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: 8044437
• 负责人: Kenneth M Kozloff
• 金额: $ 22.37万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044437
• 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; 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（由申请方提供）：颌骨骨坏死（ONJ）是一种与双膦酸盐使用相关的新出现的疾病，通常用于癌症治疗。目前，尚不清楚双膦酸盐在ONJ的调节中发挥什么作用（如果有的话）。到目前为止，还没有公认的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因作用。与未受影响的骨骼部位相比，由于增强的药物递送或增强的药物保留，下颌骨中的高局部双膦酸盐浓度可能放大双膦酸盐的抗骨坏死作用。这可能会干扰拔牙后所需的骨重建-通常是ONJ的前期事件。或者，下颌部位的高局部双膦酸盐释放可能导致粘膜和上皮组织的直接毒性和损伤，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易于产生高或低局部双膦酸盐浓度的解剖部位。ASBMR ONJ工作组已经确定双膦酸盐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，本提案的目的是使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物，与其他未受影响的骨骼部位相比，量化双膦酸盐在下颌骨中的递送和保留。该建议的中心前提是，下颌骨代表了一个独特的骨骼位置，与不与ONJ相关的肢体相比，该位置促进了单位骨表面积的高双膦酸盐浓度。 将在正常、低和高骨转换条件下使用远红荧光帕米膦酸盐成像化合物评估双膦酸盐递送和保留，以可视化局部双膦酸盐浓度。将在下颌骨、股骨和胫骨中评估单位骨表面积的荧光，并将其与局部骨转换水平相关联，以确定转换在药物递送和后续保留或清除中的作用。本提案的结果将阐明下颌的局部生理学是否通过增加输送或高保留使其倾向于高浓度的双膦酸盐，并将生成数据，表明休药期是否有效，或者可以通过旨在清除局部双膦酸盐浓度的相关策略来提高。通过确定控制骨骼中双膦酸盐浓度的因素，这些数据可以定义重要的参数和实验问题，用于开发和应用准确有效的ONJ未来模型。 公共卫生相关性：颌骨骨坏死（ONJ）是一种口腔内骨暴露的有害疾病，目前还没有公认的研究模型。该提案将确定局部骨转换如何负责双膦酸盐在骨骼中的输送和保留，以及解剖差异是否可能使下颌骨易于局部高浓度双膦酸盐-ONJ的潜在风险因素。预计该提案的数据将为ONJ的准确和未来模型的开发和应用定义重要参数和实验问题。