Bone Turnover Effects on Bisphosphonate Concentration in the Mandible

骨转换对下颌骨双膦酸盐浓度的影响

• 批准号: 8246394
• 负责人: Kenneth M Kozloff
• 金额: $ 18.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246394
• 关键词: Advisory Committees; Anatomic Sites; Anatomy; Area; Binding; Biodistribution; Biological Availability; Biological Markers; Bone Surface; Bone necrosis; Bone remodeling; Data; Dental Care; Deposition; Development; Disease; Disease model; Drug Delivery Systems; Environment; Epithelial; Event; Excision; Femur; Fluorescence; Future; Healed; Holidays; Image; Injection of therapeutic agent; Jaw; Lead; Limb structure; Location; Mandible; Modeling; Necrosis; Oral cavity; Osteoclasts; Pharmaceutical Preparations; Physiology; Play; Recommendation; Regulation; Research; Research Proposals; Risk Factors; Role; Site; Skeleton; Specificity; Study models; Testing; Time; Tissues; Tooth structure; Toxic effect; Tracer; Treatment Efficacy; Withholding Treatment; bisphosphonate; bone; bone turnover; cancer therapy; design; drug clearance; healing; interest; model design; optical imaging; pamidronate; public health relevance; skeletal; tibia

DESCRIPTION (provided by applicant): Osteonecrosis of the jaw (ONJ) is an emerging condition that has been associated with bisphosphonate use, typically in the context of cancer treatment. Currently, it is unknown what role, if any, bisphosphonates play in the regulation of ONJ. As of yet there are no accepted models of ONJ. However, several mechanisms have been proposed to describe a causing role for bisphosphonates in the disease. High local bisphosphonate concentration in the mandible due to enhanced drug delivery or enhanced drug retention may amplify anti- osteoclastic effects of bisphosphonates compared to non-affected skeletal sites. This may interfere with bone remodeling required following tooth removal- typically a preceding event in ONJ. Alternatively, high local bisphosphonate release from mandibular sites may lead to direct toxicity and damage to mucosal and epithelial tissues, potentially leading to local necrosis. Proper design of models for ONJ requires an understanding of whether the mandible represents an anatomic site prone to high or low local bisphosphonate concentration. The ASBMR task force on ONJ has identified the examination of bisphosphonate bioavailability and biodistribution as a key research question for the disease. Therefore, the purpose for this proposal is to quantify the delivery and retention of bisphosphonates in the mandible compared to other non-affected skeletal sites using near-infrared fluorescent imaging compounds validated by our lab as tracer markers for local bisphosphonate concentration. The central premise of this proposal is that the mandible represents a unique skeletal location that promotes high bisphosphonate concentration per bone surface area when compared to limbs not associated with ONJ. Bisphosphonate delivery and retention will be assessed under normal, low, and high bone turnover conditions using a far-red fluorescent pamidronate imaging compound to visualize local bisphosphonate concentration. Fluorescence per bone surface area will be assessed in the mandible, femur, and tibia, and correlated with local levels of bone turnover to determine the role of turnover in the delivery, and subsequent retention or clearance of drug. Findings from this proposal will clarify whether the local physiology of the jaw predisposes it to high concentrations of bisphosphonate through increased delivery or high retention, and will generate data suggesting whether drug holidays are effective, or can be boosted through relevant strategies designed to clear local bisphosphonate concentration. By determining the factors governing bisphosphonate concentration in the skeleton, these data can define important parameters and experimental questions for the development and application of accurate and valid future models for ONJ. PUBLIC HEALTH RELEVANCE: Osteonecrosis of the jaw (ONJ) is an detrimental condition of exposed bone in the oral cavity for which there are currently no accepted models for study. This proposal will determine how local bone turnover is responsible for the delivery and retention of bisphosphonates in the skeleton, and whether anatomic differences may predispose the mandible to high local bisphosphonate concentration-a potential risk factor for ONJ. It is expected that data from this proposal will define important parameters and experimental questions for the development and application of accurate and future models of ONJ.

描述(由申请人提供)：颌骨骨坏死(ONJ)是一种新兴的疾病，与双膦酸盐的使用有关，通常在癌症治疗中使用。目前，双膦酸盐在ONJ的调节中起什么作用，如果有的话，还不清楚。到目前为止，还没有被接受的ONJ模型。然而，已经提出了几种机制来描述双膦酸盐在疾病中的致病作用。与未受影响的骨骼部位相比，由于药物输送增强或药物滞留增加，下颌骨局部高浓度的双膦酸盐可能会增强双膦酸盐的抗破骨作用。这可能会干扰拔牙后所需的骨重建--通常是在ONJ之前发生的事件。另一种情况是，下颌骨局部释放大量双膦酸盐可能会导致直接毒性和对粘膜和上皮组织的损害，可能导致局部坏死。ONJ模型的正确设计需要了解下颌骨是否代表一个容易产生高或低局部双磷酸盐浓度的解剖部位。ASBMR关于ONJ的特别工作组已经确定双膦酸盐的生物利用度和生物分布的检查是该疾病的关键研究问题。因此，这项建议的目的是利用我们实验室验证的近红外荧光成像化合物作为局部双膦酸盐浓度的示踪标记来量化双膦酸盐在下颌骨中的传递和滞留，并与其他未受影响的骨骼部位进行比较。这项建议的中心前提是，与与ONJ无关的四肢相比，下颌骨代表着一个独特的骨骼位置，促进了每一骨表面积的高双磷酸盐浓度。在正常、低和高骨转换条件下，将使用远红荧光帕米膦酸盐成像化合物来可视化局部双膦酸盐浓度，以评估双膦酸盐的传递和保留。将评估下颌骨、股骨和胫骨的每个骨表面积的荧光，并将其与局部骨转换水平相关联，以确定转换在药物传递和随后的保留或清除中的作用。这项提案的结果将澄清，颌骨的局部生理是否通过增加递送或高滞留使其容易受到高浓度双膦酸盐的影响，并将产生数据，表明药物假期是否有效，或是否可以通过旨在清除局部双膦酸盐浓度的相关战略来促进。通过确定影响骨架中双膦酸盐浓度的因素，这些数据可以为开发和应用准确有效的ONJ未来模型定义重要的参数和实验问题。 公共卫生相关性：颌骨坏死(ONJ)是口腔中暴露的骨骼的一种有害状态，目前还没有公认的模型可供研究。这项建议将确定局部骨周转如何导致双膦酸盐在骨骼中的传递和保留，以及解剖差异是否会使下颌骨易受局部高浓度双膦酸盐的影响--这是ONJ的潜在危险因素。预计来自这项提议的数据将为开发和应用准确的和未来的ONJ模型确定重要的参数和实验问题。