Targeting cortical bone state by quantitative in-vivo ultrasound imaging

骨质疏松症（Osteoporosis，OP）是全球人口老龄化的重要健康问题之一。根据目前预测骨状态的金标准（用双能X射线吸收测定法DXA测量的骨矿物质密度BMD），大多数患有骨质疏松相关骨折或骨折风险高的个体未被诊断为骨质疏松。皮质骨（约占人体骨骼质量的80%）的机械完整性是几个解剖部位骨强度的关键因素。由于不平衡的皮质内重塑，出现了一些大孔，导致孔径分布的特征性变化，皮质孔隙率（Ct.Po）增加，厚度（Ct.Th）降低。这些结构改变与受损的粘弹性组织基质性质一起显著降低骨强度。在之前的两国DFG-ANR项目“TaCoSound”（2015-2018）中，对人类胫骨和股骨近端的骨特性及其与股骨近端刚度和极限强度的相关性进行了系统的离体调查。在过去的2年中，申请人和国际合作伙伴提出了原始的定量体内超声US成像模式，以i）根据皮质骨壳的折射校正超声图像评估声速（类似于Ct.Po和粘弹性组织特性）和Ct.Th，以及ii）根据从皮质孔反向散射的声波的“频谱指纹”评估相应的孔径分布。本项目建立在TaCoSound和最近的研究结果的基础上，这些研究结果表明，股骨近端强度的大多数（82%）变化可以通过Ct.Th（69%）和胫骨中段大孔隙的患病率（18%）来预测。有前途的体外和初步的体内结果表明，第一次在人类中，皮质孔径分布可以进行非侵入性评估，并与衰减提供了上级骨折的歧视性能相比，DXA。然而，改进的图像重建算法和一个更全面的后向散射模型需要开发之前，广泛的临床应用。TaCoSoundInVivo旨在开发一种US成像模式，结合了强大的和空间分辨的估计宏观和微观结构以及粘弹特性的皮质骨，并将其应用于一个代表性的健康，骨质疏松和骨质疏松人群的队列。将对超声参数的骨折区分性能进行基准测试，i）在体外对充分表征的骨模型进行基准测试，ii）通过部位匹配的高分辨率外周定量计算机断层扫描（HRpQCT）进行体内基准测试。我们期望观察与年龄、性别和疾病相关的变化，并且多个US参数可以识别骨折风险增加的人，特别是BMD正常或降低的人。

Osteoporosis (OP) is one of the most important global health problems of our aging population. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are not diagnosed as osteoporotic according to the current gold standard to predict bone status (bone mineral density BMD measured with dual energy x-ray absorptiometry DXA). The mechanical integrity of cortical bone (~80% of the human skeleton mass) is a key factor of bone strength at several anatomical sites. As a consequence of an unbalanced intracortical remodeling some large pores appear, leading to a characteristic change of the pore size distribution, increased cortical porosity (Ct.Po) and reduced thickness (Ct.Th). These structural alterations together with compromised viscoelastic tissue matrix properties dramatically reduce bone strength. In a previous bi-national DFG-ANR project “TaCoSound” (2015-2018) a systematic ex-vivo survey of bone properties in human tibia and proximal femur and their associations with proximal femur stiffness and ultimate strength has been conducted. During the past 2 years, the applicant and international collaboration partners proposed original quantitative in-vivo ultrasound US imaging modalities to i) assess sound velocity (resembling Ct.Po and viscoelastic tissue properties) and Ct.Th from refraction-corrected ultrasound images of the cortical bone shell, and ii) to assess from the "spectral fingerprint" of acoustic waves backscattered from cortical pores the respective pore size distribution. The present project builds on TaCoSound and recent findings suggesting that the majority (82%) of variations of proximal femur strength can be predicted by Ct.Th (69%) and the prevalence of large pores (18%) in the tibia midshaft. Promising ex-vivo and preliminary in-vivo results demonstrate that - for the first time in humans – cortical pore size distribution can be assessed noninvasively and together with attenuation provides superior fracture discrimination performance compared to DXA. However, improved image reconstruction algorithms and a more comprehensive backscatter model need to be developed prior a broad clinical application.TaCoSoundInVivo aims at the development of an US imaging modality that combines robust and spatially resolved estimations of macro- and microstructural as well as viscoelastic properties of cortical bone and will apply it on a representative cohort of healthy, osteopenic and osteoporotic people. The fracture discrimination performance of US parameters will be benchmarked i) ex-vivo on well characterized bone phantoms and ii) in-vivo by means of site-matched high-resolution peripheral quantitative computed tomography (HRpQCT). We anticipate to observe age-, gender and disease associated alterations, and that multiple US parameters can identify people at increased fracture risk, particularly in people with normal or reduced BMD.