups by ALP and PTH. However, vitamin D deficiency was higher in the ASD groups. Although LEV causes lower BMD depletion, the highest rate of vitamin D impairment was seen in the LEV group.[28]
In the present study, the serum Ca level was lower in the CBZ and LEV groups, and ALP higher in the CBZ group, but no statistical significance was evident concerning Z-scores and ALP, PTH.
Vitamin D deficiency is an important cause of low bone mineralization. This deficiency may be extrinsic (inadequate dietary intake, decreased exposure to sunlight), intrinsic (obesity or gastrointestinal system disorders..) or acquired (increased catabolism or metabolic clearance) similar to that by anti-seizure drugs.[5]
Vitamin D status and the need for supplementation in children using ASDs are other important considerations regarding BMD. A recent meta-analysis revealed that vitamin D levels decreased in children using VPA and CBZ. Thus, routine monitoring of vitamin D levels and supplementation should be considered for children with epilepsy.[29] Turan et al[30] compared VPA, CBZ, and PB monotherapy groups and healthy controls and reported no significant difference in vitamin D levels.[30] Elsewhere, Tekgul et al[17] administered daily 400 IU vitamin D to 56 children with epilepsy. Only three patients (5%) had a BMD less than −1.5, a score relatively lower than the rates in the previous studies concerning ambulatory children on long-term ASD treatment without vitamin D supplementation.[17] In contrast, an Iranian report cited less vitamin D deficiency with 50,000 U per month vitamin supplement in children with epilepsy (26.7% of 90 children with epilepsy and 76.7% of 90 healthy children had vitamin D deficiency), but no significant difference in terms of lumbar BMDs.[31] Our study population was recruited from children living in the province of Van located in Eastern Turkey, near the Iranian border. Thus, the low vitamin D status among our subjects is consistent with the above report.
Ambulatory status, physical activity, Ca intake, vitamin D status, and ASDs have varying influences on BMD in children with epilepsy. As seen in Table 3, studies have investigated the effect of ASDs on BMD with reference to the drugs' enzyme-inducing properties, individual or combined regimens, and duration of therapy.
The presence of numerous ASDs makes evaluation of varying combinations of medications difficult in a single study. In the present study, we only included patients receiving VPA, CBZ, and LEV monotherapy since the number of patients using other drugs was small. We also excluded polytherapy combinations other than VPA + LEV for similar reasons. This is the main limitation of our study. However, the primary strength of the study lies in the homogeneity of the groups, i.e., participation of subjects from the same geographic region and similar socioeconomic backgrounds, with similar eating habits, and physical activity and sun exposure characteristics.
#
Conclusion
Epilepsy is the most commonly seen disease in pediatric neurology outpatient clinics. There is an ongoing interest in BMD and vitamin D levels of patients with epilepsy, not only with regard to ASDs but also with respect to underlying comorbidities (mental retardation, cerebral palsy, and other systemic disorders), amount of sun exposure, physical activity, diet as well as ambulatory status.
The present study, along with the previous ones, has shown that ASDs are not solely responsible for low bone mineralization, but other factors may play a role. Vitamin D status must be considered in all patients and DXA in patients with disabilities. Besides, sunlight exposure, physical activity, and good nutrition are recommended to improve the patients' quality of life.
#
#
Conflict of Interest
None declared.
Acknowledgment
The authors thank all the patients and their families for their participation in the study.
