OPN, BSP, and Bone Quality-Structural, Biochemical, and Biomechanical Assessment in OPN-/-, BSP-/-, and DKO Mice.

Osteopontin (OPN) and Bone Sialoprotein (BSP), abundantly expressed by osteoblasts and osteoclasts, appear to have important, partly overlapping functions in bone. In gene-knockout (KO, -/-) models of either protein and their double (D)KO in the same CD1/129sv genetic background, we analyzed the morphology, matrix characteristics, and biomechanical properties of femur bone in 2 and 4 month old, male and female mice. OPN-/- mice display inconsistent, perhaps localized hypermineralization, while the BSP-/- are hypomineralized throughout ages and sexes, and the low mineralization of young DKO mice recovers with age. The higher contribution of primary bone remnants in OPN-/- shafts suggests a slow turnover, while their lower percentage in BSP-/- indicates rapid remodeling, despite FTIR-based evidence in this genotype of a high maturity of the mineralized matrix. In 3-point bending assays, OPN-/- bones consistently display higher Maximal Load, Work to Max. Load and in young mice Ultimate Stress, an intrinsic characteristic of the matrix. Young male and old female BSP-/- also display high Work to Max. Load along with low Ultimate Stress. Principal Component Analysis confirms the major role of morphological traits in mechanical competence, and evidences a grouping of the WT phenotype with the OPN-/- and of BSP-/- with DKO, driven by both structural and matrix parameters, suggesting that the presence or absence of BSP has the most profound effects on skeletal properties. Single or double gene KO of OPN and BSP thus have multiple distinct effects on skeletal phenotypes, confirming their importance in bone biology and their interplay in its regulation.

Dietary supplementation with nacre reduces cortical bone loss in aged female mice.

Aging is associated with detrimental bone loss leading to fragility fractures in both men and women. Notably, a majority of bone loss with aging is cortical, as well as a large number of fractures are non-vertebral and at the non-hip sites. Nacre is a product of mollusks composed of calcium carbonate embedded in organic components. As our previous study demonstrated the protective effect of nacre supplementation on trabecular bone loss in ovariectomized rats, we sought to evaluate the effect of dietary nacre on bone loss related to aging in female mice which do not suffer true menopause as observed in women. The current study compared the effect of a 90-day long nacre-supplemented diet to that of Standard or CaCO3 diets on both bone mass and strength in 16-month-old C57BL/6 female mice. Multiple approaches were performed to assess the microarchitecture and mechanical properties of long bones, analyze trabecular histomorphometry, and measure bone cell-related gene expressions, and bone turnover markers. In the cortex, dietary nacre improved cortical bone strength in line with lower expression levels of genes reflecting osteoclasts activity compared to Standard or CaCO3 diets (p < 0.05). In the trabeculae, nacre-fed mice were characterized by a bone remodeling process more active than the other groups as shown by greater histomorphometric parameters and osteoblast-related gene expressions (p < 0.05). But these differences were not exhibited at the level of the trabecular microarchitecture at this age. Collectively, these data suggest that dietary nacre should be a potential candidate for reducing aging-associated cortical bone loss in the elderly.

Prediction of osteoporotic degradation of tibia human bone at trabecular scale.

A theoretical numerical model is proposed to predict patient dependent osteoporotic bone degradation. The model parameters are identified through a particle swarm optimization algorithm and based on individual patient high resolution peripherical quantitative computer tomography (HRpQCT) scan data. The degradation model is based on cellular activity initiated by the elastic strain energy developed in the bone microstructure through patient's body weight. The macro (organ scale) and meso (trabecular scale) scale analyses are carried out and predicted bone volume fraction and microstructure evolution are compared with in-vivo experimental bone degradation for four elderly women over a period of 10 years. A significant correlation (r > 0.9) is observed between the model predictions and in-vivo experiments in all cases with an average deviation error of 1.46%. The model can easily be extended to other patients and provide good predictions for different population categories such as ethnicity, gender, age, etc.

Assessing the Elasticity of Child Cortical Bone.

A better understanding of the mechanical behaviour of child bone is essential to improve the diagnosis of pediatric bone disorders that may influence bone development. Even though the process of bone growth is well described, there are still lacks of knowledge on intrinsic material properties of child bone and particularly on child bone considered as "non-pathological". Geometry, material properties, microstructure and biochemical components are associated with child bone fragility and remain difficult to assess for two main reasons: the scarcity of the bone samples and their small dimensions. In this context, ultrasonic methods offer interesting possibilities by exploiting in particular their non-destructive character. In this chapter, the elasticity properties of Non Pathological Child Cortical Bone (NPCCB) obtained by ultrasonic methods are presented. The objective was to contribute to the construction of a reference database on NPCCB that would serve as a point of comparison for analyzing the effect of a pathology or treatment. After the presentation of the hypotheses on the elasticity and anisotropy of NPCCB, ultrasonic transmission-mode and resonance spectroscopy methods are described. Results are presented and discussed with respect to microstructural and biochemical properties.

