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

描述(由申请人提供)：颌骨坏死(ONJ)是双磷酸盐(BP)治疗的公认并发症，对多发性骨髓瘤(MM)患者具有显著的发病率。了解其发病机制对ONJ的早期发现和治疗至关重要。我们假设ONJ的发病机制与导致骨坏死的软组织成分有关。一旦牙槽骨暴露，就会形成感染性生物膜，进一步刺激组织，刺激破骨细胞，导致骨吸收，骨结合的BP释放到口腔中。此外，粘膜的完整性对于保护潜在的牙槽骨免受口腔病原体的侵袭和为皮质骨提供血液供应也是必不可少的。因此，维持一个恶性循环，将导致无法愈合的粘膜损伤和骨坏死，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。这一假说得到了我们的初步体外研究的支持，这些研究表明，短暂暴露于低水平的BP可诱导牙龈成纤维细胞和口腔表皮粘膜细胞的正常增殖，并诱导其凋亡。为了验证假设：目标1将重点测量患有ONJ的MM患者和没有ONJ的MM患者在BP暴露时间、年龄、MM治疗和MM状态方面匹配的对照队列共60名患者唾液中的“游离”BP。在目标2中，我们将前瞻性跟踪100名患ONJ风险最高的MM患者，所有患者都是根据BP暴露的时间、年龄和MM状态进行选择。临床、牙科评估以及血液和唾液样本将每3个月采集一次，为期18个月；在任何牙科手术时将收集额外的样本，对于那些发展为ONJ的患者，预计这一高危群体每年将有7-10名患者。样本将分析那些正在发生ONJ的人的微生物种类变化、血压水平和炎性细胞因子的变化。这些发现将建立长期使用后BP药代动力学的变化，对微生物移位以及细胞因子和骨转换标志物变化的前瞻性研究将为ONJ的发病机制提供一个预测模型，该模型可以为ONJ的针对性干预和治疗提供前瞻性的进一步发展。 公共卫生相关性：随着新药的引入，多发性骨髓瘤患者的存活率有所提高；需要研究努力，以更好地管理与长期治疗相关的副作用，如双膦酸类相关的颌骨骨坏死。这项拟议的工作将确定双膦酸盐的药代动力学，并前瞻性地跟踪高危多发性骨髓瘤患者，以确定与颌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软组织愈合延迟的原因，这可能会进一步发展为有针对性的治疗干预。

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.