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

描述（由申请人提供）：颌骨骨坏死（ONJ）是公认的双膦酸盐（BP）治疗的并发症，在多发性骨髓瘤（MM）患者中具有显著的发病率。了解其发病机制对早期发现和治疗ONJ至关重要。我们假设ONJ的发病机制与软组织成分有关，有助于骨坏死。一旦牙槽骨暴露，就会形成感染性生物膜，导致组织进一步受到刺激，随后破骨细胞受到刺激，随后骨吸收，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害和向皮质骨提供血液供应至关重要。因此，维持一个恶性循环，将导致无法愈合的粘膜病变和骨坏死。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。我们的初步体外研究支持了这一假设，表明短暂暴露于低水平BP可诱导细胞凋亡，抑制牙龈成纤维细胞和口腔表皮粘膜细胞的正常增殖。为了验证这一假设：目的1将重点研究有ONJ的MM患者和无ONJ的MM患者的唾液中“游离”血压的测量，这些患者的血压暴露时间、年龄、MM治疗和MM状态相匹配，共60例患者。在目标2中，我们将前瞻性随访100名患ONJ风险最高的MM患者，所有患者均根据BP暴露时间、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个月收集一次，进行18个月的随访；在任何牙科手术时都将收集额外的样本，对于那些发展为ONJ的人，预计每年有7-10名患者是这一高风险群体。将分析样本中微生物种类的变化、血压水平和炎症细胞因子的变化。这些发现将建立长期使用后BP药代动力学的变化，对微生物迁移和细胞因子及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，为ONJ的重点干预和治疗提供前瞻性研究。

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.