Clinical Validation of BCT

描述（由申请人提供）：骨折风险评估是骨质疏松症的诊断和管理不可或缺的一部分，骨质疏松症是一个毁灭性的临床问题，超过4000万美国人处于危险之中。由于从2D DXA扫描获得的区域BMD测量的局限性-这是目前诊断骨质疏松症的临床标准-最近已经清楚，需要更好地识别那些最有可能发生骨质疏松性骨折的人。一种基于3D生物力学的技术，我们称之为生物力学计算机断层扫描（BCT），通过结合工程有限元分析，3D定量计算机断层扫描（QCT）和骨生物力学来解决这一需求。BCT的主要结局参数是对骨折生物力学风险的估计，该风险考虑了患者的3D骨骼几何形状和骨密度分布、体重、身高、转子软组织厚度（对于髋部骨折）和年龄等因素，从而将焦点转移到骨骼的整体结构和力学，而不是简单的密度。BCT已经证明了它能够在尸体上产生准确的、非侵入性的骨强度测量结果，现在已经准备好进行临床开发。O. N.诊断是提供BCT作为DXA的临床替代品。为此，该项目的总体目标是检验一个科学假设，即与区域BMD相比，BCT是女性和男性脊柱和髋关节临床骨折风险的上级预测因子。为此，我们将采用两阶段方法分析两个独特的临床队列，以提供BCT技术的严格和一般临床验证。我们将首先应用BCT分析“马约队列”，这是一个年龄分层的随机样本，来自罗切斯特MN的大约700名社区居民男性和女性，骨折发生率得到了很好的表征。在根据该样本校准BCT结果后，我们将表征BCT结果的标准值（作为年龄的函数）和骨折阈值，这是BCT医学报告最终临床解释的基本信息。在对马约队列的BCT结果进行校准后，我们将前瞻性地测试BCT的能力-无需任何进一步的校准-使用“AGES队列”预测新发骨折，并继续测试我们的假设，即BCT是比区域BMD更好的骨折预测器。来自冰岛雷克雅未克的超过5500名居民的AGES队列是独一无二的，因为男性和女性的髋关节和脊柱临床骨折数据（如QCT扫描）都足够用于严格的统计检验。该项目的第一阶段将重点分析马约队列中女性的髋部骨折发生率，预计将提供BCT在预测髋部骨折发生率与年龄相关的增加方面优于区域BMD的上级能力的证据。由于这一整体项目可能会显着提高识别那些女性和男性的能力在最高风险的骨质疏松性骨折，它代表了一个关键的一步，建立BCT作为临床替代DXA，并在预防护理和治疗这类骨折的重要进步。 该项目将为生物力学计算机断层扫描提供临床验证，这是一种有前途的临床替代DXA诊断骨质疏松症。BCT的成功临床实施有可能极大地改善骨折风险的非侵入性评估，这将代表骨质疏松症预防和治疗的重要进展。

DESCRIPTION (provided by applicant): Fracture risk assessment is integral to the diagnosis and management of osteoporosis, a devastating clinical problem of which over 40 million Americans are at risk. Due to limitations in areal BMD measures obtained from 2D DXA scans - which is the current clinical standard for diagnosis of osteoporosis - it has recently become clear that those at greatest risk of osteoporotic fracture need to be better identified. A 3D biomechanics-based technique, which we term Biomechanical Computed Tomography (BCT), addresses this need through a combination of engineering finite element analysis, 3D quantitative computed tomography (QCT), and bone biomechanics. The main outcome parameter of BCT is an estimate of the biomechanical risk of a bone fracture that accounts for such factors as the patient's 3D bone geometry and distribution of bone density, body-weight, height, trochanteric soft tissue thickness (for hip fractures), and age, thereby shifting focus to the overall structure and mechanics of bone rather than simply density. BCT has already demonstrated its ability to produce accurate, noninvasive measures of bone strength on cadavers, and is now ready for clinical development. The long-term objective of O. N. Diagnostics is to offer BCT as a clinical alternative to DXA. Toward that end, the overall goal of the proposed project is to test the scientific hypothesis that, compared to areal BMD, BCT is a superior predictor of clinical fracture risk at the spine and hip for both women and men. To do this, we will analyze two unique clinical cohorts in a two-stage approach to provide a rigorous and general clinical validation of the BCT technique. We will first apply BCT to analysis of the "Mayo cohort", an age-stratified random sample of approximately 700 community-dwelling men and women from Rochester MN for which fracture incidence is well characterized. After calibrating the BCT outcomes against this sample, we will characterize normative values (as a function of age) and fracture threshold values of the BCT outcomes, essential information for eventual clinical interpretation of a BCT medical report. Having calibrated the BCT outcomes on the Mayo cohort, we will then prospectively test the ability of BCT - without any further calibration - to predict incident fractures using the "AGES cohort" and proceed to test our Hypothesis that BCT is a better predictor of fracture than areal BMD. The AGES cohort of over 5500 residents from Reykjavik, Iceland, is unique since both hip and spine clinical fracture data are available for both men and women (as are the QCT scans) in sufficient numbers for rigorous statistical testing. Phase I of the project will focus on analysis of hip fracture incidence for women in the Mayo cohort and is expected to provide evidence of the superior ability of BCT over areal BMD in predicting the age-related increases in hip fracture incidence. Because this overall project may significantly improve the ability to identify those women and men at highest risk of osteoporotic fracture, it represents a key step in establishing BCT as a clinical alternative to DXA, and an important advancement in the preventative care and treatment of such fractures. This project will provide clinical validation to Biomechanical Computed Tomography, a promising clinical alternative to DXA for the diagnosis of osteoporosis. Successful clinical implementation of BCT has the potential to greatly improve non-invasive assessment of fracture risk, which would represent an important advance in the preventative care and treatment of osteoporosis.