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

• 批准号: 8359081
• 负责人: James Christopher Fritton
• 金额: $ 11.79万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359081
• 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

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.). PUBLIC HEALTH RELEVANCE: The relevance of this research to public health is in innovatively addressing the unmet need to provide criteria on when an osteoporosis drug regimen should be altered or discontinued, known as a holiday. These guidelines for patients and their doctors to discontinue use of an osteoporosis drug should be made on a science-based evaluation of the mechanical integrity of bone. This study will develop a test that could help provide a better estimate for fracture risk after many years of treatment for osteoporosis.

描述（由申请人提供）：本项目的目标是开发一种创新方法，从尺寸和成分与人体髂嵴或股骨骨折活检相似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没有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在解决未满足的临床需要，提供标准时，抑制骨重建的药物治疗方案应该改变或停止。个别患者停止使用骨质疏松症药物的指南-“假期”-没有任何明确的科学证据。提出的研究为制定此类指南提供了依据，不仅适用于广泛使用的双膦酸盐;还有大量正在开发的有前途的新药，这些新药也有可能影响动态循环载荷下骨组织的使用寿命。 该项目的开发是基于骨组织通常以动态方式加载的事实，但用于治疗骨病的药物的开发几乎没有动态测试方法。PI的实验室最近证明，在动态疲劳载荷期间，双膦酸盐的重塑抑制与皮质骨组织的使用寿命降低有关。临床应用这些知识的主要限制是这些测试方法是破坏性的，时间密集型的，需要多个样本。相对快速和非破坏性的动态测试是可用的，可以预测许多材料的使用寿命，在疲劳过程中经历损坏。在本项目中，我们将确定该测试，动态材料分析（DMA），是否可以预测双膦酸盐处理和未处理骨的使用寿命。虽然从DMA中获得这些信息的效用似乎是显而易见的，但在良好控制的双膦酸盐给药后获得的骨组织中尚未完成此类工作。我们将从处理过的狗骨中产生光束，其大小与临床获得的活检相似。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改变了皮质骨组织耗散能量的能力。在第二个目标中，将使用相同的骨样本，通过我们已经建立的方法确定组织的使用寿命。这两个目标的完成将使我们能够确定DMA是否区分经历从0到接近100%的各种水平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他们的数百万有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方案（即，药物假期，转换为合成代谢方案等）。 公共卫生相关性：这项研究与公共卫生的相关性在于创新性地解决了未满足的需求，即提供骨质疏松症药物治疗方案何时应该改变或停止的标准，即所谓的假期。这些指导患者和他们的医生停止使用骨质疏松症药物的指南应该基于对骨骼机械完整性的科学评估。这项研究将开发一种测试，可以帮助提供一个更好的估计骨折风险后，多年的骨质疏松症治疗。