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: 7862569
• 负责人: Jose Ignacio Aguirre
• 金额: $ 7.29万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7862569
• 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，颌骨坏死（ONJ）已被确定为双膦酸盐（BP）治疗的潜在并发症。这种骨病的特点是坏死骨积聚并暴露在口腔中，持续时间超过 6 至 8 周。 ONJ 在接受强效氮 (N-)BP 唑来膦酸 (ZOL) 或帕米膦酸抑制骨转移治疗的癌症患者中最常见，但在阿仑膦酸 (ALN) 治疗的骨质疏松患者中也有报道，其程度要小得多。虽然多个病例报告研究表明 ONJ 的发生率和严重程度与 N-BP 抑制破骨细胞骨吸收的效力以及这些药物的累积剂量有关，但尚未建立基于机制的因果关系。因此，开发动物模型来研究 ONJ 的病理生理学将是增强我们对这种骨病认识的基本工具。我们的长期目标是阐明 ONJ 的病因和病理生理学，以便为新的有效预防和治疗策略奠定基础。本提案的目的是开发 ONJ 动物模型，并确定不同效力的 N-BP 对坏死骨去除和骨愈合的影响。我们的中心假设是 ONJ 是一个两个阶段的过程：1）危险因素引发口腔内的过程，导致硬组织坏死； 2) N-BP 已被充分证明可以抑制破骨细胞吸收，阻止坏死骨的清除，导致坏死骨在颌骨积聚，从而延迟骨愈合的开始和后续进展。我们计划利用患有牙周炎的稻鼠（Oryzomys palustris）来测试我们的中心假设，并确定 ZOL 和 ALN 对以下方面的影响：1）通过对牙周疾病进行离体评估，包括牙槽骨的放射学评估、软组织受累和牙齿松动度的评估，以及对牙周组织进行组织计量分析，确定 ZOL 和 ALN 对牙周损伤进展的影响。 组织; 2)通过使用组织化学/组织学技术评估坏死骨积累来去除坏死骨，并且还通过使用定量组织形态计量学评估骨吸收指标； 3）利用定量组织形态计量学和免疫组织化学技术，检测牙周组织中的新骨形成和血管生成，作为骨愈合的指标； 4)使用实时PCR技术表达与骨吸收、骨形成和血管生成相关的基因。我们假设 N-BP 众所周知且理想的抗再吸收作用在 ONJ 的发展中起着核心作用。因此，在该项目完成时，我们期望提供直接证据，证明与效力较低的 BP ALN 相比，有效的 BP ZOL 将导致颌骨中坏死骨的积累增加，从而损害骨愈合。我们还期望开发一种 ONJ 动物模型，以促进我们对这种骨病的认识和理解的进一步发展。项目叙述：颌骨坏死 (ONJ) 是双膦酸盐 (BP) 治疗的潜在不良副作用。多个病例报告研究表明，ONJ 的发生率和严重程度与血压和药物累积剂量有关。然而，人们对这种骨病知之甚少，部分原因是缺乏合适的 ONJ 动物模型。拟议的研究将深入了解沼泽稻大鼠（一种牙周炎动物模型）中发生 ONJ 样病变的组织水平机制，并将在细胞和分子水平上阐明 BP 唑来膦酸盐比 BP 阿仑膦酸盐诱发 ONJ 样病变的发生率更高的基础。

项目成果

Breeding, husbandry, veterinary care, and hematology of marsh rice rats (Oryzomys palustris), a small animal model for periodontitis.

• 发表时间: 2015
• 期刊: Journal of the American Association for Laboratory Animal Science : JAALAS
• 作者: J. Aguirre;K. Edmonds;B. Zamora;Jennifer E. Pingel;L. Thomas;Denisse Cancel;Laura Schneider;M. Reinhard;A. Battles;M. Akhter;D. Kimmel;T. Wronski

Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis.

• DOI: 10.1002/jbmr.1669
• 发表时间: 2012-10
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Aguirre JI;Akhter MP;Kimmel DB;Pingel JE;Williams A;Jorgensen M;Kesavalu L;Wronski TJ
• 通讯作者: Wronski TJ