Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients

Abstract

Osteonecrosis of the jaw is associated with aminobisphosphonate use in patients treated with intravenous doses for the prevention of bony metastases. A more complete understanding of the natural history of bisphosphonate-related osteonecrosis of the jaws (BRONJ), factors associated with risk, and its pathobiology has been limited by the availability of human material and the absence of clinical predictability. We now describe an animal model, developed in female Sprague-Dawley rats, in which we replicate many of the clinical, radiographic, and histologic features described in humans. Animals treated with a sequence of zoledronic acid (ZA) and dexamethosone (DX) over a one to three week period developed BRONJ-like changes following extraction of mandibular or maxillary molars. Whereas the extraction sites of control animals underwent predictable healing with rapid epithelialization, animals treated with ZA/DX demonstrated clinical and histological evidence of ulceration overlying areas of necrotic bone. In contrast to images from control animals, radiographs from animals treated with ZA/DX demonstrated poor definition of the alveolar ridge with mixed radiodensity. Modest increases in the extent of the inflammatory infiltrate were seen fourteen days after extraction in ZA-only treated animals compared to control or ZA/DX-treated rats. However, by post-extraction day 28, no differences were observed. Tissue vascularity was most pronounced in ZA-only treated animals compared to ZA/DX or control specimens. Apoptosis of epithelial cells was not observed in any experimental groups, and no evidence of Actinomyces was observed as determined by Periodic Acid Schiff (PAS) staining. The administration of ZA/DX preceding dental extractions in rats therefore results in the development of bony and soft tissue changes that are similar to those noted humans who develop BRONJ, and may provide a useful model for study of its pathogenesis, as well as strategies for its prevention and treatment.