Bone fracture risk is influenced by bone quality, which encompasses bone's composition as well as its multiscale organization and architecture. Aging and disease deteriorate bone quality, leading to reduced mechanical properties and higher fracture incidence. Largely unexplored is how bone quality and mechanical competence progress during longitudinal bone growth. Human femoral cortical bone was acquired from fetal (n = 1), infantile (n = 3), and 2‐ to 14‐year‐old cases (n = 4) at the mid‐diaphysis. Bone quality was assessed in terms of bone structure, osteocyte characteristics, mineralization, and collagen orientation. The mechanical properties were investigated by measuring tensile deformation at multiple length scales via synchrotron X‐ray diffraction. We find dramatic differences in mechanical resistance with age. Specifically, cortical bone in 2‐ to 14‐year‐old cases exhibits a 160% greater stiffness and 83% higher strength than fetal/infantile cases. The higher mechanical resistance of the 2‐ to 14‐year‐old cases is associated with advantageous bone quality, specifically higher bone volume fraction, better micronscale organization (woven versus lamellar), and higher mean mineralization compared with fetal/infantile cases. Our study reveals that bone quality is superior after remodeling/modeling processes convert the primary woven bone structure to lamellar bone. In this cohort of female children, the microstructural differences at the femoral diaphysis were apparent between the 1‐ to 2‐year‐old cases. Indeed, the lamellar bone in 2‐ to 14‐year‐old cases had a superior structural organization (collagen and osteocyte characteristics) and composition for resisting deformation and fracture than fetal/infantile bone. Mechanistically, the changes in bone quality during longitudinal bone growth lead to higher fracture resistance because collagen fibrils are better aligned to resist tensile forces, while elevated mean mineralization reinforces the collagen scaffold. Thus, our results reveal inherent weaknesses of the fetal/infantile skeleton signifying its inferior bone quality. These results have implications for pediatric fracture risk, as bone produced at ossification centers during children's longitudinal bone growth could display similarly weak points. © 2019 American Society for Bone and Mineral Research.

Bone continuously adapts to its mechanical environment by structural reorganization to maintain mechanical strength. As the adaptive capabilities of bone are portrayed in its nano-and microstructure, the existence of dark and bright osteons with contrasting preferential collagen fiber orientation (longitudinal and oblique-angled, respectively) points at a required tissue heterogeneity that contributes to the excellent fracture resistance mechanisms in bone. Dark and bright osteons provide an exceptional opportunity to deepen our understanding of how nanoscale tissue properties influence and guide fracture mechanisms at larger length scales. To this end, a comprehensive structural, compositional, and mechanical assessment is performed using circularly polarized light microscopy, synchrotron nanocomputed tomography, focused ion beam/scanning electron microscopy, quantitative backscattered electron imaging, Fourier transform infrared spectroscopy, and nanoindentation testing. To predict how the mechanical behavior of osteons is affected by shifts in collagen fiber orientation, finite element models are generated. Fundamental disparities between both osteon types are observed: dark osteons are characterized by a higher degree of mineralization along with a higher ratio of inorganic to organic matrix components that lead to higher stiffness and the ability to resist plastic deformation under compression. On the contrary, bright osteons contain a higher fraction of collagen and provide enhanced ductility and energy dissipation due to lower stiffness and hardness.

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The recent identification of homozygous WNT1 mutations in individuals with osteogenesis imperfecta type XV (OI-XV) has suggested that WNT1 is a key ligand promoting the differentiation and function of bone-forming osteoblasts. Although such an influence was supported by subsequent studies, a mouse model of OI-XV remained to be established. Therefore, we introduced a previously identified disease-causing mutation (G177C) into the murine Wnt1 gene. Homozygous Wnt1G177C/G177C mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1G177C/G177C mice had skeletal fractures. This increased bone fragility was not fully explained by reduced bone mass but also by impaired bone matrix quality. Importantly, the homozygous presence of the G177C mutation did not interfere with the osteoanabolic influence of either parathyroid hormone injection or activating mutation of LRP5, the latter mimicking the effect of sclerostin neutralization. Finally, transcriptomic analyses revealed that short-term administration of WNT1 to osteogenic cells induced not only the expression of canonical WNT signaling targets but also the expression of genes encoding extracellular matrix modifiers. Taken together, our data demonstrate that regulating bone matrix quality is a primary function of WNT1. They further suggest that individuals with WNT1 mutations should profit from existing osteoanabolic therapies.