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Effects of carbamazepine, eslicarbazepine, valproic acid and levetiracetam on bone microarchitecture in rats

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Abstract

Background

Metabolic bone disease and fractures are a great problem for patients with epilepsy. The use of antiepileptic drugs (AEDs) is known to play an essential role in the progression of bone loss by various pathophysiological mechanisms. The aim of this study was to evaluate the effects of AEDs on bone microstructure as an additional cause of an increased fracture risk in patients with epilepsy.

Methods

Five groups of each of 12 female rats were orally dosed daily for 8 weeks with either carbamazepine (CBZ) (60 mg/kg), eslicarbazepine (ESL) (80 mg/kg), valproic acid (VPA) (300 mg/kg), levetiracetam (LEV) (50 mg/kg) or saline (control (CTL)). Following killing, dissected femurs were analyzed using X-ray micro-computed tomography (µCT), dual-energy X-ray absorptiometry (DXA) and biomechanical testing. In addition, serum bone turnover markers (BTM) were monitored throughout the experiment.

Results

Compared to CTL treatment, VPA decreased bone volume fraction by 19%, decreased apparent density by 14% and increased structural model index by 41%. No changes were observed in bone biomechanics nor mineral density evaluated by DXA or in levels of BTM.

Conclusions

Our findings suggest that VPA affects the microarchitectural properties of the bone. The AEDs CBZ, ESL and LEV appear to have less adverse effects on bone biology and may be a better choice when treating patients with respect to bone health.

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Acknowledgements

The authors specially thank Tanja Hegner and Katja Serena for taking care of the animals and Kira Joensen and Britt Lisette Corfixen for analyzing the samples.

Funding

The study has been funded by an unrestricted educational grant from Eisai Co, Ltd and grants from the Jascha Foundation and the A. P. Møller Foundation, Fonden til Lægevidenskabens Fremme. The sponsors had no role in study design, collection of data, analysis or interpretation of data.

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Authors and Affiliations

  1. Epilepsy Unit, Department of Neurology, Rigshospitalet Glostrup, Valdemar Hansens vej 13, 6th floor, 2600, Glostrup, Denmark

    Sarah Seberg Diemar & Noémi Becser Andersen

  2. OPEN, Open Patient Data Explorative Network, Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, J. B. Winsløws vej 19, 5000, Odense C, Denmark

    Sarah Seberg Diemar, Ming Ding & Niklas Rye Jørgensen

  3. Department of Endocrinology and Nephrology, Nordsjællands Hospital, Dyrehavevej 29, 3400, Hillerød, Denmark

    Anne-Sophie Sejling & Pia Eiken

  4. Department of Clinical Biochemistry, Rigshospitalet Glostrup, Valdemar Hansens vej 1-23, 2600, Glostrup, Denmark

    Maria Ellegaard & Niklas Rye Jørgensen

  5. Orthopaedic Research Laboratory, Department of Orthopaedic Surgery and Traumatology, Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, J. B. Winsløws vej 4, 5000, Odense C, Denmark

    Ming Ding

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  1. Sarah Seberg Diemar
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Contributions

Concept and design of the study: SSD, ASS, PE, NBA, NRJ. Conducting experiments: SSD, ME, MD. Analyzing and interpreting data: SSD, ASS, PE, ME, MD, NBA, NRJ. Writing, critically reviewing and approving the manuscript: SSD, ASS, PE, ME, MD, NBA, NRJ.

Corresponding author

Correspondence to Sarah Seberg Diemar.

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Conflict of interest

SSD has received unrestricted research grants from Eisai Co, Ltd. A-SS has since the initiation of the work been employed by Novo Nordisk A/S. NRJ, ME, and MD have no conflicts of interest to disclose. PE is an advisory board member for Amgen Inc. and Eli Lilly A/S, and on the speakers’ bureau for Amgen Inc. and Eli Lilly A/S, and own shares in Novo Nordisk A/S. NBA is a lecturer at scientific meetings organized by Eisai Co, Ltd, and has received unrestricted research grants from Eisai Co, Ltd.

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Diemar, S.S., Sejling, AS., Eiken, P. et al. Effects of carbamazepine, eslicarbazepine, valproic acid and levetiracetam on bone microarchitecture in rats. Pharmacol. Rep 72, 1323–1333 (2020). https://doi.org/10.1007/s43440-020-00087-1

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