Pathophysiology of Biphosphonate-Induced ONJ in a Novel Animal Model

新型动物模型中双膦酸盐诱导的 ONJ 的病理生理学

• 批准号: 7587053
• 负责人: Jose Ignacio Aguirre
• 金额: $ 7.32万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-08 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587053
• 关键词: Adrenal Cortex Hormones; Adult; Adverse effects; Alendronate; Animal Model; Animals; Bone Diseases; Bone Resorption; Bone necrosis; Bone remodeling; Breast; Cancer Patient; Case Study; Complication; Dental; Development; Diphosphates; Dose; Esophagitis; Evaluation; Excision; Exostoses; Functional disorder; Gene Expression; Goals; Histological Techniques; Ibandronate; Impairment; Incidence; Intervention; Intravenous; Jaw; Knowledge; Lesion; Malignant neoplasm of prostate; Mandible; Metastatic Neoplasm to the Bone; Modeling; Molecular; Multiple Myeloma; Names; Necrosis; Nitrogen; Oral; Oral cavity; Oryzomys; Osteogenesis; Osteoporosis; Patients; Periodontal Diseases; Periodontitis; Periodontium; Pharmaceutical Preparations; Pilot Projects; Plant Roots; Postmenopause; Prevention strategy; Process; Rattus; Reporting; Research; Research Personnel; Rice Rats; Risedronate; Risk Factors; Role; Severities; Staging; Techniques; Testing; Time; Tissues; Tooth Extraction; Tooth Mobility; Trauma; Woman; Zoledronate; alveolar bone; analog; angiogenesis; animal model development; base; bisphosphonate; bone; bone healing; bone loss; c new; expectation; indexing; insight; novel; oncology; oral tissue; pamidronate; soft tissue; tool

DESCRIPTION (provided by applicant): In recent years, osteonecrosis of the jaw (ONJ) has been identified as a potential complication of bisphosphonate (BP) treatment. This bone disorder is characterized by the accumulation of necrotic bone with exposure in the oral cavity that persists for more than 6 to 8 weeks. ONJ is observed most frequently in cancer patients treated with the potent nitrogen (N-)BPs zoledronate (ZOL) or pamidronate for inhibition of bone metastases, but it has also been reported to a much lesser extent in alendronate (ALN)-treated osteoporotic patients. While multiple case report studies suggest that the incidence and severity of ONJ are associated with the potency of N-BPs to inhibit osteoclastic bone resorption and cumulative dose of these drugs, no mechanism-based cause and effect relationship has yet been established. Therefore, the development of animal models to study the pathophysiology of ONJ will be a fundamental tool to enhance our understanding of this bone disorder. Our long-term goal is to elucidate the causes and pathophysiology of ONJ in order to create the basis for new effective strategies for prevention and treatment. The objectives of this proposal are to develop an animal model for ONJ, and to establish the effects of N-BPs of different potencies on the removal of necrotic bone and bone healing. Our central hypothesis is that ONJ is a two-stage process: 1) risk factors initiate processes in the oral cavity that cause necrosis of hard tissues; and 2) N-BPs, well-proven to inhibit osteoclastic resorption, block the removal of necrotic bone, causing an accumulation of necrotic bone in the jaw that in and of itself delays the initiation and subsequent progress of bone healing. We plan to test our central hypothesis by utilizing rice rats (Oryzomys palustris) with established periodontitis and determine the effects of ZOL and ALN on: 1) the progression of the periodontal damage by performing an ex-vivo evaluation of the periodontal disease, including a radiographic assessment of the alveolar bone, the evaluation of soft tissue involvement and tooth mobility, and by conducting a histometric analysis of the periodontal tissue; 2) the removal of necrotic bone by the assessment of necrotic bone accumulation using histochemical/histological techniques, and also on indices of bone resorption by using quantitative histomorphometry; 3) new bone formation and angiogenesis, as indices of bone healing, in the periodontium by using quantitative histomorphometry and immunohistochemical techniques; and 4) the expression of genes associated with bone resorption, bone formation, and angiogenesis using real time PCR techniques. We postulate that the well- known and desirable anti-resorptive effect of N-BPs has a central role in the development of ONJ. Consequently, at the completion of this project, it is our expectation to provide direct evidence that the potent BP ZOL will induce a higher accumulation of necrotic bone in the jaw, with subsequent impairment of bone healing as compared to that induced by the less potent BP ALN. It is also our expectation to develop an animal model for ONJ that will facilitate further advances in our knowledge and understanding of this bone disorder. Project Narrative: Osteonecrosis of the jaw (ONJ) is a potential adverse side effect of bisphosphonate (BP) treatment. Multiple case report studies suggest that the incidence and severity of ONJ are associated with the potency of BP and cumulative dose of the drug. However, this bone disorder is poorly understood, due in part to lack of appropriate animal models for ONJ. The proposed research will provide insight into a tissue-level mechanism for the development of ONJ-like lesions in marsh rice rats, an animal model for periodontitis, and will elucidate the basis, at the cellular and molecular levels, for the higher incidence of the BP zoledronate to induce ONJ- like lesions as compared with the BP alendronate.

