Osteoporosis constitutes a major worldwide public health burden characterized by enhanced skeletal fragility. Bone metabolism is the combination of bone resorption by osteoclasts and bone formation by osteoblasts. Whereas increase in bone resorption is considered as the main contributor of bone loss that may lead to osteoporosis, this loss is accompanied by increased bone marrow adiposity. Osteoblasts and adipocytes share the same precursor cell and an inverse relationship exists between the two lineages. Therefore, identifying signaling pathways that stimulate mesenchymal stem cells osteogenesis at the expense of adipogenesis is of major importance for developing new therapeutic treatments. For this purpose, we identified by transcriptomic analysis the oxytocin receptor pathway as a potential regulator of the osteoblast/adipocyte balance of human multipotent adipose-derived stem (hMADS) cells. Both oxytocin (OT) and carbetocin (a stable OT analogue) negatively modulate adipogenesis while promoting osteogenesis in both hMADS cells and human bone marrow mesenchymal stromal cells. Consistent with these observations, ovariectomized (OVX) mice and rats, which become osteoporotic and exhibit disequilibrium of this balance, have significant decreased OT levels compared to sham-operated controls. Subcutaneous OT injection reverses bone loss in OVX mice and reduces marrow adiposity. Clinically, plasma OT levels are significantly lower in postmenopausal women developing osteoporosis than in their healthy counterparts. Taken together, these results suggest that plasma OT levels represent a novel diagnostic marker for osteoporosis and that OT administration holds promise as a potential therapy for this disease.

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Microcomputed tomography (microCT) produces three-dimensional (3D) images of trabecular bone. We compared conventional microCT (CmicroCT) with a polychromatic x-ray cone beam to synchrotron radiation (SR) microCT with a monochromatic parallel beam for assessing trabecular bone microarchitecture of 14 subchondral femoral head specimens from patients with osteoarthritis (n=10) or osteoporosis (n=4). SRmicroCT images with a voxel size of 10.13 microm were reconstructed from 900 2D radiographic projections (angular step, 0.2 degrees). CmicroCT images with a voxel size of 10.77 microm were reconstructed from 205, 413, and 825 projections obtained using angular steps of 0.9 degrees, 0.45 degrees, and 0.23 degrees, respectively. A single threshold was used to binarize the images. We computed bone volume/ tissue volume (BV/TV), bone surface/bone volume (BS/BV), trabecular number (Tb.N), trabecular thickness (Tb.Th and Tb.Th*), trabecular spacing (Tb.Sp), degree of anisotropy (DA), and Euler density. With the 0.9 degrees angular step, all CmicroCT values were significantly different from SRmicroCT values. With the 0.23 degrees and 0.45 degrees rotation steps, BV/TV, Tb.Th, and BS/BV by CmicroCT differed significantly from the values by SRmicroCT. The error due to slice matching (visual site matching +/- 10 slices) was within 1% for most parameters. Compared to SRmicroCT, BV/TV, Tb.Sp, and Tb.Th by CmicroCT were underestimated, whereas Tb.N and Tb. Th* were overestimated. A Bland and Altman plot showed no bias for Tb.N or DA. Bias was -0.8 +/- 1.0%, +5.0 +/- 1.1 microm, -5.9 +/- 6.3 microm, and -5.7 +/- 29.1 microm for BV/TV, Tb.Th*, Tb.Th, and Tb.Sp, respectively, and the differences did not vary over the range of values. Although systematic differences were noted between SRmicroCT and CmicroCT values, correlations between the techniques were high and the differences would probably not change the discrimination between study groups. CmicroCT provides a reliable 3D assessment of human defatted bone when working at the 0.23 degrees or 0.45 degrees rotation step; the 0.9 degrees rotation step may be insufficiently accurate for morphological bone analysis.

Bone intrinsic strength is conditioned by several factors, including material property and trabecular micro-architecture. Bone mineral density (BMD) is a good surrogate for material property. Architectural anisotropy is of special interest in mechanics-architecture relations and characterizes the degree of directional organization of a material. We have developed anisotropy indices from the Fast Fourier Transform (FFT) on bone radiographs. We have validated these indices in a cross-sectional uni-center case-control study including 39 postmenopausal women with vertebral fracture and 70 age-matched control cases. BMD was measured at the lumbar spine and femoral neck. A fractal analysis of texture was performed on calcaneus radiographs at three regions of interest (ROIs), and the result was expressed as the H parameter (fractal dimension =H-2). The anisotropy evaluation was based on the FFT spectrum of these three ROIs extracted on calcaneus radiographs. On the FFT spectrum, we have measured the spreading angle of the longitudinal trabeculae called the dispersion longitudinal index (DLI) and the spreading angle of the transversal trabeculae called the dispersion transversal index (DTI). From the measured parameters, an anisotropy index was derived, and the degree of anisotropy (DA) calculated with DLI and DTI. We have compared the results from the vertebral fracture cases and control cases. The best distinction was obtained for the largest ROI located in the great tuberosity of the calcaneus for all parameters ( P <10(-4)).( )The DA parameter showed a higher value in vertebral fracture cases (1.746+/-0.169) than in control cases (1.548+/-0.136); P <10(-4), and the difference persisted after removal of the subjects with hormonal replacement therapy. The analysis of the receiver operating characteristics (ROC) has shown the best results with DA and Hmean: areas under curves (AUCs) respectively of 0.765 and 0.683, while AUCs associated to LS-BMD and FN-BMD were 0.614 and 0.591 lower, respectively. We determined the odds ratios (OR) by uni- and multivariate analysis. Crude ORs were respectively 3.91 (95% CI: 2.22-6.87) and 3.08 (95% CI: 1.72-5.52) for DA and Hmean. Crude ORs were respectively 1.71 (95% CI: 1.15-2.56) and 1.56 (95% CI: 1.05-2.31) for LS-BMD and FN-BMD. All ORs were statistically significant, and those associated to Hmean and anisotropy indices were higher than those of BMD measurements. From a multivariate analysis including anisotropy indices, Hmean, age and FN-BMD, the remaining significant ORs were respectively 6.33 (95% CI: 2.80-14.30) and 3.08 (95% CI: 1.48-6.37) for DA and Hmean. These data have shown that anisotropy indices on calcaneus radiographs can distinguish vertebral fracture cases from control cases. This analysis provides complementary information concerning the BMD and fractal parameter. These data suggest that we can improve the fracture risk evaluation by adding information related to the directional organization of trabecular bone derived from the FFT spectrum on conventional radiogra...