title: Establishment of an Animal Model of Bisphosphonate-Related Osteonecrosis of the Jaws in Spontaneously Diabetic Torii Rats.
abstract: BACKGROUND
  We evaluated the side effects of bisphosphonate (BP) on tooth extraction socket healing in spontaneously diabetic Torii (SDT) rats, an established model of non-obese type 2 diabetes mellitus, to develop an animal model of BP-related osteonecrosis of the jaws (BRONJ).
  
  
  METHODS
  Male Sprague-Dawley (SD) rats and SDT rats were randomly assigned to the zoledronic acid (ZOL)-treated groups (SD/ZOL or SDT/ZOL) or to the control groups (SD/control or SDT/control). Rats in the SD/ZOL or SDT/ZOL groups received an intravenous bolus injection of ZOL (35 μg/kg) every 2 weeks. Each group consisted of 6 rats each. Twenty-one weeks after ZOL treatment began, the left maxillary molars were extracted. The rats were euthanized at 2, 4, or 8 weeks after tooth extraction, and the total maxillae were harvested for histological and histochemical studies.
  
  
  RESULTS
  In the oral cavity, bone exposure persisted at the tooth extraction site in all rats of the SDT/ZOL group until 8 weeks after tooth extraction. In contrast, there was no bone exposure in SD/control or SDT/control groups, and only 1 of 6 rats in the SD/ZOL group showed bone exposure. Histologically, necrotic bone areas with empty lacunae, microbial colonies, and less invasion by inflammatory cells were observed. The number of tartrate-resistant acid phosphatase-positive osteoclasts was lower in the SDT/ZOL group than in the SD/control group. The mineral apposition rate was significantly lower in the SDT/ZOL group compared with the SD/control group.
  
  
  CONCLUSIONS
  This study demonstrated the development of BRONJ-like lesions in rats and suggested that low bone turnover with less inflammatory cell infiltration plays an important role in the development of BRONJ.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takaoka
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Yamamura
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nishioka
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Tamaoka
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Segawa
authors.affiliation: Planning and Development Section, CLEA Japan, Inc., Meguro-ku, Tokyo, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Laboratory of Immunobiology, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo, Japan.
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kishimoto
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Urade
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D015519:Bone Density; D016723:Bone Remodeling; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D004164:Diphosphonates / Q000009:adverse effects*; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008437:Maxilla / Q000378:metabolism / Q000473:pathology*; D008963:Molar / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D000071681:Tartrate-Resistant Acid Phosphatase; D014081:Tooth Extraction; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D007527:Isoenzymes; D000077211:Zoledronic Acid; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase