Dynamic Analysis of Bone Tissue Biopsies after Treatment with Bisphosphonates

描述(申请人提供)：该项目的目标是开发一种创新的方法，从体外样本中机械采样骨组织的使用寿命，这些样本在大小和组成上与从人的经椎骨或股骨骨折活检中获得的样本相似。目前评估骨质量的临床方法没有提供任何关于皮质骨组织剩余使用寿命的直接力学决定因素，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解决了未得到满足的临床需求，即提供何时应该改变或停止抑制骨重塑的药物方案的标准。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。所提出的研究为制定此类指南提供了理论基础，不仅适用于广泛使用的双膦酸盐；还有大量有希望的新药正在开发中，这些新药也可能在动态循环载荷下影响骨组织的使用寿命。 这个项目的发展是基于这样一个事实，即骨组织通常以动态方式加载，但用于治疗骨病的药物的开发几乎是在缺乏动态测试方法的情况下进行的。PI的实验室最近证明，在动态疲劳负荷期间，双膦酸盐抑制重塑与皮质骨组织使用寿命的减少有关。将这一知识应用于临床的主要限制是，这些测试方法具有破坏性、时间密集型和需要多个样本。一种相对快速和非破坏性的动态测试可以预测在疲劳过程中经历损伤的许多材料的使用寿命。在这个项目中，我们将确定这种测试，动态材料分析(DMA)，是否可以预测双膦酸骨处理和未处理骨的使用寿命。虽然从DMA获得这些信息的效用似乎是显而易见的，但在控制良好的双膦酸剂量后获得的骨组织还没有完成这样的工作。我们将从经过处理的狗骨中产生与临床活检相似的大小的光束。第一个目标将使用非破坏性的DMA来确定增加的重塑抑制是否改变了皮质骨组织的能量分散能力。在第二个目标中，将使用相同的骨样本来确定组织的使用寿命，这是我们已经建立的方法。这两个目标的完成将使我们能够确定DMA是否将经历从0到近100%的不同程度重塑抑制的骨组织区分开来，并预测使用寿命。这样的测试将有助于指导医生及其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、改用合成代谢疗法等)。 公共卫生相关性：这项研究与公共健康的相关性在于创新性地解决了未得到满足的需求，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，即所谓的假日。这些关于患者和他们的医生停止使用骨质疏松药物的指南应该建立在对骨骼机械完整性的科学评估的基础上。这项研究将开发一种测试，有助于在多年治疗骨质疏松症后更好地估计骨折风险。

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.