Epilepsy Research (2014) 108, 442—447
journal homepage: www.elsevier.com/locate/epilepsyres
Effect of oxcarbazepine on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy Dae Lim Koo a,1, Kyoung Jin Hwang b,1, Suk Won Han c, Ji Young Kim b, Eun Yeon Joo b,∗, Won-Chul Shin d, Hyang Woon Lee e, Dae-Won Seo b, Seung Bong Hong b,∗ a
Department of Neurology, Seoul National University Boramae Hospital, Seoul, Republic of Korea Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Seoul, Republic of Korea c Department of Neurology, East Suwon Hospital, Suwon, Republic of Korea d Department of Neurology, Kyung Hee University East-West Neo Medical Center, Seoul, Republic of Korea e Department of Neurology, Ewha Womans University School of Medicine, Seoul, Republic of Korea b
Received 12 January 2013; received in revised form 20 August 2013; accepted 17 September 2013 Available online 1 October 2013
KEYWORDS Oxcarbazepine; Epilepsy; Bone mineral density; Bone metabolism
Summary Purpose: Antiepileptic drugs (AEDs) may cause adverse effects on bone metabolism and bone mineral density (BMD). The aim of this study is to determine the effect of oxcarbazepine (OXC) monotherapy on biochemical markers of bone metabolism and BMD in epilepsy patients. Methods: Forty-one new onset drug naïve epilepsy patients were recruited (19 females, 22 males; mean age: 28.2 ± 8.4 years). We measured biochemical markers of bone metabolism (serum calcium, phosphate, bone alkaline phosphatase, parathyroid hormone, osteocalcin, insulin-like growth factor (IGF)-1, C-telopeptide, Vitamin D3 levels) and BMD by DEXA (dual energy X-ray absorptiometry) method in all patients before and after a long-term OXC monotherapy. Results: Most of biochemical markers were not changed significantly, but serum calcium (p = 0.0087) and bone specific ALP was reduced (p = 0.0499) significantly after OXC monotherapy in epilepsy patients. BMD at the lumbar spine (L2 to L4) was significantly increased after OXC monotherapy (p = 0.0001), revealed by repeated measures ANOVA with Bonferroni’s correction of confounders including sex, age, average dose, and treatment duration. However, BMD at the lumbar spine (L2 to L4) was significantly increased (p = 0.012) only in female patients in each gender analysis.
∗ Corresponding authors at: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 IrwonDong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Tel.: +82 2 3410 3592; fax: +82 2 3410 0052. E-mail addresses: [email protected] (E.Y. Joo), [email protected], [email protected] (S.B. Hong). 1 These two first authors contributed equally to this work.
0920-1211/$ — see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2013.09.009
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Conclusions: This study demonstrates that a long-term OXC monotherapy does not appear to have harmful effect on bone health in drug naïve epilepsy patients. © 2013 Elsevier B.V. All rights reserved.
Introduction The effects of antiepileptic drugs (AEDs) on bone metabolism were first reported nearly four decades ago. Since then, many reports have indicated that the use of AEDs was associated low vitamin D levels, increased bone turnover, decreased bone mineral density (BMD), and thereby decreased bone strength with increased fracture risk (Lee et al., 2010; Souverein et al., 2005; Vestergaard et al., 2004). However, the underlying pathophysiological mechanisms are not clearly understood. Classic AEDs, such as phenobarbital (PB), primidone (PRM), phenytoin (PHT), and carbamazepine (CBZ) are inducers of microsomal enzymes such as hepatic cytochrome P-450 enzyme system. The most frequently suggested mechanism of these enzyme inducers in bone metabolism is the hepatic induction of the P-450 enzyme system leading to increased catabolism of 25-hydroxyvitamin D (25-OHD), causing relative hypocalcemia, increased levels of parathyroid hormone (PTH), and subsequent low BMD (Babayigit et al., 2006; Mosekilde et al., 1979; Pack and Morrell, 2001; Pack et al., 2008; Souverein et al., 2006; Valimaki et al., 1994; Verrotti et al., 2010). The CBZ, which is structurally similar to oxcarbazepine (OXC), may have multiple mechanisms such as enhanced catabolism of 25-OHD, direct effect on function of bone cells, and direct inhibition of intestinal calcium transport which is not mediated by 25-OHD (Feldkamp et al., 2000; von Borstel Smith et al., 2007). On the contrary to these enzyme inducers, valproic acid, which is known as the inhibitor of CYP-450, may also cause adverse effects on bone health (Boluk et al., 2004; Ecevit et al., 2004; Kumandas et al., 2006). Some old AEDs can evoke direct adverse effects on bone metabolism by another mechanism of bone-mineralization defects, independent of the effects of AEDs on 25-OHD (Hahn et al., 1978). PHT can have a direct adverse effect on bone cells, resulting in decrease in BMD (Chung and Ahn, 1994; Valimaki et al., 1994). Direct effects of these drugs on bone cells were proposed as an alternative mechanism of bone-mineralization defects in epilepsy patients (Feldkamp et al., 2000; Verrotti et al., 2002). The effects of so-called new AEDs on bone are much less known compared to those of classic AEDs. Recent studies showed that lamotrigine (LTG) monotherapy does not have osteopenic effects nor does it cause significant changes in bone metabolism (Kim et al., 2007; Pack et al., 2005; Sheth and Hermann, 2007). Although levetiracetam (LEV) has not shown negative effect on bone (Koo et al., 2013; NissenMeyer et al., 2007; Verrotti et al., 2010), more long-term studies are needed. Topiramate (TPM) also has been considered as favorable AED in bone metabolism, but a recent study suggested that a long-term therapy with TPM could cause the adverse effect on bone health in premenopausal women with epilepsy (Heo et al., 2011). Zonisamide (ZSM) may cause a bone loss by accelerating bone resorption rather
than inhibiting bone formation in an animal study (Takahashi et al., 2003). OXC is a keto analog of CBZ with comparable efficacy but superior safety. It is currently indicated as monotherapy in adults with partial epilepsy and as adjunctive therapy in adults and children with partial or secondarily generalized seizures. Only a few studies evaluated the effect of OXC on BMD. Some studies demonstrated that OXC was associated with reduced 25-OHD levels and elevated biomarkers that suggest increased bone turnover (Babayigit et al., 2006; Cansu et al., 2008; Mintzer et al., 2006). However, a recent study reported that OXC did not have an adverse effect on bone mineral metabolism (Cetinkaya et al., 2009). These controversial results urge further studies exploring the effect of OXC on bone metabolism. The aim of our study is (1) to estimate the changes in BMD and biochemical markers of bone metabolism after a long-term OXC monotherapy in drug naïve epilepsy patients and (2) to evaluate the dose-dependent effect of OXC on bone health.
