Dynamic Analysis of Bone Tissue Biopsies after Treatment with Bisphosphonates

描述（由申请人提供）：该项目的目标是开发一种创新的方法，从离体样品中机械取样骨组织的使用寿命，其大小和组成与从人类经髂嵴或股骨骨折活检中提取的样品相似。目前评估骨质量的临床方法并没有提供任何皮质骨组织剩余使用寿命的直接力学决定因素，而皮质骨组织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，提供了何时应该改变或停止抑制骨重塑的药物方案的标准。个别患者停止使用骨质疏松药物的指导方针——“假期”——并没有明确的科学依据。提出的研究为制定这样的指导方针提供了理论依据，不仅适用于广泛使用的双膦酸盐；有大量有前途的新药正在开发中，也有可能影响骨组织在动态循环载荷下的使用寿命。

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.