BISPHOSPHONATE USE AND BONE QUALITY

描述(申请人提供)：双膦酸盐(BP)在目前使用这些药物的400多万美国人中阻止骨丢失和预防与骨质疏松相关的骨折，但长期使用BP可能与临床上负重机械强度的损失有关。对医学界来说，这仍然是一项尚未回答的重大挑战。这项拟议研究的广泛的长期目标是提供有关BP对骨骼硬度和强度的时间依赖效应的新信息，从而提高医生和患者对使用BP治疗全球2亿多名骨质疏松患者的信心。这项研究的目的是使用一种先进的概念方法和从母研究中获得的数据，量化长期BP治疗后骨骼承载机械能力的变化。该提案检验了长期BP治疗的中心假设，即长期BP治疗的特征是骨质量的有利和不利变化具有时间依赖性。其具体目标是：1)建立一支新的跨学科研究团队，提供有限元(FEA)和高级回归分析方面所需的专业知识；2)使用Micro-CT成像构建骨骼的3D模型，将父母研究得出的结构和材料数据纳入这些模型，通过有限元分析对这些模型进行评估，计算功能相关的骨骼刚度和强度参数；以及3)使用高级回归方法分析BP治疗后这些参数随时间的变化。这些目标将通过在小组中增加新的跨学科调查员来实现，以提供所需的技术专长。在这项盲法横断面研究中，采用的研究方法包括显微CT成像和有限元分析。先进的非线性回归分析将被用来评估BP治疗持续时间与骨硬度和强度之间的关系。拟议研究的结果预计将表明BP治疗何时达到最大益处、这一益处的持续时间、这一益处开始下降的时间，以及这一益处可能回到基线或降至以下的时间。这些发现应该会消除关于BP治疗安全性的普遍不确定性，从而提供重大的健康和经济利益。拟议研究的预期结果与国家航空航天监测系统的任务密切相关。它们将改变目前治疗骨质疏松症的治疗模式，并增加医生和患者对BP使用的信心。由于新成立的跨学科团队的努力以及他们继续应用他们的集体专业知识来解决其他代谢性骨骼疾病，持续的收益将会增加。

DESCRIPTION (provided by applicant): Bisphosphonates (BPs) halt bone loss and prevent osteoporosis-related fractures in the more than 4 million Americans currently using these drugs, but long-term BP use may be linked to clinically relevant loss of load-bearing mechanical strength. This remains a significant unanswered challenge to the medical community. The broad long-term objective of the proposed study is to provide new information regarding the time- dependent effects of BP on bone stiffness and strength and thus to improve the confidence of physicians and patients regarding use of BPs for treating the world's more than 200 million osteoporotic patients. The goal of this study is to use an advanced conceptual approach and data obtained from the parent study, to quantify bones load-bearing mechanical competence as a function of long-term BP treatment. The proposal tests the central hypothesis that long-term BP treatment is characterized by time- dependent favorable and unfavorable changes in bone quality. The specific aims are to: 1) build a new interdisciplinary research team that contributes needed expertise in finite element (FEA) and advanced regression analyses 2) use micro-CT imaging to construct 3D models of bone, incorporate parent-study derived structure and material data into these models, evaluate these models by using FEA, calculate functionally relevant bone stiffness and strength parameters, and 3) analyze the BP treatment time-dependent changes in these parameters using advanced regression methods. These aims will be accomplished by adding new interdisciplinary investigators to the team to provide the needed technical expertise. Research methods to be used in this blinded cross-sectional study of 60 human bone samples identified in the parent study include micro-CT imaging and finite element analyses. Advanced nonlinear regression analyses will be used to evaluate the relationships between BP treatment duration and bone stiffness and strength. The results of the proposed study are expected to indicate when the maximum benefit of BP treatment is attained, the duration of this benefit, the time at which this benefit begins to decline, and the time at whih this benefit might return to baseline or dip below. These findings should remove the prevailing uncertainty regarding the safety of BP treatment and thereby providing major health and economic benefits. The anticipated findings of the proposed study are of great relevance to the NIAMS mission. They will change the current therapeutic paradigm for osteoporosis treatment and provide increased confidence to physicians and patients regarding BP use. Sustained benefits will accrue due to the efforts of the newly created interdisciplinary team and their continuing application of their collective expertise to address other metabolic bone diseases.