Clinical Validation of BCT

描述(由申请人提供)：骨折风险评估是诊断和治疗骨质疏松症不可或缺的一部分，骨质疏松症是一种毁灭性的临床问题，超过4000万美国人面临风险。由于从2D DXA扫描获得的面骨密度测量的局限性--这是目前诊断骨质疏松症的临床标准--最近变得明显的是，需要更好地识别那些骨质疏松性骨折风险最大的人。一种基于三维生物力学的技术，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、三维定量计算机断层扫描(QCT)和骨生物力学来满足这一需求。BCT的主要结果参数是对骨折的生物力学风险的估计，该参数考虑了患者的3D骨几何形状和骨密度的分布、体重、身高、粗隆间软组织厚度(对于髋部骨折)和年龄，从而将重点转移到骨的整体结构和力学上，而不是简单的密度。BCT已经证明了它能够在身体上产生准确的、非侵入性的骨强度测量，现在已经准备好用于临床开发。ON.Diagnostics的长期目标是提供BCT作为DXA的临床替代品。为此，拟议项目的总体目标是检验科学假设，即与面积骨密度相比，BCT是女性和男性脊柱和髋部临床骨折风险的更好预测因子。为此，我们将用两个阶段的方法分析两个独特的临床队列，以提供对BCT技术的严格和一般的临床验证。我们将首先应用BCT来分析“Mayo队列”，这是一个年龄分层的随机样本，来自罗切斯特明尼苏达州的大约700名居住在社区的男性和女性，其骨折发生率具有良好的特征。在对照此样本校准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，这是最终临床解释BCT医学报告的基本信息。在对Mayo队列中的BCT结果进行校准后，我们将前瞻性地测试BCT使用“年龄队列”来预测意外骨折的能力，而无需任何进一步的校准，并继续检验我们的假设，即BCT是比面骨密度更好的骨折预测因子。来自冰岛雷克雅未克的5500多名居民的年龄队列是独一无二的，因为有足够多的男性和女性髋部和脊柱临床骨折数据(QCT扫描也是如此)，用于严格的统计测试。该项目的第一阶段将侧重于分析Mayo队列中女性的髋部骨折发病率，预计将提供证据，证明BCT在预测与年龄相关的髋部骨折发病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风险最高的女性和男性的能力，它代表着在将BCT确立为DXA的临床替代品方面的关键一步，以及在此类骨折的预防护理和治疗方面的重要进步。 该项目将为生物力学计算机断层扫描提供临床验证，它是诊断骨质疏松症的DXA的一种有前途的临床替代方法。BCT的成功临床应用有可能极大地改进对骨折风险的非侵入性评估，这将是骨质疏松预防护理和治疗方面的重要进步。

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.