Osteoporosis is a disorder of bone remodeling leading to reduced bone mass, structural deterioration, and increased bone fragility. The established diagnosis is based on the measurement of areal bone mineral density by dual-energy X-ray absorptiometry (DXA), which poorly captures individual bone loss and structural decay. Enlarged cortical pores in the tibia have been proposed to indicate structural deterioration and reduced bone strength in the hip. Here, we report for the first time the in vivo assessment of the cortical pore-size distribution together with frequency-dependent attenuation at the anteromedial tibia midshaft by means of a novel ultrasonic cortical backscatter (CortBS) technology. We hypothesized that the CortBS parameters are associated with the occurrence of fragility fractures in postmenopausal women (n = 55). The discrimination performance was compared with those of DXA and high-resolution peripheral computed tomography (HR-pQCT). The results suggest a superior discrimination performance of CortBS (area under the receiver operating characteristic curve [AUC]: 0.69 ≤ AUC ≤ 0.75) compared with DXA (0.54 ≤ AUC ≤ 0.55) and a similar performance compared with HR-pQCT (0.66 ≤ AUC ≤ 0.73). CortBS is the first quantitative bone imaging modality that can quantify microstructural tissue deteriorations in cortical bone, which occur during normal aging and the development of osteoporosis.
© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Most bone loss during the development of osteoporosis occurs in cortical bone at the peripheral skeleton. Decreased cortical thickness(Ct.Th) and the prevalence of large pores at the tibia are associated with reduced bone strength at the hip. Ct.Th and cortical sound velocity, i.e., a surrogate marker for changes of cortical porosity (Ct.Po), are key biomarkers for the identification of patients at high fracture risk. In this study, we have developed a method using a conventional ultrasound array transducer to determine thickness (Ct.Th) and the compressional sound velocity propagating in the radial bone direction (Ct.ν 11 ) using a refraction-corrected multifocus imaging approach. The method was validated in-silico on porous bone plate models using a 2-D finite-difference time-domain method and ex vivo on plate-shaped plastic reference materials and on plate-shaped cortical bovine tibia samples. Plane-wave pulse-echo measurements provided reference values to assess precision and accuracy of our method. In-silico results revealed the necessity to account for inclination-dependent transmission losses at the bone surface. Moreover, the dependence of Ct.ν 11 on both porosity and pore density was observed. Ct.Th and Ct.ν 11 obtained ex vivo showed a high correlation (R2 > 0.99) with reference values. The ex-vivo accuracy and precision for Ct.ν 11 were 29.9 m/s and 0.94%, respectively, and those for Ct.Th were 0.04 mm and 1.09%, respectively. In conclusion, this numerical and experimental study demonstrates an accurate and precise estimation of Ct.Th and Ct.ν 11 . The developed multifocus technique may have high clinical potential to improve fracture risk prediction using noninvasive and nonionizing conventional ultrasound technology with image guidance.
Alterations of structure and density of cortical bone are associated with fragility fractures and can be assessed in vivo in humans at the tibia. Bone remodeling deficits in aging women have been recently linked to an increase in size of cortical pores. In this ex vivo study, we characterized the cortical microarchitecture of 19 tibiae from human donors (aged 69 to 94 years) to address, whether this can reflect impairments of the mechanical competence of the proximal femur, i.e., a major fracture site in osteoporosis. Scanning acoustic microscopy (12 μm pixel size) provided reference microstructural measurements at the left tibia, while the bone vBMD at this site was obtained using microcomputed tomography (microCT). The areal bone mineral density of both left and right femoral necks (aBMDneck) was measured by dual-energy X-ray absorptiometry (DXA), while homogenized nonlinear finite element models based on high-resolution peripheral quantitative computed tomography provided hip stiffness and strength for one-legged standing and sideways falling loads. Hip strength was associated with aBMDneck (r = 0.74 to 0.78), with tibial cortical thickness (r = 0.81) and with measurements of the tibial cross-sectional geometry (r = 0.48 to 0.73) of the same leg. Tibial vBMD was associated with hip strength only for standing loads (r = 0.59 to 0.65). Cortical porosity (Ct.Po) of the tibia was not associated with any of the femoral parameters. However, the proportion of Ct.Po attributable to large pores (diameter > 100 μm) was associated with hip strength in both standing (r = -0.61) and falling (r = 0.48) conditions. When added to aBMDneck, the prevalence of large pores could explain up to 17% of the femur ultimate force. In conclusion, microstructural characteristics of the tibia reflect hip strength as well as femoral DXA, but it remains to be tested whether such properties can be measured in vivo.
