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Monotherapy with Levetiracetam Versus Older AEDs: A Randomized Comparative Trial of Effects on Bone Health

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Abstract

Long-term anti-epileptic drug (AED) therapy is associated with increased fracture risk. This study tested whether substituting the newer AED levetiracetam has less adverse effects on bone than older AEDs. An open-label randomized comparative trial. Participants had “failed” initial monotherapy for partial epilepsy and were randomized to substitution monotherapy with levetiracetam or an older AED (carbamazepine or valproate sodium). Bone health assessments, performed at 3 and 15 months, included areal bone mineral density (aBMD) and content at lumbar spine (LS), total hip (TH), forearm (FA), and femoral neck (FN), radial and tibial peripheral quantitative computed tomography and serum bone turnover markers. Main outcomes were changes by treatment group in aBMD at LS, TH, and FA, radial and tibial trabecular BMD and cortical thickness. 70/84 patients completed assessments (40 in levetiracetam- and 30 in older AED group). Within-group analyses showed decreases in both groups in LS (−9.0 %; p < 0.001 in levetiracetam vs. −9.8 %; p < 0.001 in older AED group), FA (−1.46 %; p < 0.001 vs. −0.96 %; p < 0.001, respectively) and radial trabecular BMD (−1.46 %; p = 0.048 and −2.31 %; p = 0.013, respectively). C-terminal telopeptides of type I collagen (βCTX; bone resorption marker) decreased in both groups (−16.1 %; p = 0.021 vs. −15.2 %; p = 0.028, respectively) whereas procollagen Ι N-terminal peptide (PΙNP; bone formation marker) decreased in older AED group (−27.3 %; p = 0.008). The treatment groups did not differ in any of these measures. In conclusion, use of both levetiracetam and older AEDs was associated with bone loss over 1 year at clinically relevant fracture sites and a reduction in bone turnover.

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Acknowledgments

The authors acknowledge Annie Roten and Tess Bright (Department of Neurology, The Royal Melbourne Hospital, Victoria, Australia) and Lauren Day (The University of Melbourne, The Department of Medicine, The Royal Melbourne Hospital) for their assistance with data collection and Dr. Ashwini Kale (The Bone Densitometry Unit, The Royal Melbourne Hospital) for her assistance with DXA and pQCT scanning. Trial Registration anzctr.org.au Identifier: ACTRN12606000102572.

Funding

This was an investigator-initiated study partly funded by UCB Pharma. UCB Pharma had no role in the study design, data collection, analysis, interpretation of data, nor in the preparation of this article. All authors had full access to the data. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication.

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Authors and Affiliations

  1. Department of Neurology, The Royal Melbourne Hospital, Melbourne, Australia

    Tahir Hakami, Terence J. O’Brien, Marian Todaro & Raju Yerra

  2. Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, 4th Floor Clinical Sciences Building Royal Parade, The Royal Melbourne Hospital, Parkville, 3050, VIC, Australia

    Tahir Hakami, Terence J. O’Brien, Sandra J. Petty, Mary Sakellarides, Jemma Christie, Marian Todaro & John D. Wark

  3. Bone & Mineral Medicine, The Royal Melbourne Hospital, Melbourne, Australia

    John D. Wark

  4. Bone Densitometry Unit, The Royal Melbourne Hospital, Melbourne, Australia

    Susan Kantor

  5. The Melbourne EpiCentre, The Royal Melbourne Hospital, Melbourne, Australia

    Alexandra Gorelik

  6. Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, Australia

    Markus J. Seibel

  7. Faculty of Medicine, Jazan University, Jazan, Saudi Arabia

    Tahir Hakami

Authors
  1. Tahir Hakami
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  2. Terence J. O’Brien
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  3. Sandra J. Petty
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  4. Mary Sakellarides
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  5. Jemma Christie
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  6. Susan Kantor
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  7. Marian Todaro
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  8. Alexandra Gorelik
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  9. Markus J. Seibel
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  10. Raju Yerra
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  11. John D. Wark
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Corresponding author

Correspondence to John D. Wark.

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Conflicts of Interest

Dr. O’Brien reports grants from UCB Pharma, during the conduct of the study; grants from NHMRC, grants from RMH Neuroscience Foundation, grants from Eisai, outside the submitted work. Dr Petty has given an invited lecture on an unrelated topic at a symposium, which was sponsored by UCB Pharma in 2015; honorarium was paid to an employer and no personal funding was received. Dr Seibel reports grants from the Australian NHMRC and speaker fees from Amgen, Eli Lilly, and Sanofi outside the submitted work. Dr. Wark reports grants from UCB PHARMA, during the conduct of the study; grants from Australian NHMRC, outside the submitted work. Others have nothing to disclose.

Human and Animal Rights and Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Melbourne Health Research and Ethics Committee) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

Additional information

Sue Kantor has passed away in December 2012.

Trial Registration anzctr.org.au Identifier: ACTRN12606000102572.

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Hakami, T., O’Brien, T.J., Petty, S.J. et al. Monotherapy with Levetiracetam Versus Older AEDs: A Randomized Comparative Trial of Effects on Bone Health. Calcif Tissue Int 98, 556–565 (2016). https://doi.org/10.1007/s00223-016-0109-7

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  • DOI: https://doi.org/10.1007/s00223-016-0109-7

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