Skeletal-wide heterogeneity of cancellous bone and methods to assess in vivo

Abstract

Since biologically important skeletal heterogeneity has only recently been recognized, skeletal-wide characterization of metabolically active regions has never been attempted. We characterized the distribution of cancellous bone across the skeletons of both humans (using whole-body dual energy computed tomography imaging (DECT)) and mice (using micro computed tomography (microCT)). Mice, clinical trial patients, and recently deceased donors were imaged, non-invasively, using a wide array of novel imaging modalities. MicroCT was characterized for proper imaging of murine cancellous bone and feasibility of imaging entire skeleton at high resolution. The abdomens of 29 clinical trial patients were imaged longitudinally using water-fat MRI (wfMRI) and DECT in order to assess marrow corrected bone mineral density (BMD) and marrow composition. Donors were imaged from head to foot using both wfMRI and DECT. Coregistered lumbar vertebral body sections were taken from the donors and analyzed for marrow fat using H&E histology. By comparing resolution, signal-to-noise ratio, and radiation dose, we found the optimal parameters to evaluate murine trabecular bone. This allows us to image the entire body which shows high average BMD at the skull and femur/tibia region but less BMD at the mid-skeleton. DECT of the entire human body provided a unique marrow correction for each skeletal site BMD. Although average correlation was high (r = 0.99), larger marrow fat ratios were seen in the limbs. A highly heterogeneous BMD distribution was observed with a maximum at the posterior skull and minimum in the proximal humerus (580mg/cm3 and 15mg/cm3, respectively). Average correlation for all skeletal sites was higher in controls than in the cancer treated group (r = 0.61 and 0.33, respectively). Whole body imaging of both mice and cadavers showed unique differences between different skeletal sites in terms of average bone mineral density and marrow composition. DECT was validated with wfMRI and histology in order to assess percent of marrow fat. In addition to commonly measured sites (spine, hip), marrow-corrected BMD of cancellous bone is heterogeneously distributed throughout the entire skeleton. Heterogeneity was greater in subjects with cancer.