描述（由申请人提供）：近年来，下颌（ONJ）的骨坏死已被确定为双膦酸盐治疗的潜在并发症。这种骨骼疾病的特征是坏死骨的积累，在口腔中暴露并持续超过6到8周。在用有效的氮（N-）BPS唑来济酸盐（ZOL）或pamidronate治疗以抑制骨转移的癌症患者中，ONJ最常观察到ONJ，但据报道，在烯烃（ALN）处理的骨质疏松患者中，它的程度较小。虽然多个病例报告研究表明，ONJ的发病率和严重程度与N-BP的效力有关抑制整骨骨吸收和这些药物的累积剂量的效力，但尚未建立基于机制的因果关系。因此，研究ONJ病理生理学的动物模型的发展将是增强我们对这种骨骼疾病的理解的基本工具。我们的长期目标是阐明ONJ的原因和病理生理学，以创建新的预防和治疗策略的基础。该提案的目标是为ONJ开发动物模型，并建立不同效力的N-BP对去除坏死骨和骨骼愈合的影响。我们的中心假设是ONJ是一个两阶段的过程：1）危险因素启动口腔中引起硬组织坏死的过程； 2）n-bps，良好的抑制破骨碎屑吸收，阻止了坏死骨的去除，导致颌骨中坏死骨的积累本身延迟了骨愈合的起始和后续进展。 We plan to test our central hypothesis by utilizing rice rats (Oryzomys palustris) with established periodontitis and determine the effects of ZOL and ALN on: 1) the progression of the periodontal damage by performing an ex-vivo evaluation of the periodontal disease, including a radiographic assessment of the alveolar bone, the evaluation of soft tissue involvement and tooth mobility, and by conducting a histometric analysis of the periodontal 组织; 2）通过使用组织化学/组织学技术评估坏死骨积累，以及使用定量的组织形态计量法来清除坏死骨； 3）通过使用定量的组织形态法和免疫组织化学技术，在牙周化中，新的骨形成和血管生成是骨骼愈合的指标； 4）使用实时PCR技术与骨吸收，骨形成和血管生成相关的基因表达。我们假设N-BP的众所周知且可取的反应作用在ONJ的发展中具有核心作用。因此，在该项目完成后，我们期望有直接的证据表明，有效的BP ZOL将在下颌中诱导更高的坏死骨积聚，而随后骨骼愈合与受较不强大的BP ALN引起的骨骼愈合受损。我们也期望为ONJ开发动物模型，这将促进我们对这种骨骼疾病的知识和理解的进一步进步。项目叙述：下颌（ONJ）的骨坏死是双膦酸盐（BP）治疗的潜在不利副作用。多个病例报告研究表明，ONJ的发病率和严重程度与BP的效力和药物的累积剂量有关。但是，这种骨疾病的理解很少，部分原因是缺乏适合ONJ的动物模型。拟议的研究将为您提供有关组织级别的机制，以开发沼泽稻病中的ONJ样病变，沼泽大鼠是牙周炎的动物模型，并将在细胞和分子水平上阐明基础，以使BP Zoledremenate的较高发生率诱导与BP相比诱导类似于BP的病变。