Methods Ninety two new onset drug naïve epilepsy patients were initially enrolled at the epilepsy clinics of three university hospitals (Samsung Medical Center, Ewha Womans University Mokdong Hospital, Kyung Hee University Medical Center) from January 23, 2009 to April 13, 2010. Patients having partial seizures with or without secondary generalization were included. Of the 92 patients, 51 patients were excluded due to following reasons. Twenty eight patients had to change to different AED or add other AED to OXC during the study period, and 11 patients dropped out due to follow-up loss. Additionally we excluded patients who had used calcium supplements (n = 4), and subjects who revealed osteoporosis with T score of -2.5 or lower (n = 4), abnormal laboratory findings (Neutrophils ≤1500/mm3 , platelets ≤100,000/mm3 , and ALT, AST, bilirubin, BUN, creatinine, Na/K ≥two times of normal level) (n = 4) from this study. Finally, 41 patients were included and had BMD and the measurement of biochemical markers for bone metabolism both at baseline and follow-up periods. The dietary habit and physical activity of the patients were evaluated periodically at a baseline period, every three months after OXC administration, and at the end of the study. The habits of daily diet including the contents of meals and snacks were checked by a general questionnaire. The physical activity was estimated by the duration and frequency of specific exercises and daily activities. The patients who avoided normal physical activity due to physical or mental impairments were excluded. All patients were instructed to keep the current degree of dietary habit and physical activity during the entire study period. Weight and height were measured and body mass index (BMI) was cal-
444 culated (kg/m2 ). OXC was given at a dose of 300 mg/day for the first 2 weeks and at a dose of 600 mg/day for the next 2 weeks. From the fifth week onwards, the dose of OXC was gradually increased up to a maximum of 1800 mg/day in order to control seizures. This study was approved by the local institutional review board at Samsung Medical Center. Written informed consent for participation in the trial was obtained from each patient or his/her legal representative. BMD was assessed twice, before and after OXC monotherapy. BMD of the lumbar spine and femur was assessed using the DEXA (dual energy X-ray absorptiometry) technique. Normal T-score is −1.0 or higher, osteopenia is defined as a T-score between −1.0 and −2.5, and osteoporosis as a T-score of −2.5 or lower. Biochemical markers of bone metabolism (vitamin D3, calcium, phosphorus, bone alkaline phosphatase (ALP), osteocalcin, PTH, C-telopeptide and insulin-like growth factor 1 (IGF-1)) were also measured twice. Seizure frequency and adverse effect of OXC were evaluated with a self-recorded seizure diary whenever the patient visited the clinic. Statistical analysis of the data was performed using SPSS v.12.0 for Windows. Paired t-test with the adjustment for multiple T tests by Bonferroni’s correction was applied to compare BMD and biochemical markers of bone metabolism before and after OXC treatment. Repeated measures ANOVA test with Bonferroni’s correction was used to exclude the interaction effect of age, sex, treatment duration, and average dose of OXC on BMD and bone metabolism. Furthermore, we analyzed the impact of OXC in each gender too. We calculated the effect size for retesting data, a measure of the magnitude of difference in bone strength. Cohen has suggested that an effect size of 0.2 to 0.3 might be a ‘‘small’’ effect, around 0.5 a ‘‘medium’’ effect and 0.8 to infinity, a ‘‘large’’ effect. Statistical significance was set at p < 0.05.
Results Characteristics of the subjects The clinical characteristics of the subjects are summarized in Table 1. The mean age was 28.2 ± 8.4 years (range; 18—52 years) and 53.7% (n = 22) of the subjects were males. There was no significant difference in BMI between men (24.4 ± 4.2 kg/m2 ) and women (24.0 ± 3.7 kg/m2 ). No patients were taking medications known to affect bone metabolism such as glucocorticoids, hypoglycemic agents, selective serotonin reuptake inhibitors (SSRI), and vitamin D or calcium supplements during the study period. Only five patients included in the present study had taken the concomitant medications which had no effect on bone strength or metabolism during the study period: antihypertensive agent (n = 3), acetaminophen (n = 1), and digestive medication (n = 1). The remaining patients did not take other medications during the study period. Nutrition status including daily calcium intake and pattern of physical exercise revealed no significant change across the total study period. The mean duration of treatment was 11.6 ± 6.0 months (median 10.8, range 6—35). The mean OXC dose at last visit was 824 ± 334 mg per day (median 750, range 300—1800). We also calculated the average dose of OXC because OXC dose at last visit could not accurately reflect the actual exposure to
D.L. Koo et al. Table 1 patients.
Demographics and clinical characteristics of
Clinical variables
Total 41 patients
Age, years (range) 28.2 ± 8.4a (18—52) Men, n (%) 22 (53.7) Height, m 1.66 ± 0.08a Weight, kg 67.3 ± 14.4a 2 BMI, kg/m 24.3 ± 4.0a OXC dose at last visit, mg/day 824 ± 334a (300—1800) (range) Baseline seizure frequency, 4.9 ± 9.1a (median 2.4) number/month Type of seizure Partial seizure, n (%) 28 (68.3) With secondary 12 (29.3) generalization Without secondary 16 (39.0) generalization Generalized seizure, n (%) 13 (31.7) Etiology Cryptogenic, n 25 Hippocampal sclerosis, n 4 Cortical dysplasia or 6 heterotopia, n Foreign tissue lesion, n 6 Baseline interictal epileptiform dischargeb Temporal, n 10 Extratemporal-unifocal, n 2 Extratemporal-bifocal, n 2 Hemispheric, n 4 Efficacy Seizure free, n (%) 25 (61.0%) ≥50% seizure reduction, n (%) 10 (24.3%) BMI, body mass index; OXC, oxcarbazepine. a Values are mean ± standard deviation. b Eleven patients showed non-epileptiform abnormalities (regional slowing).
