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Dynamic Analysis of Bone Tissue Biopsies after Treatment with Bisphosphonates

双膦酸盐治疗后骨组织活检的动态分析

基本信息

批准号：
8532826
负责人：
James Christopher Fritton
金额：
$ 16.99万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8532826
关键词：
Address Adult Adverse effects Advisory Committees Affect Aftercare American Biopsy Bone Diseases Bone Tissue Bone remodeling Canis familiaris Cellular Structures Characteristics Clinic Clinical Data Development Distal Dose Evaluation Event Exhibits Failure Fatigue Female Femoral Fractures Fracture Frequencies Fright Future Goals Guidelines Holidays Human Individual Knowledge Life Measurement Measures Mechanics Methods Minerals Modeling Monitor Nature Osteoporosis Patients Pharmaceutical Preparations Physiology Play Porosity Property Public Health Reaction Regimen Research Risk Role Sampling Science Site Societies Specimen Testing Time Tissues Translating Trochanters Work base bisphosphonate bone bone mass bone quality clinical application experience improved innovation interstitial osteoporosis with pathological fracture rib bone structure viscoelasticity

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to develop an innovative method of mechanically sampling the useful life of bone tissue from ex vivo samples similar in size and composition to those that could be taken from human transiliac crest or femoral fracture biopsies. Current clinical methods to assess bone quality do not provide any direct mechanical determinants of the remaining useful life of cortical bone tissue, thought to be one of the main determinants for fracture risk. The immediate impact of this work is in addressing the unmet clinical need to provide criteria on when a drug regimen that suppresses bone remodeling should be altered or discontinued. Guidelines for discontinuing use of an osteoporosis drug in an individual patient - a "holiday" - are not based on any clear scientific evidence. The studies proposed provide a rationale for developing such guidelines not only for the widely used bisphosphonates; there are a plethora of promising new drugs being developed that also have the potential to affect the useful life of bone tissue under dynamic cyclic loading. The development of this project was based on the fact that bone tissue is normally loaded in a dynamic fashion, but the development of agents for treating bone disease has occurred in the near absence of dynamic testing methods. The PI's lab has recently demonstrated that remodeling suppression with a bisphosphonate is associated with a decrease in the useful life of cortical bone tissue during dynamic fatigue loading. The major limitations to applying this knowledge clinically are that these testing methods are destructive, time intensive and require multiple samples. A relatively fast and non-destructive dynamic test is available that can predict the useful life of many materials that experiences damage during fatigue. In this project we will determine whether this test, Dynamic Materials Analysis (DMA), can predict useful life in bisphosphonate-treated and non-treated bone. While the utility of obtaining such information from DMA seems obvious, no such work has been completed on bone tissue obtained after well-controlled dosing with bisphosphonates. We will produce beams from treated dog bone of a size similar to that from clinically obtained biopsies. The first aim will use non-destructive DMA to determine if increased remodeling suppression changes cortical bone tissue's ability to dissipate energy. In the second aim the same bone samples will be used to determine the useful life of the tissue with methods we have already established. Completion of these two aims will allow us to determine if DMA differentiates bone tissue undergoing various levels of remodeling suppression from 0 to nearly 100%, and predicts useful life. Such a test would help guide doctors and their millions of patients at risk for osteoporotic fracture in choosing appropriate treatments and modifying regimens when required (i.e., a drug holiday, switching to an anabolic regimen, etc.).

描述（由申请人提供）：该项目的目标是开发一种创新方法，从尺寸和成分类似于从人类髂嵴或股骨骨折活检中获取的离体样本中机械采样骨组织的使用寿命。目前评估骨质量的临床方法并未提供皮质骨组织剩余使用寿命的任何直接机械决定因素，而皮质骨组织的剩余使用寿命被认为是骨折风险的主要决定因素之一。这项工作的直接影响是解决了未满足的临床需求，为何时应改变或停止抑制骨重塑的药物治疗方案提供标准。对个别患者停止使用骨质疏松症药物的指导方针——“假期”——没有任何明确的科学证据。拟议的研究不仅为广泛使用的双膦酸盐，而且为制定此类指南提供了理论依据。目前正在开发大量有前景的新药，它们也有可能影响动态循环载荷下骨组织的使用寿命。该项目的开发基于骨组织通常以动态方式加载的事实，但用于治疗骨疾病的药物的开发是在几乎缺乏动态测试方法的情况下进行的。 PI 的实验室最近证明，双磷酸盐的重塑抑制与动态疲劳载荷期间皮质骨组织的使用寿命缩短有关。在临床上应用这些知识的主要限制是这些测试方法具有破坏性、耗时且需要多个样本。相对快速且无损的动态测试可以预测许多在疲劳过程中遭受损坏的材料的使用寿命。在这个项目中，我们将确定动态材料分析 (DMA) 测试是否可以预测双膦酸盐处理和未处理的骨骼的使用寿命。虽然从 DMA 获取此类信息的效用似乎很明显，但尚未对在良好控制双膦酸盐剂量后获得的骨组织进行此类研究。我们将从经过处理的狗骨中产生光束，其尺寸与临床上获得的活检样品的尺寸相似。第一个目标将使用非破坏性 DMA 来确定增加的重塑抑制是否会改变皮质骨组织的能量耗散能力。在第二个目标中，将使用相同的骨骼样本通过我们已经建立的方法来确定组织的使用寿命。完成这两个目标将使我们能够确定 DMA 是否能够区分经历从 0% 到接近 100% 不同程度的重塑抑制的骨组织，并预测使用寿命。这样的测试将有助于指导医生和数百万面临骨质疏松性骨折风险的患者选择适当的治疗方法并在需要时修改治疗方案（即药物假期、改用合成代谢方案等）。