A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma

R. Nicole Howie, James L. Borke, Zoya Kurago, Asma Daoudi, James Cray, Ibrahim E. Zakhary, Tara L. Brown, J. Nathan Raley, Loan T. Tran, Regina Messer, Fardous Medani, Mohammed E. Elsalanty

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17 Scopus citations

Abstract

This study aims to develop a reproducible rat model for post-traumatic bisphosphonaterelated osteonecrosis of the jaw (BRONJ). In our previous studies using dental extraction as an inducing factor, only 30% - 60% of zoledronate-treated animals fulfilled the definition of clinical BRONJ. We modified the zoledronate regimen and introduced repeated surgical extraction to illicit quantifiable BRONJ in all animals. Eighty retired-breeder female Sprague- Dawley rats were divided between the treatment (IV zoledronate; 80 μg/kg/week for 13 weeks) and control (saline) groups. On week 13, the left mandibular first molar was surgically extracted, followed by the second molar a week later. Animals were euthanized at 1- week, 2-weeks, and 8-weeks following extraction. The occurrence and severity of BRONJ were scored in each animal based on gross and MicroCT analysis. Parameters of bone formation and osteoclast functions at the extraction site were compared between groups. All zoledronate-treated animals developed a severe case of BRONJ that fulfilled the clinical definition of the condition in humans. Osteoclast attachment continued to be defective eight weeks after stopping the treatment. There were no signs of kidney or liver toxicity. Our data confirmed that repeated surgical extraction (major trauma) by itself consistently precipitated massive bone necrosis in ZA-treated animals, eliminating the need to induce pre-existing infection or comorbidity. These results will be the basis for further studies examining the invivo pathogenesis and prevention of BRONJ.

Original languageEnglish (US)
Article numbere132520
JournalPloS one
Volume10
Issue number7
DOIs
StatePublished - Jul 17 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Howie, R. N., Borke, J. L., Kurago, Z., Daoudi, A., Cray, J., Zakhary, I. E., Brown, T. L., Raley, J. N., Tran, L. T., Messer, R., Medani, F., & Elsalanty, M. E. (2015). A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma. PloS one, 10(7), [e132520]. https://doi.org/10.1371/journal.pone.0132520