OXC over the whole period of the study. The average dose of OXC during study was mean 747 ± 307 mg/day (median 620, range 290—1680). Twenty-eight subjects had partial seizures with or without secondary generalization and 13 had generalized seizures. Of 41 patients, 4 had hippocampal sclerosis, 6 had cortical dysplasia or heterotopias, and 6 had foreign tissue lesions. Seizure frequency at baseline was 4.9 ± 9.1 per month. After OXC monotherapy, 25 (61.0%) subjects became seizure-free and 10 (24.3%) subjects had ≥50% reduction in seizure frequency.
Bone mineral density and biochemical markers of bone metabolism BMD at the lumbar spine (L2 to L4) was significantly increased after OXC monotherapy (p = 0.0001), as revealed by using repeated measures ANOVA with Bonferroni’s correction of confounding factors including sex, age, average dose, and treatment duration (Table 2). There were no significant changes in the BMD values and T-scores of all other regions. Among biochemical markers (25-OHD, calcium, phospho-
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Table 2 Statistical comparison of BMD and bone metabolism variables across oxcarbazepine (OXC) treatment with adjustment of confounding factors. Before OXC (mean ± SD)
Variables 3
L1-4 BMD (g/cm ) L1-4 t-score L2-4 BMD (g/cm3 ) L2-4 t-score Femur neck BMD (g/cm3 ) Femur neck t-score Femur total BMD (g/cm3 ) Femur total t-score 25-OHD (ng/ml) Calcium (mg/dl) Phosphorus (mg/dl) Bone specific ALP (g/L) Osteocalcin (ng/ml) PTH (pg/ml) C-telopeptide (ng/ml) IGF-1 (ng/ml)
0.987 −0.275 0.891 −0.506 0.786 −0.390 0.909 0.139 26.3 9.4 3.6 20.0 21.5 31.9 0.450 227.8
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.127 1.084 0.144 0.919 0.122 0.847 0.111 0.852 8.2 0.4 0.6 9.0 9.7 12.8 0.329 77.9
After OXC (mean ± SD) 1.010 −0.071 1.005 −0.268 0.790 −0.355 0.907 0.126 27.0 9.2 3.5 17. 9 19.8 35.0 0.364 225.2
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.124 1.082 0.104 0.902 0.118 0.842 0.111 0.838 8.9 0.4 0.4 6.2 6.9 15.2 0.213 88.5
Corrected p-valuea
Cohen’s d
N.S. N.S. 0.0001 N.S. N.S. N.S. N.S. N.S. N.S. 0.0087 N.S. 0.0499 N.S. N.S. N.S. N.S.
−0.183 −0.188 −0.919 −0.261 −0.033 −0.041 0.018 0.015 −0.082 0.500 0.200 0.395 0.205 −0.221 0.317 0.031
BMD, bone mineral density, SD, standard deviation; 25-OHD, 25-hydroxyvitamin D; bone specific ALP, bone specific alkaline phosphatase; PTH, parathyroid hormone. p < 0.05, significant comparing with baseline; N.S., not significant. a Adjusted p-values for age, sex, dose, and duration of treatment by using repeated measures ANOVA with Bonferroni’s correction.
rus, bone specific ALP, osteocalcin, PTH, C-telopeptide, and IGF-1), the serum levels of calcium (p = 0.0087) and bone specific ALP (p = 0.0499) were significantly decreased after OXC monotherapy. The effect sizes for retesting data were ranged from 0.02 to 0.92 (mean 0.23 ± 0.23), and the change of effect size was less than a half of standard deviation. The effect size change in those three parameters (L2 to L4 BMD, serum calcium, bone specific ALP) for bone health (mean 0.60 ± 0.28), which showed significant adjusted pvalue after OXC medication, was higher than the effect size change of the other bone parameters (mean 0.14 ± 0.10).
Gender differences in bone strength and metabolism across OXC treatment Repeated measures ANOVA with Bonferroni’s correction of confounders including age, average dose, and treatment duration were applied in each gender group. BMD at the lumbar spine (L2 to L4) was significantly increased after OXC monotherapy in female patients (p = 0.012) (e-Table 1). However, BMD in other regions and biochemical markers of bone metabolism did not change significantly in a female group. However, male patients showed a non-significant trend of BMD increase and C-telopeptide decrease after OXC therapy (p = 0.071, p = 0.099). Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.eplepsyres.2013.09.009.