Delay-and-sum (DAS) beamforming of backscattered echoes is used for conventional ultrasound imaging. Although DAS beamforming is well suited for imaging in soft tissues, refraction, scattering, and absorption, porous mineralized tissues cause phase aberrations of reflected echoes and subsequent image degradation. The recently developed refraction corrected multi-focus technique uses subsequent focusing of waves at variable depths, the tracking of travel times of waves reflected from outer and inner cortical bone interfaces, the estimation of the shift needed to focus from one interface to another to determine cortical thickness (Ct.Th), and the speed of sound propagating in a radial bone direction (Ct.ν11). The method was validated previously in silico and ex vivo on plate shaped samples. The aim of this study was to correct phase aberration caused by bone geometry (i.e., curvature and tilt with respect to the transducer array) and intracortical pores for the multi-focus approach. The phase aberration correction methods are based on time delay estimation via bone geometry differences to flat bone plates and via the autocorrelation and cross correlation of the reflected ultrasound waves from the endosteal bone interface. We evaluate the multi-focus approach by incorporating the phase aberration correction methods by numerical simulation and one experiment on a human tibia bone, and analyze the precision and accuracy of measuring Ct.Th and Ct.ν11. Site-matched reference values of the cortical thickness of the human tibia bone were obtained from high-resolution peripheral computed tomography. The phase aberration correction methods resulted in a more precise (coefficient of variation of 5.7%) and accurate (root mean square error of 6.3%) estimation of Ct.Th, and a more precise (9.8%) and accurate (3.4%) Ct.ν11 estimation, than without any phase aberration correction. The developed multi-focus method including phase aberration corrections provides local estimations of both cortical thickness and sound velocity and is proposed as a biomarker of cortical bone quality with high clinical potential for the prevention of osteoporotic fractures.
Multichannel pulse-echo ultrasound using linear arrays and single-channel data acquisition systems opens new perspectives for the evaluation of cortical bone. In combination with spectral backscatter analysis, it can provide quantitative information about cortical microstructural properties. We present a numerical study, based on the finite-difference time-domain method, to estimate the backscatter cross section of randomly distributed circular pores in a bone matrix. A model that predicts the backscatter coefficient using arbitrary pore diameter distributions was derived. In an ex vivo study on 19 human tibia bones (six males, 13 females, 83.7 ± 8.4 years), multidirectional ultrasound backscatter measurements were performed using an ultrasound scanner equipped with a 6-MHz 128-element linear array with sweep motor control. A normalized depth-dependent spectral analysis was performed to derive backscatter and attenuation coefficients. Site-matched reference values of tissue acoustic impedance Z, cortical thickness (Ct.Th), pore density (Ct.Po.Dn), porosity (Ct.Po), and characteristic parameters of the pore diameter (Ct.Po.Dm) distribution were obtained from 100-MHz scanning-acoustic microscopy images. Proximal femur areal bone mineral density (aBMD), stiffness S, and ultimate force Fu from the same donors were available from a previous study. All pore structure and material properties could be predicted using linear combinations of backscatter parameters with a median to high accuracy (0.28 ≤ adjusted R 2 ≤ 0.59). The combination of cortical thickness and backscatter parameter provided similar or better prediction accuracies than aBMD. For the first time, a method for the noninvasive assessment of the pore diameter distribution in cortical bone by ultrasound is proposed. The combined assessment of cortical thickness, sound velocity, and pore size distribution in a mobile, nonionizing measurement system could have a major impact on preventing osteoporotic fractures.