Dual-energy CT hybridation and kernel processing effects on the estimation of bone mineral mass and density: a calcination study on ex vivo human femur.

INTRODUCTION: Recent technological advances with dual-energy quantitative computed tomography (DEQCT) allow to combine two images of different level of energy to obtain simulated mono-energetic images at 60 keV (SIM60KeV-QCT) with improved image contrast in clinical practice. This study includes three topics: (1) compare bone mineral content (BMC), areal and volumetric bone mineral density (aBMD, vBMD) obtained with SIM60KeV-QCT, single-energy QCT (SEQCT), and dual X-ray absorptiometry (DXA); (2) compare ash density and weight with respective vBMD and BMC assessed on SIM60KeV-QCT, SEQCT, and DXA; and (3) compare the influence of reconstruction kernels on the accuracy of vBMD and BMC using ash density and ash weight as the reference values. METHODS: DXA, SEQCT, and DEQCT acquisitions were performed ex vivo on 42 human femurs. Standard kernel (SK) and bone kernel (BK) were applied to each stack of images. Ten diaphyses and 10 femoral necks were cut, scanned, and reconstructed using the techniques described above. Finally, the bone specimens were calcined to obtain the ash weight. RESULTS: QCT analysis (SEQCT, SIM60KeV-QCT) underestimated BMC value compared to DXA. For femoral necks, all QCT analyses provided an unbiased estimate of ash weight but underestimated ash density regardless of the kernel used. For femoral diaphysis, SEQCT BK, SIM60KeV-QCT BK, and SK underestimated ash weight but not ash density. CONCLUSION: BMC and vBMD quantifications with the SIM60KeV-QCT gave similar results as the SEQCT. Further studies are needed to optimize the use of SIM60KeV-QCT in clinical situations. SK should be used given the effect of kernels on QCT assessment.

Fracture Risk Evaluation of Bone Metastases: A Burning Issue.

Major progress has been achieved to treat cancer patients and survival has improved considerably, even for stage-IV bone metastatic patients. Locomotive health has become a crucial issue for patient autonomy and quality of life. The centerpiece of the reflection lies in the fracture risk evaluation of bone metastasis to guide physician decision regarding physical activity, antiresorptive agent prescription, and local intervention by radiotherapy, surgery, and interventional radiology. A key mandatory step, since bone metastases may be asymptomatic and disseminated throughout the skeleton, is to identify the bone metastasis location by cartography, especially within weight-bearing bones. For every location, the fracture risk evaluation relies on qualitative approaches using imagery and scores such as Mirels and spinal instability neoplastic score (SINS). This approach, however, has important limitations and there is a need to develop new tools for bone metastatic and myeloma fracture risk evaluation. Personalized numerical simulation qCT-based imaging constitutes one of these emerging tools to assess bone tumoral strength and estimate the femoral and vertebral fracture risk. The next generation of numerical simulation and artificial intelligence will take into account multiple loadings to integrate movement and obtain conditions even closer to real-life, in order to guide patient rehabilitation and activity within a personalized-medicine approach.

Cortical bone viscoelastic damping assessed with resonant ultrasound spectroscopy reflects porosity and mineral content.

Viscoelasticity is an essential property of bone related to fragility, which is altered in aging and bone disease. Bone viscoelastic behavior is attributed to several mechanisms involving collagen and mineral properties, porosities, and bone hierarchical tissue organization. We aimed to assess the relationships between cortical bone viscoelastic damping measured with Resonant Ultrasound Spectroscopy (RUS), microstructural and compositional characteristics. We measured 52 bone specimens from the femur of 26 elderly human donors. RUS provided a shear damping coefficient at a frequency of the order of 150 kHz. The characteristics of the structure of the vascular pore network and tissue mineral density were measured using synchrotron radiation high-resolution computed tomography (SR-µCT). Fourier transformed infrared microspectroscopy (FTIRM) was used to quantify mineral-to-organic phase ratio, mineral maturity, crystallinity, and collagen maturity. Cross-links were quantified from biochemistry. Viscoelastic damping was found to increase with vascular porosity (r=0.68), to decrease with the degree of mineralization of the extravascular matrix (r=-0.68), and was marginally affected by collagen. We built a multilinear model suggesting that when porosity is controlled, the variation of mineral content explains a small additional part of the variability of damping. The work supports the consideration of viscoelasticity measurement as a potential biomarker of fragility and provides a documentation of bone viscoelastic behavior and its determinants in a frequency range rarely investigated.

Ultrasounds could be considered as a future tool for probing growing bone properties.