Discussion The present study revealed that long-term OXC monotherapy did not have negative effect on bone health. We had adjusted potential confounding factors such as age,
sex, treatment duration, OXC dosage, physical activity, and calcium-containing drug. Furthermore, we analyzed the effect of OXC on BMD and bone metabolism in each gender group. To the best of our knowledge, this is the first report to estimate the effect of OXC monotherapy on bone health in drug naïve adult patients. We used repeated measures ANOVA to adjust the effects of confounding variables and calculated the effect size for retesting data to estimate the magnitude of the relationship with OXC treatment. Among biochemical bone markers, serum calcium and bone specific ALP decreased significantly after OXC treatment. However, there are several issues with respect to clinical interpretation. First, none of the patients was diagnosed as osteopenia or osteoporosis before or after a long-term OXC monotherapy. Thus the small increase of BMD at L2 to L4 spines after OXC treatment seems to be not significant clinically. Second, the lack of healthy control group constitutes a weakness of our study although all patients were drug naïve and the advanced statistical analysis was performed. Third, the measurement of bone biochemical markers revealed that only bone specific ALP and the serum calcium level decreased significantly after OXC therapy. Abnormalities of serum calcium was not always associated with low level of 25-OHD (Weinstein et al., 1984). Increased bone turnover markers, including bone specific ALP and osteocalcin, may be considered as an important contributing factors for bone disease in epilepsy patients (Feldkamp et al., 2000). Bone specific ALP increase reflects the increased turnover rate associated with bone destruction of aging, menopause, anabolic therapy, and various conditions affecting bone metabolism (Cosman et al., 1996; Garnero et al., 1996; Jenkins, 2001; Ross and Knowlton, 1998). In our study, bone specific ALP as a marker of bone formation was reduced and other biochemical markers including C-telopeptide were not changed significantly after OXC monotherapy. Therefore,
446 the alteration of a few biochemical markers across OXC therapy might be insufficient to suggest significant bone changes by OXC monotherapy. The AED effects on bone metabolism may be different between men and women. One study reported that osteopenia occurs more frequently in women, while the other study showed that osteopenia is more common in men (Farhat et al., 2002; Sato et al., 2001). Another study showed no significant change in the biochemical markers of bone metabolism and BMD after one year of OXC administration in both men and women (Cetinkaya et al., 2009). Previous studies showed conflicting results on the gender effect on bone health. In our study, only women revealed the solitary increment of L2-4 BMD without significant changes of BMD at other sites and biochemical markers after OXC monotheray whereas men showed no significant change of any test. But the sample size of each gender group was small (19—22). Further long-term studies with a larger sample size are recommended to clarify the gender effect of OXC on bone metabolism in epilepsy patients. A previous study in 14 children with idiopathic epilepsy treated with OXC for more than 1 year showed that serum ALP concentrations were higher and BMD values were significantly reduced in the patient group compared to the healthy controls (Babayigit et al., 2006). However, there was no baseline measurement for BMD and bone metabolism in patients treated with OXC. So it is not clear if the changes were induced solely by OXC administration. Cansu et al. evaluated the alterations in bone strength and metabolism in 34 children with newly diagnosed epilepsy after receiving 18 months of OXC monotherapy and reported a significant decrease in 25-OHD levels after OXC administration with no correlation between 25-OHD levels and BMD (Cansu et al., 2008). Another study in children with idiopathic focal epilepsy showed that OXC treatment is associated with reduced 25-OHD levels and elevated biochemical markers enhancing bone turnover (Babacan et al., 2012). In a study with 24 adult patients (mean age 41 ± 14 years, males 71%), OXC monotherapy for a mean period of 1.1 years showed significantly reduced 25-OHD level compared to that of the healthy group (Mintzer et al., 2006). Although reduced 25-OHD levels and elevated PTH and bone specific ALP in the OXC monotherapy group were consistent with increased bone turnover, they were not measured before OXC administration. On the other hand, another study for bone health in 28 adult epilepsy patients (mean age 28 ± 11 years, males 36%) and healthy controls showed no harmful effect on BMD and biochemical markers by OXC therapy for one year (Cetinkaya et al., 2009). Forty-one drug naïve epilepsy patients in our study revealed similar result with no definite negative effect on bone health after OXC treatment for around one year. A hypothesis for the negative effect of OXC on BMD or biochemical markers of bone metabolism is that OXC may have minimal dose-dependent induction property of the P-450 hepatic enzyme system (Isojarvi et al., 1994; Patsalos et al., 1990). The enzyme-inducing AEDs were considered to decrease 25-OHD levels secondary to hepatic enzyme induction, producing reduction in vitamin D-mediated bone mineralization and intestinal calcium absorption (Pack and Morrell, 2001; Verrotti et al., 2010). This subsequently
D.L. Koo et al. causes a compensatory increase in PTH levels, which stimulates the production of P450C1, the enzyme responsible for the conversion of 25-OHD to 1,25-dihydroxyvitamin D (1,25-OHD), which is the biologically active form of the molecule (Omdahl et al., 2002; Zerwekh et al., 1982). The chronic elevation of PTH levels causes an increase in bone turnover, which leads to long-term loss of bone mass (Souberbielle et al., 1999). An alternative explanation is that OXC may have a direct effect on bone cell proliferation, leading to reduced growth of human bone cells, as proposed for CBZ (Feldkamp et al., 2000). In conclusion, OXC monotherapy appears to have no definite harmful effects on bone health in epilepsy patients. Our study provides evidence that OXC may be a rational AED in epilepsy patients who are vulnerable to bone health problems. However, the absence of healthy control group is a weak point of our study. It should be noted that the duration of OXC treatment in our study may not be sufficient to determine certain effects on bone health that may change over time. Thus, a future prospective study is needed with larger sample size, a control group and the longer follow-up duration of OXC monotherapy.
Acknowledgments This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (No. A110097) and by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020).
