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      Effect of Long-term Carbamazepine Therapy on Bone Health

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          Abstract

          Introduction:

          Recent research reported that prolonged use of AET is associated with changes in bone metabolism, with consequent reduction in bone mineral density (BMD) and increased risk of fractures.

          Objectives:

          Therefore, the aim of our study was to investigate the effects of carbamazepine on serum levels of 25 -hydroxyvitamin D and on biomarker of bone formation and resorption (serum levels of osteocalcin).

          Material and methods:

          We measured serum levels of 25-OHD and osteocalcin (OCLN) in normal controls (n=30) and in epilepsy patients taking carbamazepine (CBZ) (n=50) in monotherapy for a period of at least twelve months. For each participant, mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry method.

          Results:

          The average value of vitamin D in serum was significantly lower in CBZ group than in control group (Vit D 17.03+12.86 vs. 32.03+6.99, p=0.0001). The average value of osteocalcin in serum was significantly higher in CBZ group than in control group (26.06+10.78 vs. 19.64+6, 54, p=0.004).BMD value in CBZ group was significantly lower than in control group (T. score CBZ: 0.08+1.38 vs. T. score control: 0.73+ 1.13, p=0.031; Z score CBZ:-0.05+1.17 vs. Z. score control: 0.55+0.79, p=0.015).

          Conclusion:

          AEDs are associated with bone disease, as evidenced by biochemical abnormalities and decreased BMD. Patients on long-term antiepileptic therapy, especially with enzyme-inducing agents, could benefit of routine measurement of biochemical markers of bone turnover, and BMD measurement as part of osteoporosis investigation.

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          Most cited references40

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          The epidemiology of epilepsy revisited.

          Epidemiology is the study of the dynamics of a medical condition in a population. There are many shortcomings in the understanding of the epidemiology of epilepsy mostly caused by methodological problems. These include diagnostic accuracy, case ascertainment, and selection bias. In this article recent progress in this area is discussed and suggestions for future research are made. It is generally accepted that in developed countries the incidence is around 50/100 000/year. In resource-poor countries, the incidence is likely to be higher. Prevalence of active epilepsy is in the range of 5-10/1000 in most locations, although it might be higher in some isolates. Age-specific incidence rates have changed, with a decrease in younger age groups and an increase in persons above 60 years. The overall prognosis for seizure control is good and over 70% will enter remission. Epilepsy carries an increased risk of premature death particularly in patients with chronic epilepsy. Sudden unexpected death has been increasingly recognized as a major culprit for this increased mortality. There is geographic variation in the incidence of epileptic syndromes likely to be associated with genetic and environmental factors, although as yet causality has not been fully established. The complete range of aetiologies in the general population is not known. Few predictors of outcome are recognized and it is difficult to prognosticate in any individual case. Knowledge is patchy about the epidemiology of sudden unexpected death in epilepsy. Future epidemiological research needs to address these issues if we are to progress.
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            Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia.

            The balance between bioactivation and degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is critical for ensuring appropriate biological effects of vitamin D. Cytochrome P450, family 24-mediated (CYP24-mediated) 24-hydroxylation of 1,25(OH)2D3 is an important step in the catabolism of 1,25(OH)2D3. The enzyme is directly regulated by vitamin D receptor (VDR), and it is expressed mainly in the kidney, where VDR is also abundant. A recent report suggests that activation of steroid and xenobiotic receptor (SXR) also enhances the expression of CYP24, providing a new molecular mechanism of drug-induced osteomalacia. However, here we showed that activation of SXR did not induce CYP24 expression in vitro and in vivo, nor did it transactivate the CYP24 promoter. Instead, SXR inhibited VDR-mediated CYP24 promoter activity, and CYP24 expression was very low in tissues containing high levels of SXR, including the small intestine. Moreover, 1,25(OH)2D3-induced CYP24 expression was enhanced in mice lacking the SXR ortholog pregnane X receptor, and treatment of humans with the SXR agonist rifampicin had no effect on intestinal CYP24 expression, despite demonstration of marked CYP3A4 induction. Combined with our previous findings that CYP3A4, not CYP24, plays the dominant role in hydroxylation of 1,25(OH)2D3 in human liver and intestine, our results indicate that SXR has a dual role in mediating vitamin D catabolism and drug-induced osteomalacia.
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              Effect of antiepileptic drugs on bone density in ambulatory patients.

              Long-term antiepileptic drug (AED) use causes multiple abnormalities in calcium and bone metabolism that have been most extensively described in institutionalized patients. The objective is to determine the effect of AED on vitamin D levels and bone density in ambulatory patients and to compare the effects of enzyme-inducing and -noninducing AED and of single vs multiple therapy on bone density. A cross-sectional evaluation was conducted of 71 patients (42 adults and 29 children/adolescents) on anticonvulsant therapy for at least 6 months who presented to neurologists at a tertiary referral center. Bone mineral density (BMD) as well as serum 25 hydroxy-vitamin D (25-OHD) levels were measured. A detailed questionnaire assessing calcium intake as well as previous and current intake of antiepileptic medications was administered to all patients. Over 50% of adults and children/adolescents had low 25-OHD levels, but this finding did not correlate with BMD. Antiepileptic therapy decreased BMD in adults. Generalized seizures, duration of epilepsy, and polypharmacy were significant determinants of BMD, more so at skeletal sites enriched in cortical bone. Subjects on enzyme-inducing drugs such as phenytoin, phenobarbital, carbamazepine, and primidone tended to have lower BMD than those on noninducers such as valproic acid, lamotrigine, clonazepam, gabapentin, topamirate, and ethosuximide. Epilepsy and its therapy, including the newer drugs, are risk factors for low bone density, irrespective of vitamin D levels. Skeletal monitoring with the institution of appropriate therapy is indicated in patients on chronic antiepileptic therapy.
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                Author and article information

                Journal
                Med Arch
                Med Arch
                Medical Archives
                Medical Archives
                Academy of Medical Sciences of Bosnia and Herzegovina
                0350-199X
                October 2018
                : 72
                : 4
                : 262-266
                Affiliations
                [1 ]Neurology Clinic, Clinical Center of Sarajevo University, Sarajevo, Bosnia and Herzegovina
                Author notes
                Corresponding author:Nevena Mahmutbegovic, MD, PhDCandidate, Neurology Clinic, Clinical Center of Sarajevo University, Bolnicka 25,71000 Sarajevo, Bosnia and Herzegovina ORCID ID: http://www.orcid.org: 0000-0002-5945-1311+387 63 284 168 nevenaradulovic@ 123456hotmail.com
                Article
                10.5455/medarh.2018.72.262-266
                6194949
                30514991
                35aea7ec-460f-48f3-b01e-9d6e62600e57
                © 2018 Enra Mehmedika Suljic, Admir Mehicevic, Nevena Mahmutbegovic

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 June 2018
                : 01 August 2018
                Categories
                Original Paper

                antiepileptics,carbamazepine,osteoporosis
                antiepileptics, carbamazepine, osteoporosis

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