Establishment and assessment of rodent models of medication-related osteonecrosis of the jaw (MRONJ)

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is primarily associated with administering antiresorptive or antiangiogenic drugs. Despite significant research on MRONJ, its pathogenesis and effective treatments are still not fully understood. Animal models can be used to simulate the pathophysiological features of MRONJ, serving as standardized in vivo experimental platforms to explore the pathogenesis and therapies of MRONJ. Rodent models exhibit excellent effectiveness and high reproducibility in mimicking human MRONJ, but classical methods cannot achieve a complete replica of the pathogenesis of MRONJ. Modified rodent models have been reported with improvements for better mimicking of MRONJ onset in clinic. This review summarizes representative classical and modified rodent models of MRONJ created through various combinations of systemic drug induction and local stimulation and discusses their effectiveness and efficiency. Currently, there is a lack of a unified assessment system for MRONJ models, which hinders a standard definition of MRONJ-like lesions in rodents. Therefore, this review comprehensively summarizes assessment systems based on published peer-review articles, including new approaches in gross observation, histological assessments, radiographic assessments, and serological assessments. This review can serve as a reference for model establishment and evaluation in future preclinical studies on MRONJ.

Fig. 1

Footprints of MRONJ rodent models. Representative MRONJ rodent models from 2009 to 2021 were established by Sonis et al., Mawardi et al., Aghaloo et al., Aguirre et al., Kang et al., Williams et al., Kim et al., Curra et al., Rao et al., and Mine et al.

Fig. 2

General procedure of establishing MRONJ rodent models. The first step is drug administration with bisphosphonates or other related drugs by subcutaneous injection, intraperitoneal injection, intravenous injection, or intramuscular injection. The second step is to deploy local stimulation identified as a common risk factor, such as tooth extraction, infection induction, or mechanical stimuli

Fig. 3

Main approaches for MRONJ treatment tested in rodent models involve novel drugs, biomaterials, and gene-engineered cells for delivery. A typical MRONJ mandible presents a prominent gingival ulcer with exposed necrotic bone (blue), osteolysis (black), and abscess formation (yellow)