Quantitative cortical micro-architectural endpoints are important for understanding structure-function relations in the context of fracture risk and therapeutic efficacy. This technique study details new image-processing methods to automatically segment and directly quantify cortical density, geometry, and micro-architecture from HR-pQCT images of the distal radius and tibia. An automated segmentation technique was developed to identify the periosteal and endosteal margins of the distal radius and tibia, and detect intra-cortical pore space morphologically consistent with Haversian canals. The reproducibility of direct quantitative cortical bone indices based on this method was assessed in a pooled dataset of 56 subjects with two repeat acquisitions for each site. The in vivo precision error was characterized using root mean square coefficient of variation (RMSCV%) from which, the least significant change (LSC) was calculated. Bland-Altman plots were used to characterize bias in the precision estimates. The reproducibility of cortical density and cross-sectional area measures was high (RMSCV <1% and <1.5%, respectively) with good agreement between young and elder medians. The LSC for cortical porosity (Ct.Po) was somewhat smaller in the radius (0.58%) compared with the distal tibia (0.84%) and significantly different between young and elder medians in the distal tibia (LSC: 0.75% vs. 0.92%; p<0.001). The LSC for pore diameter and distribution (Po.Dm and Po.Dm.SD) ranged between 15 and 23μm. Bland-Altman analysis revealed moderate bias for integral measures of area and volume, but not density nor microarchitecture. This study indicates HR-pQCT measures of cortical bone density and architecture can be measured in vivo with high reproducibility and limited bias across a biologically relevant range of values. The results of this study provide informative data for the design of future clinical studies of bone quality.

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Increases in cortical porosity (Ct.Po) and decreases in cortical thickness (Ct.Th) are associated with increased bone fragility. The purpose of this study was to validate an autosegmentation method for high-resolution peripheral quantitative computed tomography (HR-pQCT) scans to measure Ct.Po and Ct.Th and use it to compare Ct.Po and Ct.Th between pre-and postmenopausal women with normal, osteopenic, and osteoporotic areal bone mineral density (aBMD). The Ct.Po and Ct.Th measurements were validated using cadaver forearms (n ¼ 10) and micro-computed tomography (mCT) as the gold standard. The analysis was applied to distal radius and tibia HRpQCT scans from a subset of participants from the Calgary, Alberta, cohort of the Canadian Multicentre Osteoporosis Study (n ¼ 280, 18 to 90 years). Analysis of covariance compared Ct.Po and Ct.Th outcomes between 63 normal premenopausal (dual-energy X-ray absorptiometry femoral neck T-score > À1), 87 normal postmenopausal, 121 osteopenic postmenopausal, and 9 osteoporotic postmenopausal women. Linear regression analysis and Bland-Altman plots were used to assess the agreement between the HRpQCT and mCT measurements, resulting in r 2 values of 0.80 for Ct.Po and 0.98 for Ct.Th. At both sites, Ct.Po was higher in postmenopausal (all groups) than in premenopausal women (3.2% to 12.9%, p < .001). Ct.Th was not significantly different between normal premenopausal and postmenopausal women at either site; however, both osteopenic and osteoporotic women had thinner (À12.8% to À30.3%, p < .01), more porous (2.1% to 8.1%, p < .001) cortices than normal postmenopausal women. Our method offers promise as a valuable tool to measure Ct.Po and Ct.Th in vivo and investigate associations among cortical bone structure, age, and disease status. ß

An understanding of normal microarchitectural bone development patterns of common murine models is needed. Longitudinal, structural, and mineralization trends were evaluated by in vivo CT over 12 time points from 6-48 wk of age at the vertebra and tibia of C3H/HeN, C57BL/6, and BALB/C mice. Longitudinal growth occurred rapidly until 8-10 wk, slowed as the growth plate bridged, and fused at 8-10 mo. Structural augmentation occurred through formation of trabeculae at the growth plate and thickening of existing ones. In the vertebrae, BV/TV increased rapidly until 12 wk in all strains. Between 12 and 32 wk, the architecture was stable with BV/TV deviating <1.1%, 1.6%, and 3.4% for the C57BL/6, BALB/C, and C3H/ HeN mice. In contrast, the tibial architecture changed continuously but more moderately for BV/TV and TbTh compared with the vertebra and with comparable or larger changes for TbN and TbSp. Age-related trabecular deterioration (decreased BV/TV and TbN; increased TbSp and structure model index) was evident at both sites at 32 wk. In all strains, the cortex continued to develop after trabecular values peaked. The temporal plateau of BMD was variable across mouse strains and site, whereas tissue mineral density was attained at ∼6 mo for all sites and strains. Geometric changes at the tibial diaphysis occurred rapidly until 8-10 wk, providing the C57BL/6 mice and C3H/HeN mice with the highest torsional and compressive rigidity, respectively. In summary, key skeletal development milestones were identified, and architectural topology at the vertebra was found to be more stable than at the tibia.

Changes to the bone architecture and mechanics within twelve weeks after OVX highlight the importance of early diagnosis and treatment of osteoporosis.