Targeting cortical bone quality by ultrasound biomarkers - relations to porosity, stiffness and strength

骨质疏松症（Osteoporosis， OP）是老龄化人口中最重要的全球性健康问题之一，它降低了人们的活动能力和生活质量，增加了死亡率，并给医疗保健系统带来了巨大的负担。OP和其他退行性骨病变是由骨吸收和骨形成之间的不平衡引起的，导致骨小梁网络的稀薄，以及皮质组织中部分再填充的基本多细胞单位（BMUs）的积累。后者导致皮质变薄，孔隙度增加，皮质骨刚度改变，随后导致骨强度降低。OP被认为是诊断最不充分的疾病之一。除了电离辐射在纵向筛查中的有限适用性外，现在人们普遍接受双x线吸收仪（DXA），这是测量骨矿物质密度的既定诊断工具，仅能预测约60%的个体骨折。长期以来，骨强度评估主要集中在小梁骨，而忽视了皮质骨的衰变在骨脆性发病机制和65岁以上男女骨折发生率中的作用。最近的研究指出皮质骨的重要性，提示诊断和风险评估应包括皮质骨的准确评估。基于x射线的技术很难捕捉到皮质骨丢失。近年来，定量超声的创新基础研究已转向使用引导波和后向散射波测量皮质骨。目前正在探索复杂的方法，通过求解逆问题，可以为每位患者单独提供有效的刚度系数、皮质内孔隙度和皮质厚度。这个协同项目的目的是建立皮质骨丢失的新型超声生物标志物，它可以分别使用多向轴向传输和高频背散射测量分析的导波传播来定量评估皮质厚度、刚度和孔隙度，并将这些超声生物标志物与测量部位的局部皮质骨强度(组织失效、毫米长度)和股骨近端强度（器官衰竭）。测量将在离体人体供体的股骨-胫骨对中进行。通过最先进的技术，如扫描声学显微镜、微型计算机断层扫描、共振超声光谱和机械失效测试，将确定胫骨中轴、股骨近端和股骨颈皮质骨组织的结构、弹性和失效特性。股骨近端强度将通过实验确定，在两种机械载荷配置下，并通过基于高分辨率定量CT的有限元分析。目标超声生物标志物有望在骨病理的诊断和纵向监测中开辟前景。

Osteoporosis (OP) is one of the most important global health problems of our aging population, which reduces mobility and quality of life, increases mortality, and sets dramatic burden to the healthcare system. OP and other degenerative bone pathologies are caused by a dis-balance between bone resorption and bone formation, leading to a rarefication of the trabecular network, and accumulation of partially refilled basic multicelluar units (BMUs) in cortical tissue. The latter result in cortical thinning, increased porosity, alterations of cortical bone stiffness and subsequently, to a reduction of bone strength.OP is considered as one of the most underdiagnosed diseases. Besides the limited applicability of ionizing radiations for longitudinal screening, it is now well accepted that dual X-ray absorptiometry (DXA), the established diagnostic tool for measuring bone mineral density and predicts only ~60% of the individual fracture.Bone strength assessment has long focused on trabecular bone, which has neglected the role of the decay of cortical bone in the pathogenesis of bone fragility and in the incidence of fractures in women and men aged 65 years or more. Recent studies are pointing towards the importance of cortical bone, suggesting that diagnosis and risk assessment should include accurate evaluation of cortical bone.Cortical bone loss is poorly captured by X-ray based techniques. Recently, innovative basic research on quantitative ultrasound has shifted towards measurements of cortical bone using guided and backscattered waves. Sophisticated approaches are currently explored in which, by solving an inverse problem, effective stiffness coefficients, intra-cortical porosity, and cortical thickness could be provided individually for each patient.The aims of this concerted project are to establish novel ultrasound biomarkers of cortical bone loss, which allow quantitative assessment of cortical thickness, stiffness, and porosity using guided waves propagation by multidirectional axial transmission and high-frequency backscatter measurement analyses, respectively, and to relate these ultrasound biomarkers to local cortical bone strength at the measurement sites (tissue failure, mm-length scale) and to proximal femur strength (organ failure). Measurements will be conducted ex-vivo in femur-tibia pairs from human donors. Structure, elastic and failure properties of cortical bone tissue will be determined at tibia midshaft, proximal femoral shaft and femoral neck by means of state-of-the art techniques, such as scanning acoustic microscopy, micro-computed tomography, resonance ultrasound spectroscopy, and mechanical failure testing. Proximal femur strength will be determined experimentally, in two mechanical loading configurations, and by high-resolution quantitative CT based finite element analysis. The targeted ultrasound biomarkers are anticipated to open perspectives in the diagnosis and longitudinal monitoring of bone pathologies.