title: A Model for Osteonecrosis of the Jaw with Zoledronate Treatment following Repeated Major Trauma.
abstract: This study aims to develop a reproducible rat model for post-traumatic bisphosphonate-related 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 (i.v. 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 in-vivo pathogenesis and prevention of BRONJ.
authors.affiliation: College of Dental Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: R Nicole
authors.initials: RN
authors.lastname: Howie
authors.affiliation: College of Dental Medicine, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: James L
authors.initials: JL
authors.lastname: Borke
authors.affiliation: College of Dental Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Kurago
authors.affiliation: College of Science and Mathematics, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Asma
authors.initials: A
authors.lastname: Daoudi
authors.affiliation: College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Cray
authors.affiliation: School of Dentistry, University of Detroit-Mercy, Detroit, Michigan, United States of America.
authors.forename: Ibrahim E
authors.initials: IE
authors.lastname: Zakhary
authors.affiliation: College of Dental Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Brown
authors.affiliation: College of Dental Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: J Nathan
authors.initials: JN
authors.lastname: Raley
authors.affiliation: College of Dental Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Loan T
authors.initials: LT
authors.lastname: Tran
authors.affiliation: College of Dental Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Regina
authors.initials: R
authors.lastname: Messer
authors.affiliation: College of Dental Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Fardous
authors.initials: F
authors.lastname: Medani
authors.affiliation: College of Dental Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Mohammed E
authors.initials: ME
authors.lastname: Elsalanty
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology*; D004164:Diphosphonates / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000009:adverse effects*; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008334:Mandible / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D017207:Rats, Sprague-Dawley; D000071681:Tartrate-Resistant Acid Phosphatase; D014081:Tooth Extraction; D014945:Wound Healing / Q000187:drug effects; D014947:Wounds and Injuries / Q000150:complications*; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D007527:Isoenzymes; D000077211:Zoledronic Acid; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase