Bisphosphonates (BPs) have been used clinically for over 30 years to treat postmenopausal osteoporosis, hypercalcemia of malignancy and metabolic bone diseases. Although the use of BPs have been beneficial for these pathologies, several recent reports have linked BP usage to osteonecrosis of the jaw. A common factor amongst these case reports suggests a significant link of dental disease and bisphosphonate treatment in the development of bisphosphonate related osteonecrosis of the jaw (BRONJ). Since the pathophysiology of BRONJ is unknown, we developed two BRONJ animal models where aggressive periodontal and periapical disease was induced with zoledronic acid (ZA) treatment in the rat and mouse, respectively.
Ligature-induced periodontal disease caused significant alveolar bone loss while ZA treatment attenuated this effect in rats. Significant changes of alveolar bone morphology including sequestration and extensive periosteal bone formation were observed by microCT in the ligated site of BP treated animals. These findings were confirmed histologically, demonstrating necrotic bone with diffuse loss of osteocytes and empty lacunae, rimming of the necrotic bone by squamous epithelium and inflammation, and exposure to the oral cavity. Importantly, the rat lesions were strikingly similar to those of BRONJ patients.
Mandibular tooth drillings causing pulpal exposure in the right first and second mandibular molars caused significant periapical lesion development in the mouse. Periapical lesion were quantified from radiographic images and showed a significant increase in lesion space in vehicle versus ZA treated mice. Significant qualitative differences were seen in the morphology of the alveolar bone in ZA treated mice through microCT analysis. Periosteal bone formation was significantly increased in periapical disease induced ZA treated mice versus control mice. Extensive necrotic bone areas were demonstrated the absence of lacunae in osteocytes. TRAP staining shows no significant difference in the number of osteoclasts between ZA versus vehicle treated animals. However, significant morphologic differences were observed by the detachment osteoclasts and flattening of the ruffled border in ZA treated mice. BRONJ developed in 100% of periapical disease induced ZA treated mice.
Our data suggest that dental disease and BP therapy is sufficient and necessary for BRONJ development. These animal models can serve as tools to understand the pathophysiology of BRONJ.