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447 Pack, A.M., Morrell, M.J., Marcus, R., Holloway, L., Flaster, E., Done, S., Randall, A., Seale, C., Shane, E., 2005. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann. Neurol. 57, 252—257. Pack, A.M., Morrell, M.J., Randall, A., McMahon, D.J., Shane, E., 2008. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology 70, 1586—1593. Patsalos, P.N., Zakrzewska, J.M., Elyas, A.A., 1990. Dose dependent enzyme induction by oxcarbazepine? Eur. J. Clin. Pharmacol. 39, 187—188. Ross, P.D., Knowlton, W., 1998. Rapid bone loss is associated with increased levels of biochemical markers. J. Bone Miner. Res. 13, 297—302. Sato, Y., Kondo, I., Ishida, S., Motooka, H., Takayama, K., Tomita, Y., Maeda, H., Satoh, K., 2001. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 57, 445—449. Sheth, R.D., Hermann, B.P., 2007. Bone mineral density with lamotrigine monotherapy for epilepsy. Pediatr. Neurol. 37, 250—254. Souberbielle, J.C., Cormier, C., Kindermans, C., 1999. Bone markers in clinical practice. Curr. Opin. Rheumatol. 11, 312—319. Souverein, P.C., Webb, D.J., Petri, H., Weil, J., Van Staa, T.P., Egberts, T., 2005. Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General Practice Research Database. Epilepsia 46, 304—310. Souverein, P.C., Webb, D.J., Weil, J.G., Van Staa, T.P., Egberts, A.C., 2006. Use of antiepileptic drugs and risk of fractures: case—control study among patients with epilepsy. Neurology 66, 1318—1324. Takahashi, A., Onodera, K., Kamei, J., Sakurada, S., Shinoda, H., Miyazaki, S., Saito, T., Mayanagi, H., 2003. Effects of chronic administration of zonisamide, an antiepileptic drug, on bone mineral density and their prevention with alfacalcidol in growing rats. J. Pharmacol. Sci. 91, 313—318. Valimaki, M.J., Tiihonen, M., Laitinen, K., Tahtela, R., Karkkainen, M., Lamberg-Allardt, C., Makela, P., Tunninen, R., 1994. Bone mineral density measured by dual-energy x-ray absorptiometry and novel markers of bone formation and resorption in patients on antiepileptic drugs. J. Bone Miner. Res. 9, 631—637. Verrotti, A., Coppola, G., Parisi, P., Mohn, A., Chiarelli, F., 2010. Bone and calcium metabolism and antiepileptic drugs. Clin. Neurol. Neurosurg. 112, 1—10. Verrotti, A., Greco, R., Latini, G., Morgese, G., Chiarelli, F., 2002. Increased bone turnover in prepubertal, pubertal, and postpubertal patients receiving carbamazepine. Epilepsia 43, 1488—1492. Vestergaard, P., Rejnmark, L., Mosekilde, L., 2004. Fracture risk associated with use of antiepileptic drugs. Epilepsia 45, 1330—1337. von Borstel Smith, M., Crofoot, K., Rodriguez-Proteau, R., Filtz, T.M., 2007. Effects of phenytoin and carbamazepine on calcium transport in Caco-2 cells. Toxicol. In Vitro 21, 855—862. Weinstein, R.S., Bryce, G.F., Sappington, L.J., King, D.W., Gallagher, B.B., 1984. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J. Clin. Endocrinol. Metab. 58, 1003—1009. Zerwekh, J.E., Homan, R., Tindall, R., Pak, C.Y., 1982. Decreased serum 24,25-dihydroxyvitamin D concentration during long-term anticonvulsant therapy in adult epileptics. Ann. Neurol. 12, 184—186.
journal homepage: www.elsevier.com/locate/epilepsyres
Effect of oxcarbazepine on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy Dae Lim Koo a,1, Kyoung Jin Hwang b,1, Suk Won Han c, Ji Young Kim b, Eun Yeon Joo b,∗, Won-Chul Shin d, Hyang Woon Lee e, Dae-Won Seo b, Seung Bong Hong b,∗ a
Department of Neurology, Seoul National University Boramae Hospital, Seoul, Republic of Korea Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Seoul, Republic of Korea c Department of Neurology, East Suwon Hospital, Suwon, Republic of Korea d Department of Neurology, Kyung Hee University East-West Neo Medical Center, Seoul, Republic of Korea e Department of Neurology, Ewha Womans University School of Medicine, Seoul, Republic of Korea b
Received 12 January 2013; received in revised form 20 August 2013; accepted 17 September 2013 Available online 1 October 2013
KEYWORDS Oxcarbazepine; Epilepsy; Bone mineral density; Bone metabolism
Summary Purpose: Antiepileptic drugs (AEDs) may cause adverse effects on bone metabolism and bone mineral density (BMD). The aim of this study is to determine the effect of oxcarbazepine (OXC) monotherapy on biochemical markers of bone metabolism and BMD in epilepsy patients. Methods: Forty-one new onset drug naïve epilepsy patients were recruited (19 females, 22 males; mean age: 28.2 ± 8.4 years). We measured biochemical markers of bone metabolism (serum calcium, phosphate, bone alkaline phosphatase, parathyroid hormone, osteocalcin, insulin-like growth factor (IGF)-1, C-telopeptide, Vitamin D3 levels) and BMD by DEXA (dual energy X-ray absorptiometry) method in all patients before and after a long-term OXC monotherapy. Results: Most of biochemical markers were not changed significantly, but serum calcium (p = 0.0087) and bone specific ALP was reduced (p = 0.0499) significantly after OXC monotherapy in epilepsy patients. BMD at the lumbar spine (L2 to L4) was significantly increased after OXC monotherapy (p = 0.0001), revealed by repeated measures ANOVA with Bonferroni’s correction of confounders including sex, age, average dose, and treatment duration. However, BMD at the lumbar spine (L2 to L4) was significantly increased (p = 0.012) only in female patients in each gender analysis.
∗ Corresponding authors at: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 IrwonDong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Tel.: +82 2 3410 3592; fax: +82 2 3410 0052. E-mail addresses: [email protected] (E.Y. Joo), [email protected], [email protected] (S.B. Hong). 1 These two first authors contributed equally to this work.
0920-1211/$ — see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eplepsyres.2013.09.009
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Conclusions: This study demonstrates that a long-term OXC monotherapy does not appear to have harmful effect on bone health in drug naïve epilepsy patients. © 2013 Elsevier B.V. All rights reserved.
