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

Kazuki Takaoka,Masami Shinohara,Emi Segawa,Toshihiro Nishioka,Hiromitsu Kishimoto,Tetsuya Abe,Haruyasu Ueda,Masahiro Urade,Joji Tamaoka,Michiyo Yamamura,Valérie Geoffroy

doi:10.1371/journal.pone.0144355

Kazuki Takaoka, Masami Shinohara + Show 9 more

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https://doi.org/10.1371/journal.pone.0144355

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Journal: PloS one	Publication Date: Dec 14, 2015
Citations: 14	License type: CC BY 4.0

Affiliation: Hyogo Medical University, Hyogo University

Abstract

BackgroundWe 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).Materials and MethodsMale 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.ResultsIn 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.ConclusionsThis 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.

Highlights

Bisphosphonates (BPs) are selectively taken up by osteoclasts and strongly inhibit bone resorption by inducing osteoclast apoptosis [1,2]
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)
Bone exposure persisted at the tooth extraction site in all rats of the SDT/ Zoledronic acid (ZOL) group until 8 weeks after tooth extraction

Summary

Introduction

Bisphosphonates (BPs) are selectively taken up by osteoclasts and strongly inhibit bone resorption by inducing osteoclast apoptosis [1,2]. O’Ryan et al [11] retrospectively reviewed healthcare databases, medical charts, and clinic files to identify all patients exposed to IV BPs who had a diagnosis of BRONJ They reported that the most common clinical comorbidity in their cohort was diabetes mellitus (32.2%), which is considered a systemic risk factor for the development of BRONJ. We focused on the risk factor of diabetes and studied the side effects of ZOL on tooth extraction socket healing and the development of BRONJ-like lesions in spontaneously diabetic Torii (SDT) rats, which is an established animal model of non-obese type 2 diabetes. 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).

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