Mechanical Function of Trabecular Bone: Bone Loss Assessment Beyond BMD

描述（由申请人提供）：目前诊断与年龄相关的骨质流失和骨质疏松症的金标准是测量骨矿物质密度（BMD），这是通过双能x射线吸收仪（DEXA）测定的每总骨量的矿物质量。当测量脊柱、手腕和股骨颈时，骨密度与骨量密度高度相关。然而，根据骨密度测试诊断为骨质疏松症的女性中，有相当一部分人没有骨折，而许多骨密度正常的女性却有。这些研究表明，BMD测量缺乏敏感性和特异性，无法有效识别骨强度下降和有骨折风险的患者，这表明骨量密度之外的其他因素在骨质疏松症中起重要作用：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骨的结构方面，影响骨的复杂结构的强度和骨折的风险。来自外围定量计算机断层扫描（pQCT）和磁共振成像（MRI）的骨骼图像可以提供小梁微结构的测量，并产生用于有限元分析（FEA）的3D数值模型，以估计骨骼的力学特性。然而，这些成像技术在评估骨质流失方面的广泛应用受到其高成本、图像分辨率和与pQCT相关的x射线剂量的限制。骨质疏松性骨折在老化骨骼中的发生率与骨骼力学性能受损高度相关。因此，本提案的总体目标是研究一种替代的骨脆弱性评估方法，这种方法既不是基于骨密度，也不是基于骨图像的有限元分析，而是基于骨的实际力学行为的测量。我们建议测试一种基于骨小梁各向异性弹性常数的新型力学功能标准，以及一种使用孔隙弹性超声断层扫描（PEUT）无创评估这种力学性能的方法。骨的各向异性变化确实会在相同的骨体积内导致弱（受损）和强（功能）的力学方向，导致力学功能受损，或者当骨在受损方向上加载时增加骨折风险。由于骨小梁刚度是通过PEUT（一种高频力学测试）获得的，因此它自然地将骨数量（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依赖力学性能的测量中。因此，PEUT方法有望提供骨力学功能的直接信息，与BMD测量相比，它应该具有更高的敏感性和特异性，以区分有骨折风险的患者。随着这种无创多孔弹性超声断层扫描方法的发展，我们期望为基于骨力学特性的实际变化评估骨质流失和骨质疏松症提供另一种范式。这种方法可能是我们理解和评估骨质流失方式的概念转变的起源，促进了我们对骨力学功能作为方向相关参数（张量）的理解，而不是标量值（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).