Clinical Validation of BCT - Phase II

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疾病，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--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有骨质疏松性骨折风险的人。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)和骨折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分布、体重、身高、粗隆软组织厚度(对于髋部骨折)、肌力矩臂(对于脊柱)以及与年龄相关的维持超负荷事件的风险(如背部弯曲跌倒或抬起重物)。在将BCT转化为临床实践的更大背景下，我们试图在这个第二阶段SBIR项目中检验这样一个总体假设，即对于髋部和脊柱骨折以及女性和男性，BCT是比面积骨密度更好的骨质疏松性骨折预测因子。在这个项目的第一阶段，我们成功地应用了这项技术来解释观察到的与年龄相关的髋部骨折发生率的趋势。对于第二阶段，我们计划首先改进我们的BCT技术，以生产一个全自动、高可靠和高精度的软件套件，能够分析为任何覆盖髋部和/或脊柱的医学测试采集的CT扫描，而不需要外部校准模体。对于目标2，为了确保临床骨折的最佳预测，我们将通过校准两个队列(密歇根州罗切斯特的梅奥诊所750名男性和女性，以及美国6个地点的3,500名男性的MRO队列)的结果，进一步完善我们的整体BCT流程。在这个校准过程中需要解决的问题包括确定测量软组织厚度、肌力矩臂和脊柱负荷的最佳方法。这项分析还将使我们能够校准我们的功能，以应对与年龄相关的超负荷事件风险，这可能取决于骨折类型(髋部与脊柱)和性别。在目标3中，我们将汇编BCT结果的标准数据，这是解释临床结果的关键信息。在改进和校准了整个BCT技术并确定了Mayo和MROS队列中最成功的临床骨折BCT预测指标后，我们将在目标4中以完全前瞻性的方式测试这些预测指标的有效性，而不会对BCT技术进行任何进一步的修改。为此，我们将分析冰岛雷克雅未克5500名男女的髋部和脊柱骨折的年龄队列。综上所述，这项多队列的国际验证研究将为骨质疏松性骨折的病因提供新的见解，为BCT方法提供重要的进展，并对BCT的临床表现进行彻底评估。因此，该项目将对骨质疏松症的研究和临床实践产生重大影响。公共卫生相关性：该项目将为生物力学计算机断层扫描提供临床验证，这是诊断骨质疏松症的DXA的一种有前途的临床替代方案。成功地将BCT转化为临床实践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 condition of which over 40 million Americans are at risk. Due to limitations in areal BMD measures obtained from 2D DXA scans - the current clinical standard for diagnosis of osteoporosis - it has recently become clear that those at 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 fracture 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), muscle moment arm (for spine), and the age-related risk of sustaining an overload event (such as a fall or lifting of a heavy object with back bent). In the larger context of translating BCT to clinical practice, we seek in this Phase II SBIR project to test the overall hypothesis that BCT is a better predictor of osteoporotic fracture than is areal BMD, for both hip and spine fracture and for both women and men. In Phase I of this project, we successfully applied this technique to explain observed age-related trends in hip fracture rates. For Phase II, we plan in our first Aim to refine our BCT technique to produce a fully automated, highly reliable and highly accurate software suite with the capability to analyze CT scans acquired for any medical test with coverage of the hip and/or spine without an external calibration phantom. For Aim 2, in order to ensure optimal prediction of clinical fractures, we will further refine our overall BCT process by calibrating results from the two cohorts (the Mayo Clinic cohort of 750 men and women in Rochester MN, and the MrOS cohort of 3,500 men in six U.S. locations). Issues to be resolved in this calibration process include determining optimal methods for measuring soft tissue thickness, muscle moment arms, and spine loading. This analysis will also enable us to calibrate our function for age- related risk of sustaining an overload event, which may depend on both fracture type (hip vs. spine) and sex. In Aim 3, we will compile normative data for BCT outcomes, critical information for interpretation of clinical results. Having refined and calibrated the overall BCT technique and identified the most successful BCT predictors of clinical fracture in the Mayo and MrOS cohorts, we will proceed in Aim 4 to test the validity of these predictors in a fully prospective manner, without any further modification of the BCT technique. For this, we will analyze the AGES cohort of 5,500 women and men in Reykjavik, Iceland, for incident hip and spine fracture. Taken together, this multi-cohort international validation study will provide new insight into osteoporotic fracture etiology, important advancements for the BCT method, and a thorough evaluation of BCT clinical performance. This project should therefore have a significant impact on osteoporosis research and clinical practice. PUBLIC HEALTH RELEVANCE: Statement of Relevance This project will provide clinical validation to Biomechanical Computed Tomography, a promising clinical alternative to DXA for the diagnosis of osteoporosis. Successful translation of BCT to clinical practice 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.