Clinical Validation of BCT

描述（由申请人提供）：骨折风险评估是骨质疏松症诊断和治疗不可或缺的一部分，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。由于目前诊断骨质疏松症的临床标准——2D DXA扫描所获得的面积骨密度测量的局限性，最近人们清楚地认识到，需要更好地识别骨质疏松性骨折风险最高的人群。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的主要结果参数是对骨折的生物力学风险的估计，考虑了诸如患者的三维骨骼几何形状和骨密度分布、体重、身高、粗隆软组织厚度（对于髋部骨折）和年龄等因素，从而将重点转移到骨骼的整体结构和力学上，而不仅仅是密度。BCT已经证明了其对尸体进行准确、无创的骨强度测量的能力，现在已经准备好进行临床开发。O. N. Diagnostics的长期目标是提供BCT作为DXA的临床替代方案。为了达到这一目的，该项目的总体目标是验证这样一个科学假设，即与实际骨密度相比，BCT是女性和男性脊柱和髋关节临床骨折风险的优越预测指标。为此，我们将分两阶段分析两个独特的临床队列，为BCT技术提供严格和普遍的临床验证。我们首先将BCT应用于“梅奥队列”的分析，这是一个年龄分层的随机样本，来自明尼苏达州罗切斯特市的大约700名社区居民的男性和女性，其中骨折发生率有很好的特征。在根据样本校准BCT结果后，我们将描述BCT结果的规范值（作为年龄的函数）和骨折阈值，这是最终临床解释BCT医学报告的重要信息。在Mayo队列中校准BCT结果后，我们将使用“AGES队列”前瞻性测试BCT预测意外骨折的能力（无需进一步校准），并继续验证我们的假设，即BCT比面积骨密度更能预测骨折。来自冰岛雷克雅未克的5500多名居民的AGES队列是独一无二的，因为男性和女性的髋部和脊柱临床骨折数据（以及QCT扫描）都足够多，可以进行严格的统计测试。该项目的第一阶段将侧重于梅奥队列中女性髋部骨折发生率的分析，并有望提供证据，证明BCT在预测与年龄相关的髋部骨折发生率增加方面优于面积骨密度。由于这一整体项目可能显著提高识别骨质疏松性骨折高危人群的能力，因此它代表了将BCT作为临床替代DXA的关键一步，也是此类骨折预防护理和治疗的重要进展。

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.