Establishment of an Animal Model of Bisphosphonate-Related Osteonecrosis of the Jaws in Spontaneously Diabetic Torii Rats

• Published in: PloS one Vol. 10; no. 12; p. e0144355
• Main Authors: Takaoka, Kazuki, Yamamura, Michiyo, Nishioka, Toshihiro, Abe, Tetsuya, Tamaoka, Joji, Segawa, Emi, Shinohara, Masami, Ueda, Haruyasu, Kishimoto, Hiromitsu, Urade, Masahiro
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.12.2015; Public Library of Science (PLoS)
• Subjects: Acid phosphatase; Acid phosphatase (tartrate-resistant); Acid Phosphatase - genetics; Acid Phosphatase - metabolism; Acid resistance; Acids; Animals; Apposition; Biocompatibility; Bisphosphonate-Associated Osteonecrosis of the Jaw - complications; Bisphosphonate-Associated Osteonecrosis of the Jaw - metabolism; Bisphosphonate-Associated Osteonecrosis of the Jaw - pathology; Bone Density; Bone Remodeling; Bone turnover; Cancer; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Dielectric properties; Diphosphonates - adverse effects; Disease Models, Animal; Drug delivery systems; Drug dosages; Euthanasia; Exposure; Fractures; Gene Expression; Humans; Imidazoles - adverse effects; Infiltration; Inflammation; Injections, Intravenous; Intravenous administration; Isoenzymes - genetics; Isoenzymes - metabolism; Laboratory animals; Lesions; Male; Maxilla - metabolism; Maxilla - pathology; Maxillofacial surgery; Medical research; Medicine; Microorganisms; Molar - metabolism; Molar - pathology; Molars; Oral cavity; Osteoclasts; Osteoclasts - metabolism; Osteoclasts - pathology; Osteonecrosis; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Risk factors; Rodents; Side effects; Surgery; Tartrate-Resistant Acid Phosphatase; Teeth; Tooth Extraction; Wound healing; Zoledronic Acid; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0144355

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). 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. 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. 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.