-
References
- 1 Prager C, Cross HJ. Diagnosis and management of the epilepsies in children. Prescriber 2018; 29 (04) 13-19
- 2 Vestergaard P. Effects of antiepileptic drugs on bone health and growth potential in children with epilepsy. Paediatr Drugs 2015; 17 (02) 141-150
- 3 Samaniego EA, Sheth RD. Bone consequences of epilepsy and antiepileptic medications. Semin Pediatr Neurol 2007; 14 (04) 196-200
- 4 2019 ISCD official positions pediatric skeletal health assessment in children from infancy to adolescence. Accessed March 21, 2022 at: https://iscd.org/learn/official-positions/
- 5 Minisola S, Colangelo L, Pepe J, Diacinti D, Cipriani C, Rao SD. Osteomalacia and vitamin D status: a clinical update 2020. JBMR Plus 2020; 5 (01) e10447
- 6 Tutkavul K. Epilepsi ve Kemik Sağlığı (epilepsy and bone health). Epilepsi Dergisi 2018; 24 (Suppl. 01) 70-73
- 7 Özemir ZA, Yalçın AD. Antiepileptik İlaçların Kemik Yoğunluğuna ve Metabolizmasına Etkileri (effects of antiepileptic drugs on bone density and metabolism). Epilepsi. J Turk Epilepsy Soc 2017; 23 (01) 1-8
- 8 Gafni RI, Baron J. Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy X-ray absorptiometry (DEXA). J Pediatr 2004; 144 (02) 253-257
- 9 Goksen D, Darcan S, Coker M, Kose T. Bone mineral density of healthy Turkish children and adolescents. J Clin Densitom 2006; 9 (01) 84-90
- 10 Turan S, Topcu B, Gökçe İ. et al. Serum alkaline phosphatase levels in healthy children and evaluation of alkaline phosphatase z-scores in different types of rickets. J Clin Res Pediatr Endocrinol 2011; 3 (01) 7-11
- 11 Sheth RD, Wesolowski CA, Jacob JC. et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995; 127 (02) 256-262
- 12 Akin R, Okutan V, Sarici U, Altunbaş A, Gökçay E. Evaluation of bone mineral density in children receiving antiepileptic drugs. Pediatr Neurol 1998; 19 (02) 129-131
- 13 Kafali G, Erselcan T, Tanzer F. Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12 years. Clin Pediatr (Phila) 1999; 38 (02) 93-98
- 14 Erbayat Altay E, Serdaroğlu A, Tümer L, Gücüyener K, Hasanoğlu A. Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid. J Pediatr Endocrinol Metab 2000; 13 (07) 933-939
- 15 Öner N, Kaya M, Karasalihoğlu S, Karaca H, Celtik C, Tütüncüler F. Bone mineral metabolism changes in epileptic children receiving valproic acid. J Paediatr Child Health 2004; 40 (08) 470-473
- 16 Ecevit C, Aydoğan A, Kavakli T, Altinöz S. Effect of carbamazepine and valproate on bone mineral density. Pediatr Neurol 2004; 31 (04) 279-282
- 17 Tekgul H, Dizdarer G, Demir N, Ozturk C, Tutuncuoglu S. Antiepileptic drug-induced osteopenia in ambulatory epileptic children receiving a standard vitamin D3 supplement. J Pediatr Endocrinol Metab 2005; 18 (06) 585-588
- 18 Kumandas S, Koklu E, Gümüs H. et al. Effect of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-3. J Pediatr Endocrinol Metab 2006; 19 (04) 529-534
- 19 Babayigit A, Dirik E, Bober E, Cakmakci H. Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol 2006; 35 (03) 177-181
- 20 Coppola G, Fortunato D, Auricchio G. et al. Bone mineral density in children, adolescents, and young adults with epilepsy. Epilepsia 2009; 50 (09) 2140-2146
- 21 Aksoy A, Sönmez FM, Deger O, Hosver I, Karagüzel G. The effects of antiepileptic drugs on the relationships between leptin levels and bone turnover in prepubertal children with epilepsy. J Pediatr Endocrinol Metab 2011; 24 (9-10): 703-708
- 22 Serin HM, Koç ZP, Temelli B, Esen İ. The bone mineral content alterations in pediatric patients medicated with levetiracetam, valproic acid, and carbamazepine. Epilepsy Behav 2015; 51: 221-224
- 23 Yaghini O, Tonekaboni SH, Amir Shahkarami SM, Ahmad Abadi F, Shariat F, Abdollah Gorji F. Bone mineral density in ambulatory children with epilepsy. Indian J Pediatr 2015; 82 (03) 225-229
- 24 Osman NMM, Aziz RAA, Soliman GT, Mohamed AG. Bone mineral density evaluation of epileptic children on anti-convulsive medications. Egypt J Radiol Nucl Med 2017; 48 (04) 1083-1090
- 25 Shin C, Lee NY, Han JY. et al. Effects of anticonvulsant monotherapy on bone mineral density in children. J Korean Child Neurol Soc 2018; 26 (04) 269-271
- 26 Fong CY, Kong AN, Noordin M, Poh BK, Ong LC, Ng CC. Determinants of low bone mineral density in children with epilepsy. Eur J Paediatr Neurol 2018; 22 (01) 155-163
- 27 McNamara NA, Romanowski EMF, Olson DP, Shellhaas RA. Bone health and endocrine comorbidities in pediatric epilepsy. Semin Pediatr Neurol 2017; 24 (04) 301-309
- 28 Durá-Travé T, Gallinas-Victoriano F, Malumbres-Chacón M, Moreno-Gónzalez P, Aguilera-Albesa S, Yoldi-Petri ME. Vitamin D deficiency in children with epilepsy taking valproate and levetiracetam as monotherapy. Epilepsy Res 2018; 139: 80-84
- 29 Xu Z, Jing X, Li G. et al. Valproate decreases vitamin D levels in pediatric patients with epilepsy. Seizure 2019; 71: 60-65
- 30 Turan MI, Cayir A, Ozden O, Tan H. An examination of the mutual effects of valproic acid, carbamazepine, and phenobarbital on 25-hydroxyvitamin D levels and thyroid function tests. Neuropediatrics 2014; 45 (01) 16-21
- 31 Inaloo S, Paktinat M, Saki F. et al. Bone mineral density loss in ambulatory children with epilepsy in spite of using supplemental vitamin D in Southern Iran: a case-control study. J Bone Miner Metab 2019; 37 (03) 537-544
Address for correspondence
Publication History
Received: 03 March 2022
Accepted: 18 April 2022
Article published online:
02 August 2022
© 2022. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Prager C, Cross HJ. Diagnosis and management of the epilepsies in children. Prescriber 2018; 29 (04) 13-19
- 2 Vestergaard P. Effects of antiepileptic drugs on bone health and growth potential in children with epilepsy. Paediatr Drugs 2015; 17 (02) 141-150
- 3 Samaniego EA, Sheth RD. Bone consequences of epilepsy and antiepileptic medications. Semin Pediatr Neurol 2007; 14 (04) 196-200
- 4 2019 ISCD official positions pediatric skeletal health assessment in children from infancy to adolescence. Accessed March 21, 2022 at: https://iscd.org/learn/official-positions/
- 5 Minisola S, Colangelo L, Pepe J, Diacinti D, Cipriani C, Rao SD. Osteomalacia and vitamin D status: a clinical update 2020. JBMR Plus 2020; 5 (01) e10447
- 6 Tutkavul K. Epilepsi ve Kemik Sağlığı (epilepsy and bone health). Epilepsi Dergisi 2018; 24 (Suppl. 01) 70-73
- 7 Özemir ZA, Yalçın AD. Antiepileptik İlaçların Kemik Yoğunluğuna ve Metabolizmasına Etkileri (effects of antiepileptic drugs on bone density and metabolism). Epilepsi. J Turk Epilepsy Soc 2017; 23 (01) 1-8
- 8 Gafni RI, Baron J. Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy X-ray absorptiometry (DEXA). J Pediatr 2004; 144 (02) 253-257
- 9 Goksen D, Darcan S, Coker M, Kose T. Bone mineral density of healthy Turkish children and adolescents. J Clin Densitom 2006; 9 (01) 84-90
- 10 Turan S, Topcu B, Gökçe İ. et al. Serum alkaline phosphatase levels in healthy children and evaluation of alkaline phosphatase z-scores in different types of rickets. J Clin Res Pediatr Endocrinol 2011; 3 (01) 7-11
- 11 Sheth RD, Wesolowski CA, Jacob JC. et al. Effect of carbamazepine and valproate on bone mineral density. J Pediatr 1995; 127 (02) 256-262
