Pathophysiologic Mechanisms of Bisphosphonate Related Osteonecrosis of the Jaws

双膦酸盐相关颌骨骨坏死的病理生理机制

• 批准号: 8893945
• 负责人: SOTIRIOS TETRADIS
• 金额: $ 38.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893945
• 关键词: Abscess; Adult; Affect; Alveolar ridge; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Bone necrosis; Calvaria; Cancer Patient; Classification; Clinical; Complex; Complication; Cyclooxygenase Inhibitors; Data; Defect; Dental; Dental Pulp Necrosis; Dental caries; Deposition; Development; Disease; Disease Progression; Dose; Drug usage; Effectiveness; Enzymes; Etiology; Femur; Fistula; Functional disorder; Grant; Healed; Health; Histologic; In Vitro; Incidence; Infection; Inflammation; Jaw; Jaw Fractures; Lead; Lesion; Malignant Bone Neoplasm; Malignant Neoplasms; Measures; Metabolic Bone Diseases; Metastatic Neoplasm to the Bone; Modeling; Modification; Mus; Necrosis; Onset of illness; Oral; Oral cavity; Oral mucous membrane structure; Osteoblasts; Osteoclasts; Osteocytes; Osteoporosis; Pain; Pathogenesis; Pathologic; Pathway interactions; Patients; Periapical Diseases; Periodontal Diseases; Pharmaceutical Preparations; Pharmacologic Actions; Play; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Rattus; Recording of previous events; Regimen; Regulation; Reporting; Research; Risk; Role; Severities; Severity of illness; Signaling Molecule; Staging; Swelling; Symptoms; TNFSF11 gene; Testing; Time; Tissues; Tooth Diseases; Tooth Extraction; Tooth structure; Toxic effect; Trauma; Withdrawal; Wound Healing; alveolar bone; angiogenesis; bisphosphonate; bone; bone healing; bone turnover; burden of illness; cell type; cyclooxygenase 1; cyclooxygenase 2; healing; inhibitor/antagonist; maxillofacial; mouse model; novel therapeutic intervention; oral biofilm; research study; response; soft tissue

DESCRIPTION (provided by applicant): Antiresorptive agents, such as bisphosphonates (BPs) and Denosumab, are used to manage bone malignancy and metabolic bone diseases. Antiresorptive related osteonecrosis of the jaws (ONJ), a serious complication, particularly of the most potent regimens, presents as clinically exposed bone in the maxillofacial region for more than 8 weeks, and is associated with severe pain, swelling, infection, fistulae, and jaw fracture. ONJ pathophysiology remains largely elusive. ONJ presence under medications with distinct pharmacologic actions strongly points to osteoclast inhibition as central in disease pathogenesis. A puzzling, unanswered, question is ONJ's predilection for the jaws. ONJ is most commonly associated with tooth extraction in patients receiving high dose antiresorptives. However, in adults, teeth are extracted mainly due to severe periodontal disease or extensive caries that cause pulpal necrosis and periapical disease. Furthermore, several ONJ patients present without history of tooth extraction. From studies supported by this grant, we have reported the importance of dental disease for the establishment of ONJ in rats and mice. Interestingly, in both animal models, histologically necrotic bone is present. However, bone exposure, consistent with clinical ONJ, is seen in only 33% of the animals with osteonecrosis, suggesting that bone exposure is not prerequisite for bone necrosis. Equipped with these models, we have established qualitative and quantitative measures that mimic patient ONJ and evaluate disease burden. Preliminary data, presented herein, indicate that osteonecrotic changes occur as early as two weeks, while extraction of diseased teeth leads to incomplete soft tissue healing and bone exposure. Pharmacologic treatments alleviate ONJ severity, providing possible interventional tactics with clinical implications. Osteoblast lineage experiments demonstrate expansion of osteoblast precursors in the alveolar bone of BP treated mice with dental disease. Importantly, inflammation and BP treatment induce osteonecrosis in calvariae and femurs of mice, suggesting that, given the right conditions, other bones are subject to BP-associated osteonecrosis. Our objective is to characterize pathophysiologic mechanisms of ONJ and explore potential interventional approaches to ameliorate disease severity. We hypothesize that severe dental disease plays a central role in antiresorptive induced ONJ. We propose: 1. To study early responses in ONJ development, and elucidate the effect of BP withdrawal and diseased tooth extractions in ONJ progression, 2. To explore cyclooxygenase (COX) pathway involvement in ONJ pathophysiology, and 3. To study the effects of BPs and inflammation on calvariae and femoral defect healing.

描述（由申请人提供）：抗骨吸收剂，例如双膦酸盐（BP）和狄诺塞麦（Denosumab），用于治疗骨恶性肿瘤和代谢性骨疾病。抗骨吸收相关的颌骨坏死 (ONJ)，一种严重的并发症，尤其是颌骨的并发症 最有效的治疗方案，临床上表现为颌面部区域骨暴露超过 8 周，并与严重疼痛、肿胀、感染、瘘管和颌骨骨折相关。 ONJ 的病理生理学在很大程度上仍然难以捉摸。具有独特药理作用的药物中 ONJ 的存在强烈表明破骨细胞抑制是疾病发病机制的核心。一个令人费解且没有答案的问题是 ONJ 对下巴的偏爱。 ONJ 最常见于接受高剂量抗骨吸收药物的患者拔牙。然而，在成年人中，拔牙主要是由于严重的牙周病或广泛的龋齿导致牙髓坏死和根尖周病。此外，一些 ONJ 患者没有拔牙史。根据这项资助支持的研究，我们报告了牙齿疾病对于大鼠和小鼠 ONJ 建立的重要性。有趣的是，在两种动物模型中，都存在组织学上坏死的骨。然而，与临床 ONJ 一致的骨暴露仅见于 33% 的骨坏死动物，这表明骨暴露并不是骨坏死的先决条件。借助这些模型，我们建立了模拟患者 ONJ 并评估疾病负担的定性和定量测量方法。本文提供的初步数据表明，骨坏死变化早在两周内就会发生，而拔除患病牙齿会导致软组织愈合不完全和骨骼暴露。药物治疗可减轻ONJ的严重程度，提供可能的具有临床意义的介入策略。成骨细胞谱系实验表明，经 BP 治疗的患有牙科疾病的小鼠的牙槽骨中成骨细胞前体细胞的扩增。重要的是，炎症和血压治疗会引起小鼠颅骨和股骨的骨坏死，这表明，在适当的条件下，其他骨骼也会发生与血压相关的骨坏死。我们的目标是描述 ONJ 的病理生理机制，并探索改善疾病严重程度的潜在干预方法。我们假设严重的牙科疾病在抗吸收诱导的 ONJ 中起着核心作用。我们建议：1. 研究 ONJ 发展的早期反应，并阐明 BP 撤药和拔除患病牙齿对 ONJ 进展的影响，2. 探索环氧合酶 (COX) 通路参与 ONJ 病理生理学，3. 研究 BP 和炎症对颅骨和股骨缺损愈合的影响。