Role of periapical diseases in bisphosphonates-related osteonecrosis of the jaws

Abstract

Despite the efficacy of bisphosphonates (Bps) in management of skeletal diseases, they have been associated with a severe adverse reaction, bisphosphonates-related osteonecrosis of the jaws (BRONJ). Since it was firstly reported in 2003, more BRONJ cases have been widely identified and aroused the attention worldwide. However, the pathogenesis behind this severe disease is still poorly-understood. The present study aims to: 1) Investigate the role of periapical diseases in inducing BRONJ using an ovariectomized (OVX) mouse model; 2) Assess the influence of periapical disease in development of BRONJ in immunocompromised mouse; 3) Investigate the role of An upon the occurrence and aggravation of BRONJ. In the first study, C57BL/6N female OVX mice received oncologic dose of zoledronic acid (ZA) or vehicle administration for 12 weeks. After 8 weeks of drug administration, a pulpal exposure (PE) operation was performed to induce periapical disease. Animals were sacrificed 4 weeks later and the mandibles were subjected to micro-computed tomography (micro-CT) and histomorphometric examinations. Micro-CT analysis demonstrated that periapical diseases significantly increased alveolar bone resorption and the resorption was greatly attenuated by ZA treatment. The results also showed that concurrent ZA therapy and periapical lesions significantly increased bone density and histological osteocyte necrosis. It suggests that periapical infectious diseases could be a risk factor for BRONJ development. Based on these findings, the influence of periapical disease in the development of BRONJ in an immunocompromised status was investigated in this OVX mouse model. Micro-CT observations illustrated that concomitant ZA and steroids produced a considerably elevated BMD and strengthened microstructure. Histological results displayed an aggravated severity of osteocyte necrosis in animals under both ZA and steroid administration. The results indicate that BRONJ is a multifactorial disorder of Bps therapy and periapical diseases may increase the predisposition of having BRONJ in an immunocompromised condition. To further understand the role of oral bacteria in the progression of BRONJ, Actinomyces naeslundii (An) a notorious pathogenic microorganism for bone invasion and frequently isolated from BRONJ lesions, were inoculated into the oral cavity of OVX mice with exposed pulp cavity. Real-time polymerase chain reaction assay demonstrated that large amount of bacterial were detected in their oral cavity but An were not routinely found in the oral cavity of mice. The results showed that An inoculation significantly aggravated alveolar bone resorption and changed bone microstructure in the presence of periapical diseases. Moreover, it substantially increased the incidence of subclinical osteonecrosis. In conclusion, BRONJ is a multifactorial disorder of long-term Bps therapy. Periapical disease is a risk factor involved in its development and suppressant immunological status may increase the predisposition of having BRONJ. In addition, An infection may play a critical role in the initiation of BRONJ. The presence of odontogenic infectious diseases combined with immunocompromised condition might be the prerequisite of An infection of the jaws and promote the risk for or persistence and progression of BRONJ.