- 12 Akin R, Okutan V, Sarici U, Altunbaş A, Gökçay E. Evaluation of bone mineral density in children receiving antiepileptic drugs. Pediatr Neurol 1998; 19 (02) 129-131
- 13 Kafali G, Erselcan T, Tanzer F. Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12 years. Clin Pediatr (Phila) 1999; 38 (02) 93-98
- 14 Erbayat Altay E, Serdaroğlu A, Tümer L, Gücüyener K, Hasanoğlu A. Evaluation of bone mineral metabolism in children receiving carbamazepine and valproic acid. J Pediatr Endocrinol Metab 2000; 13 (07) 933-939
- 15 Öner N, Kaya M, Karasalihoğlu S, Karaca H, Celtik C, Tütüncüler F. Bone mineral metabolism changes in epileptic children receiving valproic acid. J Paediatr Child Health 2004; 40 (08) 470-473
- 16 Ecevit C, Aydoğan A, Kavakli T, Altinöz S. Effect of carbamazepine and valproate on bone mineral density. Pediatr Neurol 2004; 31 (04) 279-282
- 17 Tekgul H, Dizdarer G, Demir N, Ozturk C, Tutuncuoglu S. Antiepileptic drug-induced osteopenia in ambulatory epileptic children receiving a standard vitamin D3 supplement. J Pediatr Endocrinol Metab 2005; 18 (06) 585-588
- 18 Kumandas S, Koklu E, Gümüs H. et al. Effect of carbamezapine and valproic acid on bone mineral density, IGF-I and IGFBP-3. J Pediatr Endocrinol Metab 2006; 19 (04) 529-534
- 19 Babayigit A, Dirik E, Bober E, Cakmakci H. Adverse effects of antiepileptic drugs on bone mineral density. Pediatr Neurol 2006; 35 (03) 177-181
- 20 Coppola G, Fortunato D, Auricchio G. et al. Bone mineral density in children, adolescents, and young adults with epilepsy. Epilepsia 2009; 50 (09) 2140-2146
- 21 Aksoy A, Sönmez FM, Deger O, Hosver I, Karagüzel G. The effects of antiepileptic drugs on the relationships between leptin levels and bone turnover in prepubertal children with epilepsy. J Pediatr Endocrinol Metab 2011; 24 (9-10): 703-708
- 22 Serin HM, Koç ZP, Temelli B, Esen İ. The bone mineral content alterations in pediatric patients medicated with levetiracetam, valproic acid, and carbamazepine. Epilepsy Behav 2015; 51: 221-224
- 23 Yaghini O, Tonekaboni SH, Amir Shahkarami SM, Ahmad Abadi F, Shariat F, Abdollah Gorji F. Bone mineral density in ambulatory children with epilepsy. Indian J Pediatr 2015; 82 (03) 225-229
- 24 Osman NMM, Aziz RAA, Soliman GT, Mohamed AG. Bone mineral density evaluation of epileptic children on anti-convulsive medications. Egypt J Radiol Nucl Med 2017; 48 (04) 1083-1090
- 25 Shin C, Lee NY, Han JY. et al. Effects of anticonvulsant monotherapy on bone mineral density in children. J Korean Child Neurol Soc 2018; 26 (04) 269-271
- 26 Fong CY, Kong AN, Noordin M, Poh BK, Ong LC, Ng CC. Determinants of low bone mineral density in children with epilepsy. Eur J Paediatr Neurol 2018; 22 (01) 155-163
- 27 McNamara NA, Romanowski EMF, Olson DP, Shellhaas RA. Bone health and endocrine comorbidities in pediatric epilepsy. Semin Pediatr Neurol 2017; 24 (04) 301-309
- 28 Durá-Travé T, Gallinas-Victoriano F, Malumbres-Chacón M, Moreno-Gónzalez P, Aguilera-Albesa S, Yoldi-Petri ME. Vitamin D deficiency in children with epilepsy taking valproate and levetiracetam as monotherapy. Epilepsy Res 2018; 139: 80-84
- 29 Xu Z, Jing X, Li G. et al. Valproate decreases vitamin D levels in pediatric patients with epilepsy. Seizure 2019; 71: 60-65
- 30 Turan MI, Cayir A, Ozden O, Tan H. An examination of the mutual effects of valproic acid, carbamazepine, and phenobarbital on 25-hydroxyvitamin D levels and thyroid function tests. Neuropediatrics 2014; 45 (01) 16-21
- 31 Inaloo S, Paktinat M, Saki F. et al. Bone mineral density loss in ambulatory children with epilepsy in spite of using supplemental vitamin D in Southern Iran: a case-control study. J Bone Miner Metab 2019; 37 (03) 537-544