Osteonecrosis of the jaw (ONJ) is a recognized complication of bisphosphonate (BP) therapy that carries significant morbidity for multiple myeloma (MM) patients. Understanding the pathogenesis is crucial for early detection and therapy of ONJ. We hypothesize that ONJ pathogenesis has a soft tissue component contributing to bone necrosis. Once alveolar bone is exposed, an infectious biofilm will form, leading to further irritation of the tissues and subsequent stimulation of osteoclasts, with ensuing bone resorption and release of bone-bound BP into the oral cavity. In addition mucosal integrity is essential in protecting the underlying alveolar bone from exposure to oral pathogens and in providing blood supply to the cortical bone. Thus, sustaining a vicious cycle that will result in a non-healing mucosal lesion and bone necrosis, ONJ. We hypothesize that cytotoxic levels of free BP in the saliva initiate and/or impair soft tissue healing. This hypothesis is supported by our preliminary in vitro studies demonstrating that brief exposure to low levels of BP induced apoptosis and inhibited normal proliferation of gingival fibroblasts and oral epidermal mucosal cells. To test the hypothesis: aim 1 will focus on measurements of "free" BP in the saliva of MM patients with ONJ and a control cohort of MM patients without ONJ matched for the duration of BP exposure, age, MM treatment and MM status, a total of 60 patients. In aim 2 we will prospectively follow up 100 MM patients at the highest risk for developing ONJ, all selected based on the duration of BP exposure, age and MM status. Clinical, dental evaluations as well blood and salivary samples will be collected every 3 month for 18 month of follow up;additional samples will be collected at the time of any dental procedure and for those developing ONJ, expect 7-10 patients per year for this high risk group. Samples will be analyzed for those developing ONJ with regards to microbial species changes, BP levels and changes in inflammatory cytokines. These findings will establish the changes in BP pharmacokinetics after chronic use, the prospective study of microbial shifts and changes in cytokines and bone turnover markers will provide a predictive model for pathogenesis of ONJ that can be further developed prospectively for focused interventions and therapy of ONJ. PUBLIC HEALTH RELEVANCE: Survival of multiple myeloma patients has improved with the introduction of novel agents;there is need for research efforts to focus on better management of long-term therapy related side effects such as bisphosphonate-related osteonecrosis of the jaw. The proposed work will determine bisphosphonate pharmacokinetics and prospectively follow high-risk MM patients to identify changes in the oral bacterial species associated with osteonecrosis of the jaw. This will provide novel mechanisms to explain the delayed healing of the soft tissues in ONJ that could be further developed into focused therapeutic interventions.