Introduction The effects of antiepileptic drugs (AEDs) on bone metabolism were first reported nearly four decades ago. Since then, many reports have indicated that the use of AEDs was associated low vitamin D levels, increased bone turnover, decreased bone mineral density (BMD), and thereby decreased bone strength with increased fracture risk (Lee et al., 2010; Souverein et al., 2005; Vestergaard et al., 2004). However, the underlying pathophysiological mechanisms are not clearly understood. Classic AEDs, such as phenobarbital (PB), primidone (PRM), phenytoin (PHT), and carbamazepine (CBZ) are inducers of microsomal enzymes such as hepatic cytochrome P-450 enzyme system. The most frequently suggested mechanism of these enzyme inducers in bone metabolism is the hepatic induction of the P-450 enzyme system leading to increased catabolism of 25-hydroxyvitamin D (25-OHD), causing relative hypocalcemia, increased levels of parathyroid hormone (PTH), and subsequent low BMD (Babayigit et al., 2006; Mosekilde et al., 1979; Pack and Morrell, 2001; Pack et al., 2008; Souverein et al., 2006; Valimaki et al., 1994; Verrotti et al., 2010). The CBZ, which is structurally similar to oxcarbazepine (OXC), may have multiple mechanisms such as enhanced catabolism of 25-OHD, direct effect on function of bone cells, and direct inhibition of intestinal calcium transport which is not mediated by 25-OHD (Feldkamp et al., 2000; von Borstel Smith et al., 2007). On the contrary to these enzyme inducers, valproic acid, which is known as the inhibitor of CYP-450, may also cause adverse effects on bone health (Boluk et al., 2004; Ecevit et al., 2004; Kumandas et al., 2006). Some old AEDs can evoke direct adverse effects on bone metabolism by another mechanism of bone-mineralization defects, independent of the effects of AEDs on 25-OHD (Hahn et al., 1978). PHT can have a direct adverse effect on bone cells, resulting in decrease in BMD (Chung and Ahn, 1994; Valimaki et al., 1994). Direct effects of these drugs on bone cells were proposed as an alternative mechanism of bone-mineralization defects in epilepsy patients (Feldkamp et al., 2000; Verrotti et al., 2002). The effects of so-called new AEDs on bone are much less known compared to those of classic AEDs. Recent studies showed that lamotrigine (LTG) monotherapy does not have osteopenic effects nor does it cause significant changes in bone metabolism (Kim et al., 2007; Pack et al., 2005; Sheth and Hermann, 2007). Although levetiracetam (LEV) has not shown negative effect on bone (Koo et al., 2013; NissenMeyer et al., 2007; Verrotti et al., 2010), more long-term studies are needed. Topiramate (TPM) also has been considered as favorable AED in bone metabolism, but a recent study suggested that a long-term therapy with TPM could cause the adverse effect on bone health in premenopausal women with epilepsy (Heo et al., 2011). Zonisamide (ZSM) may cause a bone loss by accelerating bone resorption rather
than inhibiting bone formation in an animal study (Takahashi et al., 2003). OXC is a keto analog of CBZ with comparable efficacy but superior safety. It is currently indicated as monotherapy in adults with partial epilepsy and as adjunctive therapy in adults and children with partial or secondarily generalized seizures. Only a few studies evaluated the effect of OXC on BMD. Some studies demonstrated that OXC was associated with reduced 25-OHD levels and elevated biomarkers that suggest increased bone turnover (Babayigit et al., 2006; Cansu et al., 2008; Mintzer et al., 2006). However, a recent study reported that OXC did not have an adverse effect on bone mineral metabolism (Cetinkaya et al., 2009). These controversial results urge further studies exploring the effect of OXC on bone metabolism. The aim of our study is (1) to estimate the changes in BMD and biochemical markers of bone metabolism after a long-term OXC monotherapy in drug naïve epilepsy patients and (2) to evaluate the dose-dependent effect of OXC on bone health.
Methods Ninety two new onset drug naïve epilepsy patients were initially enrolled at the epilepsy clinics of three university hospitals (Samsung Medical Center, Ewha Womans University Mokdong Hospital, Kyung Hee University Medical Center) from January 23, 2009 to April 13, 2010. Patients having partial seizures with or without secondary generalization were included. Of the 92 patients, 51 patients were excluded due to following reasons. Twenty eight patients had to change to different AED or add other AED to OXC during the study period, and 11 patients dropped out due to follow-up loss. Additionally we excluded patients who had used calcium supplements (n = 4), and subjects who revealed osteoporosis with T score of -2.5 or lower (n = 4), abnormal laboratory findings (Neutrophils ≤1500/mm3 , platelets ≤100,000/mm3 , and ALT, AST, bilirubin, BUN, creatinine, Na/K ≥two times of normal level) (n = 4) from this study. Finally, 41 patients were included and had BMD and the measurement of biochemical markers for bone metabolism both at baseline and follow-up periods. The dietary habit and physical activity of the patients were evaluated periodically at a baseline period, every three months after OXC administration, and at the end of the study. The habits of daily diet including the contents of meals and snacks were checked by a general questionnaire. The physical activity was estimated by the duration and frequency of specific exercises and daily activities. The patients who avoided normal physical activity due to physical or mental impairments were excluded. All patients were instructed to keep the current degree of dietary habit and physical activity during the entire study period. Weight and height were measured and body mass index (BMI) was cal-
444 culated (kg/m2 ). OXC was given at a dose of 300 mg/day for the first 2 weeks and at a dose of 600 mg/day for the next 2 weeks. From the fifth week onwards, the dose of OXC was gradually increased up to a maximum of 1800 mg/day in order to control seizures. This study was approved by the local institutional review board at Samsung Medical Center. Written informed consent for participation in the trial was obtained from each patient or his/her legal representative. BMD was assessed twice, before and after OXC monotherapy. BMD of the lumbar spine and femur was assessed using the DEXA (dual energy X-ray absorptiometry) technique. Normal T-score is −1.0 or higher, osteopenia is defined as a T-score between −1.0 and −2.5, and osteoporosis as a T-score of −2.5 or lower. Biochemical markers of bone metabolism (vitamin D3, calcium, phosphorus, bone alkaline phosphatase (ALP), osteocalcin, PTH, C-telopeptide and insulin-like growth factor 1 (IGF-1)) were also measured twice. Seizure frequency and adverse effect of OXC were evaluated with a self-recorded seizure diary whenever the patient visited the clinic. Statistical analysis of the data was performed using SPSS v.12.0 for Windows. Paired t-test with the adjustment for multiple T tests by Bonferroni’s correction was applied to compare BMD and biochemical markers of bone metabolism before and after OXC treatment. Repeated measures ANOVA test with Bonferroni’s correction was used to exclude the interaction effect of age, sex, treatment duration, and average dose of OXC on BMD and bone metabolism. Furthermore, we analyzed the impact of OXC in each gender too. We calculated the effect size for retesting data, a measure of the magnitude of difference in bone strength. Cohen has suggested that an effect size of 0.2 to 0.3 might be a ‘‘small’’ effect, around 0.5 a ‘‘medium’’ effect and 0.8 to infinity, a ‘‘large’’ effect. Statistical significance was set at p < 0.05.
