Further development of the MRONJ minipig large animal model.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious and potentially severe side effect of antiresorptive therapy with bisphosphonates or denosumab. Recently, a large animal minipig MRONJ model was introduced which led to early necrotic lesions in the majority of extraction sites after bisphosphonate administration. The aim of this project was to modify the preoperative cumulative bisphosphonate dose (zoledronate) and hereby firstly to demonstrate the reliability and reproducibility of the established model. Secondly, the MRONJ lesions should be carefully investigated using clinical and μCT as well as detailed histological analyses. Twelve 1.5-year-old Göttingen minipigs were divided into three groups. In group 1 (n = 3) minipigs received weekly doses of zoledronate intravenously (0.05 mg/kg bodyweight) for 20 weeks. No interventions were performed. In group 2 (n = 6) animals received the identical zoledronate dosage as animals in group 1 and tooth extractions of two premolars (PM 2 and 4) in each jaw (maxilla and mandible) were performed after 12 weeks. Group 3 (n = 3) served as tooth extraction only control (no zoledronate administrations). The jaw-bones were subjected to detailed macroscopic, radiological and histological investigations. All extraction sites (24/24) in animals of group 2 showed clinical, radiological and histological signs of MRONJ (mainly stage II), whereas no bone necrosis was found in group 3. Animals of group 1 and group 2 showed further MRONJ lesions in areas where infections (periodontitis) were present. This is the first large animal model to show a 100% incidence of MRONJ at all extraction sites in bisphosphonate pretreated animals (group 2). In addition, in this preclinical model for MRONJ it is shown that tooth extractions are not mandatory for a MRONJ manifestation. MRONJ also developed in areas of gingival or periodontal infections.