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The local variability of microarchitecture of human trabecular calcaneus bone is investigated using high-resolution micro–computed tomography (µCT) scanning. The fabric tensor is employed as the measure of the microarchitecture of the pore structure of a porous medium. It is hypothesized that a fabric tensor–dependent poroelastic ultrasound approach will more effectively predict the data variance than will porosity alone. The specific aims of the present study are as follows: (1) to quantify the morphology and local anisotropy of the calcaneus microarchitecture with respect to anatomical directions; (2) to determine the interdependence, or lack thereof, of microarchitecture parameters, fabric, and volumetric bone mineral density (vBMD); and (3) to determine the relative ability of vBMD and fabric measurements in evaluating the variance in ultrasound wave velocity measurements along orthogonal directions in the human calcaneus. Our results show that the microarchitecture in the analyzed regions of human calcanei is anisotropic, with a preferred alignment along the posterior-anterior direction. Strong correlation was found between most scalar architectural parameters and vBMD. However, no statistical correlation was found between vBMD and the fabric components, the measures of the pore microstructure orientation. Therefore, among the parameters usually considered for cancellous bone (ie, classic histomorphometric parameters such as porosity, trabecular thickness, number and separation), only fabric components explain the data variance that cannot be explained by vBMD, a global mass measurement, which lacks the sensitivity and selectivity to distinguish osteoporotic from healthy subjects because it is insensitive to directional changes in bone architecture. This study demonstrates that a multidirectional, fabric-dependent poroelastic ultrasound approach has the capability of characterizing anisotropic bone properties (bone quality) beyond bone mass, and could help to better understand anisotropic changes in bone architecture using ultrasound. © 2012 American Society for Bone and Mineral Research.