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

唾液双磷酸盐在骨髓瘤患者下颌骨坏死中的作用

• 批准号: 7787674
• 负责人: Ashraf Z Badros
• 金额: $ 18.9万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787674
• 关键词: 4 year old; Active Sites; Address; Adverse effects; Age; Angiogenesis Inhibition; Apoptosis; Binding; Blood; Bone Diseases; Bone Resorption; Bone necrosis; Caring; Case-Control Studies; Cell-Matrix Junction; Cells; Characteristics; Chronic; Clinical; Complication; Data; Databases; Defect; Dental; Dental Care; Development; Disease remission; Distant; Drug Kinetics; Early Diagnosis; Elderly; Evaluation; Event; Exposure to; Functional disorder; Gingiva; Healed; Human; Hypercalcemia of Malignancy; Impaired wound healing; In Vitro; Incidence; Inflammatory; Infusion procedures; Interdisciplinary Study; Intravenous infusion procedures; Jaw; Lesion; Lytic; Measurement; Measures; Medical; Metabolic; Metastatic Neoplasm to the Bone; Microbial Biofilms; Minor; Morbidity - disease rate; Multiple Myeloma; Natural History; Necrosis; Oral; Oral cavity; Osteoclasts; Osteogenesis; Osteoporosis; Pathogenesis; Patients; Population; Predictive Factor; Predisposition; Prevention; Prospective Studies; Recording of previous events; Relapse; Reporting; Research; Retrospective Studies; Risk Factors; Role; Saliva; Salivary; Sampling; Serum; Site; Skeleton; Specimen; Testing; Therapeutic Intervention; Time; Tissues; Tooth structure; Trauma; Vascular blood supply; Work; alveolar bone; base; bisphosphonate; bone; bone turnover; cohort; cytokine; cytotoxic; follow-up; healing; high risk; improved; in vitro Bioassay; irritation; microbial; novel; oral fibroblast; oral pathogen; predictive modeling; prospective; public health relevance; sample collection; soft tissue

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.

描述（由申请人提供）：颌骨坏死（ONJ）是双磷酸盐（BP）治疗公认的并发症，对多发性骨髓瘤（MM）患者具有显着的发病率。了解 ONJ 的发病机制对于早期发现和治疗至关重要。我们假设 ONJ 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，导致组织进一步受到刺激，并随后刺激破骨细胞，从而导致骨吸收并将骨结合的BP释放到口腔中。此外，粘膜完整性对于保护下面的牙槽骨免于暴露于口腔病原体以及为皮质骨提供血液供应至关重要。因此，维持恶性循环将导致不可愈合的粘膜病变和骨坏死，ONJ。我们假设唾液中游离BP的细胞毒性水平会引发和/或损害软组织愈合。我们的初步体外研究支持了这一假设，该研究表明短暂暴露于低水平的 BP 会诱导细胞凋亡并抑制牙龈成纤维细胞和口腔表皮粘膜细胞的正常增殖。为了检验假设：目标 1 将重点测量患有 ONJ 的 MM 患者唾液中的“游离”血压，以及未患 ONJ 的 MM 患者的对照队列，这些患者与 BP 暴露时间、年龄、MM 治疗和 MM 状态相匹配，共有60名患者。在目标 2 中，我们将前瞻性地随访 100 名 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 状况进行选择。在为期 18 个月的随访中，每 3 个月采集一次临床、牙科评估以及血液和唾液样本；在进行任何牙科手术时都会收集额外的样本，对于那些患有 ONJ 的患者，预计每年有 7-10 名患者属于这一高风险群体。将对 ONJ 患者的样本进行微生物种类变化、血压水平和炎症细胞因子变化等方面的分析。这些发现将确定长期使用后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发病机制提供预测模型，并可进一步前瞻性地开发用于ONJ的针对性干预和治疗。 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，例如与双磷酸盐相关的颌骨坏死。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 MM 患者，以确定与颌骨坏死相关的口腔细菌种类的变化。这将为解释 ONJ 软组织延迟愈合提供新机制，并可进一步发展为有针对性的治疗干预措施。