Results Characteristics of the subjects The clinical characteristics of the subjects are summarized in Table 1. The mean age was 28.2 ± 8.4 years (range; 18—52 years) and 53.7% (n = 22) of the subjects were males. There was no significant difference in BMI between men (24.4 ± 4.2 kg/m2 ) and women (24.0 ± 3.7 kg/m2 ). No patients were taking medications known to affect bone metabolism such as glucocorticoids, hypoglycemic agents, selective serotonin reuptake inhibitors (SSRI), and vitamin D or calcium supplements during the study period. Only five patients included in the present study had taken the concomitant medications which had no effect on bone strength or metabolism during the study period: antihypertensive agent (n = 3), acetaminophen (n = 1), and digestive medication (n = 1). The remaining patients did not take other medications during the study period. Nutrition status including daily calcium intake and pattern of physical exercise revealed no significant change across the total study period. The mean duration of treatment was 11.6 ± 6.0 months (median 10.8, range 6—35). The mean OXC dose at last visit was 824 ± 334 mg per day (median 750, range 300—1800). We also calculated the average dose of OXC because OXC dose at last visit could not accurately reflect the actual exposure to
D.L. Koo et al. Table 1 patients.
Demographics and clinical characteristics of
Clinical variables
Total 41 patients
Age, years (range) 28.2 ± 8.4a (18—52) Men, n (%) 22 (53.7) Height, m 1.66 ± 0.08a Weight, kg 67.3 ± 14.4a 2 BMI, kg/m 24.3 ± 4.0a OXC dose at last visit, mg/day 824 ± 334a (300—1800) (range) Baseline seizure frequency, 4.9 ± 9.1a (median 2.4) number/month Type of seizure Partial seizure, n (%) 28 (68.3) With secondary 12 (29.3) generalization Without secondary 16 (39.0) generalization Generalized seizure, n (%) 13 (31.7) Etiology Cryptogenic, n 25 Hippocampal sclerosis, n 4 Cortical dysplasia or 6 heterotopia, n Foreign tissue lesion, n 6 Baseline interictal epileptiform dischargeb Temporal, n 10 Extratemporal-unifocal, n 2 Extratemporal-bifocal, n 2 Hemispheric, n 4 Efficacy Seizure free, n (%) 25 (61.0%) ≥50% seizure reduction, n (%) 10 (24.3%) BMI, body mass index; OXC, oxcarbazepine. a Values are mean ± standard deviation. b Eleven patients showed non-epileptiform abnormalities (regional slowing).
OXC over the whole period of the study. The average dose of OXC during study was mean 747 ± 307 mg/day (median 620, range 290—1680). Twenty-eight subjects had partial seizures with or without secondary generalization and 13 had generalized seizures. Of 41 patients, 4 had hippocampal sclerosis, 6 had cortical dysplasia or heterotopias, and 6 had foreign tissue lesions. Seizure frequency at baseline was 4.9 ± 9.1 per month. After OXC monotherapy, 25 (61.0%) subjects became seizure-free and 10 (24.3%) subjects had ≥50% reduction in seizure frequency.
Bone mineral density and biochemical markers of bone metabolism BMD at the lumbar spine (L2 to L4) was significantly increased after OXC monotherapy (p = 0.0001), as revealed by using repeated measures ANOVA with Bonferroni’s correction of confounding factors including sex, age, average dose, and treatment duration (Table 2). There were no significant changes in the BMD values and T-scores of all other regions. Among biochemical markers (25-OHD, calcium, phospho-
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Table 2 Statistical comparison of BMD and bone metabolism variables across oxcarbazepine (OXC) treatment with adjustment of confounding factors. Before OXC (mean ± SD)
Variables 3
L1-4 BMD (g/cm ) L1-4 t-score L2-4 BMD (g/cm3 ) L2-4 t-score Femur neck BMD (g/cm3 ) Femur neck t-score Femur total BMD (g/cm3 ) Femur total t-score 25-OHD (ng/ml) Calcium (mg/dl) Phosphorus (mg/dl) Bone specific ALP (g/L) Osteocalcin (ng/ml) PTH (pg/ml) C-telopeptide (ng/ml) IGF-1 (ng/ml)
0.987 −0.275 0.891 −0.506 0.786 −0.390 0.909 0.139 26.3 9.4 3.6 20.0 21.5 31.9 0.450 227.8
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.127 1.084 0.144 0.919 0.122 0.847 0.111 0.852 8.2 0.4 0.6 9.0 9.7 12.8 0.329 77.9
After OXC (mean ± SD) 1.010 −0.071 1.005 −0.268 0.790 −0.355 0.907 0.126 27.0 9.2 3.5 17. 9 19.8 35.0 0.364 225.2
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.124 1.082 0.104 0.902 0.118 0.842 0.111 0.838 8.9 0.4 0.4 6.2 6.9 15.2 0.213 88.5
Corrected p-valuea
Cohen’s d
N.S. N.S. 0.0001 N.S. N.S. N.S. N.S. N.S. N.S. 0.0087 N.S. 0.0499 N.S. N.S. N.S. N.S.
−0.183 −0.188 −0.919 −0.261 −0.033 −0.041 0.018 0.015 −0.082 0.500 0.200 0.395 0.205 −0.221 0.317 0.031
BMD, bone mineral density, SD, standard deviation; 25-OHD, 25-hydroxyvitamin D; bone specific ALP, bone specific alkaline phosphatase; PTH, parathyroid hormone. p < 0.05, significant comparing with baseline; N.S., not significant. a Adjusted p-values for age, sex, dose, and duration of treatment by using repeated measures ANOVA with Bonferroni’s correction.
rus, bone specific ALP, osteocalcin, PTH, C-telopeptide, and IGF-1), the serum levels of calcium (p = 0.0087) and bone specific ALP (p = 0.0499) were significantly decreased after OXC monotherapy. The effect sizes for retesting data were ranged from 0.02 to 0.92 (mean 0.23 ± 0.23), and the change of effect size was less than a half of standard deviation. The effect size change in those three parameters (L2 to L4 BMD, serum calcium, bone specific ALP) for bone health (mean 0.60 ± 0.28), which showed significant adjusted pvalue after OXC medication, was higher than the effect size change of the other bone parameters (mean 0.14 ± 0.10).
Gender differences in bone strength and metabolism across OXC treatment Repeated measures ANOVA with Bonferroni’s correction of confounders including age, average dose, and treatment duration were applied in each gender group. BMD at the lumbar spine (L2 to L4) was significantly increased after OXC monotherapy in female patients (p = 0.012) (e-Table 1). However, BMD in other regions and biochemical markers of bone metabolism did not change significantly in a female group. However, male patients showed a non-significant trend of BMD increase and C-telopeptide decrease after OXC therapy (p = 0.071, p = 0.099). Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.eplepsyres.2013.09.009.
