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Zoledronate induces bisphosphonate-related osteonecrosis of the jaw in osteopenic sheep

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Abstract

Objectives

Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) occurs in 1 % of patients with medication-induced osteoporosis treated with bisphosphonates. Sheep are an established large animal model for investigating osteoporotic skeletal changes. Zoledronate significantly reduces tissue mineral variability in ovariectomized sheep. The aim of this study was to analyze bone healing after tooth extraction in sheep with induced osteopenia and zoledronate administration.

Materials and methods

Eight adult ewes were randomly divided into two groups of four animals. All sheep underwent ovariectomy and a low-calcium diet. Dexamethasone was administered weekly for 16 weeks. Zoledronate was then given every third week for a further 16 weeks in four sheep; these infusions were repeated after extraction of two lower premolars. Four sheep without zoledronate administrations served as controls.

Results

Due to general health conditions, two sheep of the zoledronate group had to be excluded before surgery. The remaining two sheep of this group developed BP-ONJ lesions at the extraction site and various other sites in both jaws. Control group animals showed uneventful wound healing. Histology of the alveolar processes as well as lumbar spine revealed larger portions of old bone and smaller portions of new bone in the zoledronate group.

Conclusions

This animal study showed uneventful wound healing after tooth extraction in osteopenic sheep whereas zoledronate treatment leads to development of BP-ONJ-like lesions.

Clinical relevance

As bisphosphonate administration is a standard treatment for glucocorticoid-induced osteoporosis, this model can be used for further research in pathogenesis and management of bisphosphonate-related adverse events.

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Acknowledgments

This study was funded by the AO Foundation by way of the AOCMF R&D Research Commission (Grant No C-11-11-V). The study was conducted in an AAALAC accredited facility and followed the ARRIVE guidelines. We thank Luca Werner for his help with preparing and analyzing the histological samples and Stephan Zeiter for his assistance with the animal model.

Conflict of interest

Pit J. Voss declares that he has no conflict of interest.

Martin J. Stoddart declares that he has no conflict of interest.

Anke Bernstein declares that he has no conflict of interest.

Rainer Schmelzeisen declares that he has no conflict of interest.

Katja Nelson declares that he has no conflict of interest.

Vincent A. Stadelmann declares that he has no conflict of interest.

Thomas Ziebart declares that he has no conflict of interest.

Philipp J. Poxleitner declares that he has no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany

    Pit J. Voss, Rainer Schmelzeisen, Katja Nelson & Philipp J. Poxleitner

  2. AO Research Institute Davos, Clavadelerstr. 8, 7270, Davos, Switzerland

    Martin J. Stoddart, Vincent Stadelmann & Philipp J. Poxleitner

  3. Department of Orthopedics and Traumatology, University Medical Center Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany

    Anke Bernstein

  4. Department of Oral and Maxillofacial Surgery, University Hospital Mainz, Augustusplatz 2, 55131, Mainz, Germany

    Thomas Ziebart

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  1. Pit J. Voss
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Correspondence to Pit J. Voss.

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Voss, P.J., Stoddart, M.J., Bernstein, A. et al. Zoledronate induces bisphosphonate-related osteonecrosis of the jaw in osteopenic sheep. Clin Oral Invest 20, 31–38 (2016). https://doi.org/10.1007/s00784-015-1468-6

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  • DOI: https://doi.org/10.1007/s00784-015-1468-6

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