Mechanical Function of Trabecular Bone: Bone Loss Assessment Beyond BMD

描述(申请人提供)：目前诊断年龄相关性骨质丢失和骨质疏松症的金标准是测量骨密度(BMD)，这是通过双能X射线吸收法(DEXA)确定的每一总骨体积中矿物质含量的测量。在脊柱、手腕和股骨颈测量时，骨密度与骨密度高度相关。然而，根据BMD测试被诊断为骨质疏松症的女性中，有相当数量的人没有骨折，而许多BMD正常的女性却有。这些研究表明，骨密度测量缺乏敏感性和特异性，无法有效地识别骨强度降低和有骨折风险的患者，这表明除了骨密度之外，其他因素在骨质疏松症中也起着重要作用：骨微结构、各向异性和组织组成。不幸的是，基于质量密度的方法不可能揭示影响骨的复杂结构中强度和骨折风险的骨的结构方面。外周定量计算机断层扫描(PQCT)和磁共振成像(MRI)的骨图像可以提供骨小梁微结构的测量，并产生用于有限元分析(FEA)的三维数值模型来估计骨的力学性能。然而，这些成像技术用于评估骨丢失的广泛使用受到其高昂的成本、其图像的分辨率以及与pQCT相关的X射线剂量的限制。骨质疏松性骨折在老化的骨骼中的发生率与骨骼力学性能受损高度相关。因此，这项建议的总体目标是研究一种替代的骨脆性评估方法，该方法既不基于骨图像的BMD也不基于有限元分析，而是基于对骨的实际力学行为的测量。我们提出了一种新的基于骨小梁各向异性弹性常数的力学功能标准，并提出了一种使用多孔弹性超声断层扫描(PEUT)来非侵入性评估这种力学特性的方法。骨的各向异性变化确实会导致相同骨体积内的弱(受损)和强(功能)力学方向，导致机械功能受损，或者当骨骼沿受损方向加载时，骨折风险增加。由于骨小梁硬度是从PEUT(一种高频力学测试)获得的，因此它自然地将骨量(即BMD、BV/TV或孔隙度)和骨质量(即微结构、各向异性、组织组成)的影响整合到骨的方向相关的力学特性的测量中。因此，PEUT方法有望提供有关骨机械功能的直接信息，与骨密度测量相比，该方法在区分有骨折风险的患者方面应具有更高的敏感性和特异性。随着这种非侵入性孔弹超声断层扫描方法的发展，我们期望根据骨力学特性的实际变化为骨丢失和骨质疏松症的评估提供一种替代范式。这种方法可能是我们理解和评估骨丢失方式的概念转变的根源，促进了我们对骨机械功能的理解，将其作为方向相关的参数(张力量)，而不是标量(BMD)。

DESCRIPTION (provided by applicant): The current gold standard to diagnose age-related bone loss and osteoporosis is the measurement of the Bone Mineral Density (BMD), which is a measure of the amount of mineral per total bone volume determined by Dual Energy X-ray Absorptiometry (DEXA). BMD is highly correlated to bone mass density when measured in the spine, wrist and femoral neck. However, a significant number of women diagnosed with osteoporosis based on a BMD test do not suffer fractures, whereas many women with normal BMD do. These studies demonstrated that BMD measurements lack both sensitivity and specificity to effectively identify patients with decreased bone strength and at risk of fracture, indicating that other factors besides bone mass density play an important role in osteoporosis: bone microarchitecture, anisotropy and tissue composition. Unfortunately, it is not possible for mass density-based approaches to reveal the architectural aspects of bone that influence the strength and risk of fracture in bone's complex structure. Bone images from peripheral quantitative computed tomography (pQCT) and magnetic resonance imaging (MRI) can provide measurements of trabecular microarchitecture, and produce 3D numerical models that are used in finite element analysis (FEA) to estimate the mechanical properties of bone. However, the wide use of these imaging technologies to assess bone loss is limited by their high cost, the resolution of their images and the X-ray dose associated with pQCT. The incidence of osteoporotic fractures in the ageing skeleton is highly associated with impaired bone mechanical properties. Therefore, the general objective of this proposal is to investigate an alternative approach of bone fragility assessment that is neither based on BMD nor FEA from bone images, but based on measurements of the actual mechanical behavior of bone. We propose testing a novel mechanical-function criterion based on the anisotropic elastic constants of trabecular bone and a means to assess such mechanical properties non-invasively using Poroelastic Ultrasound Tomography (PEUT). Anisotropic changes of bone do result in weak (impaired) and strong (functional) mechanical directions within the same bone volume, leading to compromised mechanical function, or increased fracture risk when bone is loaded in the impaired directions. Because the trabecular stiffness are obtained from PEUT -a high frequency mechanical test- it naturally integrates the effect of both bone quantity (i.e., BMD, BV/TV, or porosity) and bone quality (i.e., microarchitecture, anisotropy, tissue composition) into a measurement of the directional-dependent mechanical properties of bone. Thus, the PEUT approach is expected to provide direct information on bone mechanical function, which should have higher sensitivity and specificity to distinguish patients at risk of fracture than BMD measurements. With the development of this non-invasive poroelastic ultrasound tomography approach, we expect to provide an alternative paradigm for assessment of bone loss and osteoporosis based in actual changes of bone mechanical properties. This approach may be at the origin of a conceptual shift on the way we understand and assess bone loss, advancing our understanding of bone mechanical function as a directional-dependent parameter (tensorial quantity) as opposed to a scalar-valued quantity (BMD).