Discussion The present study revealed that long-term OXC monotherapy did not have negative effect on bone health. We had adjusted potential confounding factors such as age,
sex, treatment duration, OXC dosage, physical activity, and calcium-containing drug. Furthermore, we analyzed the effect of OXC on BMD and bone metabolism in each gender group. To the best of our knowledge, this is the first report to estimate the effect of OXC monotherapy on bone health in drug naïve adult patients. We used repeated measures ANOVA to adjust the effects of confounding variables and calculated the effect size for retesting data to estimate the magnitude of the relationship with OXC treatment. Among biochemical bone markers, serum calcium and bone specific ALP decreased significantly after OXC treatment. However, there are several issues with respect to clinical interpretation. First, none of the patients was diagnosed as osteopenia or osteoporosis before or after a long-term OXC monotherapy. Thus the small increase of BMD at L2 to L4 spines after OXC treatment seems to be not significant clinically. Second, the lack of healthy control group constitutes a weakness of our study although all patients were drug naïve and the advanced statistical analysis was performed. Third, the measurement of bone biochemical markers revealed that only bone specific ALP and the serum calcium level decreased significantly after OXC therapy. Abnormalities of serum calcium was not always associated with low level of 25-OHD (Weinstein et al., 1984). Increased bone turnover markers, including bone specific ALP and osteocalcin, may be considered as an important contributing factors for bone disease in epilepsy patients (Feldkamp et al., 2000). Bone specific ALP increase reflects the increased turnover rate associated with bone destruction of aging, menopause, anabolic therapy, and various conditions affecting bone metabolism (Cosman et al., 1996; Garnero et al., 1996; Jenkins, 2001; Ross and Knowlton, 1998). In our study, bone specific ALP as a marker of bone formation was reduced and other biochemical markers including C-telopeptide were not changed significantly after OXC monotherapy. Therefore,
446 the alteration of a few biochemical markers across OXC therapy might be insufficient to suggest significant bone changes by OXC monotherapy. The AED effects on bone metabolism may be different between men and women. One study reported that osteopenia occurs more frequently in women, while the other study showed that osteopenia is more common in men (Farhat et al., 2002; Sato et al., 2001). Another study showed no significant change in the biochemical markers of bone metabolism and BMD after one year of OXC administration in both men and women (Cetinkaya et al., 2009). Previous studies showed conflicting results on the gender effect on bone health. In our study, only women revealed the solitary increment of L2-4 BMD without significant changes of BMD at other sites and biochemical markers after OXC monotheray whereas men showed no significant change of any test. But the sample size of each gender group was small (19—22). Further long-term studies with a larger sample size are recommended to clarify the gender effect of OXC on bone metabolism in epilepsy patients. A previous study in 14 children with idiopathic epilepsy treated with OXC for more than 1 year showed that serum ALP concentrations were higher and BMD values were significantly reduced in the patient group compared to the healthy controls (Babayigit et al., 2006). However, there was no baseline measurement for BMD and bone metabolism in patients treated with OXC. So it is not clear if the changes were induced solely by OXC administration. Cansu et al. evaluated the alterations in bone strength and metabolism in 34 children with newly diagnosed epilepsy after receiving 18 months of OXC monotherapy and reported a significant decrease in 25-OHD levels after OXC administration with no correlation between 25-OHD levels and BMD (Cansu et al., 2008). Another study in children with idiopathic focal epilepsy showed that OXC treatment is associated with reduced 25-OHD levels and elevated biochemical markers enhancing bone turnover (Babacan et al., 2012). In a study with 24 adult patients (mean age 41 ± 14 years, males 71%), OXC monotherapy for a mean period of 1.1 years showed significantly reduced 25-OHD level compared to that of the healthy group (Mintzer et al., 2006). Although reduced 25-OHD levels and elevated PTH and bone specific ALP in the OXC monotherapy group were consistent with increased bone turnover, they were not measured before OXC administration. On the other hand, another study for bone health in 28 adult epilepsy patients (mean age 28 ± 11 years, males 36%) and healthy controls showed no harmful effect on BMD and biochemical markers by OXC therapy for one year (Cetinkaya et al., 2009). Forty-one drug naïve epilepsy patients in our study revealed similar result with no definite negative effect on bone health after OXC treatment for around one year. A hypothesis for the negative effect of OXC on BMD or biochemical markers of bone metabolism is that OXC may have minimal dose-dependent induction property of the P-450 hepatic enzyme system (Isojarvi et al., 1994; Patsalos et al., 1990). The enzyme-inducing AEDs were considered to decrease 25-OHD levels secondary to hepatic enzyme induction, producing reduction in vitamin D-mediated bone mineralization and intestinal calcium absorption (Pack and Morrell, 2001; Verrotti et al., 2010). This subsequently
D.L. Koo et al. causes a compensatory increase in PTH levels, which stimulates the production of P450C1, the enzyme responsible for the conversion of 25-OHD to 1,25-dihydroxyvitamin D (1,25-OHD), which is the biologically active form of the molecule (Omdahl et al., 2002; Zerwekh et al., 1982). The chronic elevation of PTH levels causes an increase in bone turnover, which leads to long-term loss of bone mass (Souberbielle et al., 1999). An alternative explanation is that OXC may have a direct effect on bone cell proliferation, leading to reduced growth of human bone cells, as proposed for CBZ (Feldkamp et al., 2000). In conclusion, OXC monotherapy appears to have no definite harmful effects on bone health in epilepsy patients. Our study provides evidence that OXC may be a rational AED in epilepsy patients who are vulnerable to bone health problems. However, the absence of healthy control group is a weak point of our study. It should be noted that the duration of OXC treatment in our study may not be sufficient to determine certain effects on bone health that may change over time. Thus, a future prospective study is needed with larger sample size, a control group and the longer follow-up duration of OXC monotherapy.
Acknowledgments This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (No. A110097) and by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020).
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