Clinical Validation of BCT - Phase II

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，骨质疏松症是一种破坏性的临床疾病，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-目前诊断骨质疏松症的临床标准-最近已经清楚的是，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），通过工程有限元分析，3D定量计算机断层扫描（QCT）和骨折生物力学的组合来解决这一需求。BCT的主要结局参数是对骨折生物力学风险的估计，其考虑了患者的3D骨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）、肌肉力臂（对于脊柱）以及与年龄相关的承受过载事件的风险（例如背部弯曲时摔倒或举起重物）等因素。在将BCT转化为临床实践的更大背景下，我们寻求在这个II期SBIR项目中检验总体假设，即BCT是比面积BMD更好的预测骨质疏松性骨折的指标，无论是对髋部骨折还是脊柱骨折，无论是对女性还是男性。在该项目的第一阶段，我们成功地应用这项技术来解释观察到的年龄相关的髋部骨折率的趋势。对于第二阶段，我们计划在我们的第一个目标，以完善我们的BCT技术，以产生一个完全自动化的，高度可靠的和高度准确的软件套件，具有分析能力的CT扫描采集的任何医疗测试覆盖的髋关节和/或脊柱没有外部校准体模。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（罗切斯特MN的750名男性和女性的马约诊所队列和美国六个地点的3，500名男性的MrOS队列）的结果来进一步完善我们的整体BCT过程。在此校准过程中要解决的问题包括确定测量软组织厚度、肌肉力臂和脊柱载荷的最佳方法。该分析还将使我们能够校准我们的功能，用于维持过载事件的年龄相关风险，这可能取决于骨折类型（髋关节vs.脊柱）和性别。在目标3中，我们将汇编BCT结局的规范性数据，这是解释临床结果的关键信息。在完善和校准了整体BCT技术并确定了马约和MrOS队列中临床骨折最成功的BCT预测因子后，我们将在目标4中继续以完全前瞻性的方式测试这些预测因子的有效性，而不对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5,500名女性和男性的AGES队列，以了解髋关节和脊柱骨折的发生情况。总之，这项多队列国际验证研究将为骨质疏松性骨折病因学提供新的见解，BCT方法的重要进展，以及BCT临床性能的全面评价。因此，该项目应该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：相关性声明本项目将为生物力学计算机断层扫描提供临床验证，生物力学计算机断层扫描是DXA诊断骨质疏松症的一种有前途的临床替代方法。BCT的成功转化为临床实践有可能大大提高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 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.