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

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 an...

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Published inPloS 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
LanguageEnglish
Published United States Public Library of Science 14.12.2015
Public Library of Science (PLoS)
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Summary: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.
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Competing Interests: The authors have declared that no competing interests exist.
Conceived and designed the experiments: KT HK MU. Performed the experiments: KT MY TN TA JT. Analyzed the data: KT MY ES. Contributed reagents/materials/analysis tools: MS HU. Wrote the paper: KT MU.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0144355