Role of Salivary Bisphosphonates in Osteonecrosis of the Jaw in Myeloma Patients

描述（由申请方提供）：颌骨骨坏死（ONJ）是双膦酸盐（BP）治疗的公认并发症，多发性骨髓瘤（MM）患者的发病率较高。了解ONJ的发病机制对于早期发现和治疗ONJ至关重要。我们假设ONJ的发病机制有一个软组织成分，有助于骨坏死。一旦牙槽骨暴露，将形成感染性生物膜，导致组织的进一步刺激和破骨细胞的后续刺激，随之而来的是骨吸收和骨结合BP释放到口腔中。此外，粘膜的完整性对于保护下面的牙槽骨免受口腔病原体的侵害以及为皮质骨提供血液供应是必不可少的。因此，维持一个恶性循环，将导致不愈合的粘膜病变和骨坏死，ONJ。我们假设唾液中游离BP的细胞毒性水平启动和/或损害软组织愈合。我们初步的体外研究表明，短暂暴露于低水平的BP诱导的细胞凋亡和抑制牙龈成纤维细胞和口腔表皮粘膜细胞的正常增殖支持这一假设。为了检验假设：目的1将集中于测量患有ONJ的MM患者和对照组的没有ONJ的MM患者的唾液中的“游离”BP，所述对照组在BP暴露持续时间、年龄、MM治疗和MM状态方面匹配，总共60名患者。在目标2中，我们将前瞻性随访100例发生ONJ风险最高的MM患者，所有患者均基于BP暴露持续时间、年龄和MM状态进行选择。在18个月随访期间，每3个月采集一次临床、牙科评价以及血液和唾液样本;在任何牙科手术时采集额外样本，对于发生ONJ的患者，预计该高风险组每年有7-10例患者。将分析发生ONJ患者的样本，包括微生物种类变化、BP水平和炎性细胞因子变化。这些发现将确立长期使用后BP药代动力学的变化，微生物变化以及细胞因子和骨转换标志物变化的前瞻性研究将为ONJ的发病机制提供预测模型，该模型可以进一步前瞻性地开发用于ONJ的集中干预和治疗。 公共卫生相关性：随着新型药物的引入，多发性骨髓瘤患者的生存率有所改善;需要开展研究工作，重点关注更好地管理长期治疗相关的副作用，如双膦酸盐相关的颌骨骨坏死。拟议的工作将确定双膦酸盐的药代动力学和前瞻性地跟踪高危MM患者，以确定与颌骨骨坏死相关的口腔细菌种类的变化。这将提供新的机制来解释ONJ中软组织的延迟愈合，可以进一步发展为集中的治疗干预。

DESCRIPTION (provided by applicant): 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.