Juvenile bone growth is well described (physiological and anatomical) but there are still lacks of knowledge on intrinsic material properties. Our group has already published, on different samples, several studies on the assessment of intrinsic material properties of juvenile bone compared to material properties of adult bone. The purpose of this study was finally to combine different experimental modalities available (ultrasonic measurement, micro-Computed Tomography analysis, mechanical compression tests and biochemical measurements) applied on small cubic bone samples in order to gain insight into the multiparametric evaluation of bone quality. Differences were found between juvenile and adult groups in term of architectural parameters (Porosity Separation), Tissue Mineral Density (TMD), diagonal stiffness coefficients (C33, C44, C55, C66) and ratio between immature and mature cross-links (CX). Diagonal stiffness coefficients are more representative of the microstructural and biochemical parameters of child bone than of adult bone. We also found that compression modulus E was highly correlated with several microstructure parameters and CX in children group while it was not at all correlated in the adult group. Similar results were found for the CX which was linked to several microstructure parameters (TMD and E) only in the juvenile group. To our knowledge, this is the first time that, on a same sample, ultrasonic measurements have been combined with the assessment of mechanical and biochemical properties. It appears that ultrasonic measurements can provide relevant indicators of child bone quality (microstructural and biochemical parameters) which is promising for clinical application since, B-mode ultrasound is the preferred first-line modality over other more constraining imaging modalities (radiation, parent-child accessibility and access to the patient's bed) for pediatric patients.

Expression of the type 1 lysophosphatidic acid receptor in osteoblastic cell lineage controls both bone mineralization and osteocyte specification.

Lysphosphatidic acid (LPA) is a major natural bioactive lipid mediator whose biological functions affect multiple organs. These include bone as demonstrated by global Lpar1-knockout mice (Lpar1-/-) which present a bone growth defect. LPA acts on all bone cells including osteoblasts, that are responsible for bone formation, and osteoclasts, which are specialized cells that resorb bone. LPA appears as a potential new coupling molecule during bone remodeling. LPA1 is the most ubiquitous LPA receptor among the six LPA receptor family members (LPA1-6). To better understand the specific role of LPA via its receptor LPA1 in osteoblastic cell lineage we generated osteoblast-specific Lpar1 knockout mice (Lpar1-∆Ob) by crossing Lpar1flox/flox and Osx:Cre+ mouse lines. Lpar1-∆Ob mice do not recapitulate the bone defects of Lpar1-/- mice but revealed reduced bone mineralization and decreased cortical thickness, as well as increased bone porosity associated with an augmentation in the lacunae areas of osteocyte and their apoptotic yield. In vitro, primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1-/- osteoblasts revealed a remarkable premature expression of alkaline phosphatase, reduced cell proliferation associated with decreased YAP-P nuclear accumulation, and reduced mineralization activity. Osteocyte specification is markedly impaired as demonstrated by reduced expression of early (E11) and late (DMP1, DKK1, SOST) osteocyte markers ex vivo in enriched osteocytic fractions of Lpar1-∆Ob mouse bone explants. In addition, E11 expression and dendrite formation induced by FGF2 are markedly impaired in both primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1-/- osteoblasts. Taken together these results suggest a new role for LPA in bone mass control via bone mineralization and osteocyte function.

What is the influence of two strain rates on the relationship between human cortical bone toughness and micro-structure?

Cortical bone fracture mechanisms are well studied under quasi-static loading. The influence of strain rate on crack propagation mechanisms needs to be better understood, however. We have previously shown that several aspects of the bone micro-structure are involved in crack propagation, such as the complete porosity network, including the Haversian system and the lacunar network, as well as biochemical aspects, such as the maturity of collagen cross-links. The aim of this study is to investigate the influence of strain rate on the toughness of human cortical bone with respect to its microstructure and organic non-collagenous composition. Two strain rates will be considered: quasi-static loading (10-4 s-1), a standard condition, and a higher loading rate (10-1 s-1), representative of a fall. Cortical bone samples were extracted from eight female donors (age 50-91 years). Three-point bending tests were performed until failure. Synchrotron radiation micro-computed tomography imaging was performed to assess bone microstructure including the Haversian system and the lacunar system. Collagen enzymatic cross-link maturation was measured using a high performance liquid chromatography column. Results showed that that under quasi-static loading, the elastic contribution of the fracture process is correlated to both the collagen cross-links maturation and the microstructure, while the plastic contribution is correlated only to the porosity network. Under fall-like loading, bone organization appears to be less linked to crack propagation.

Compositional and mechanical properties of growing cortical bone tissue: a study of the human fibula.

Human cortical bone contains two types of tissue: osteonal and interstitial tissue. Growing bone is not well-known in terms of its intrinsic material properties. To date, distinctions between the mechanical properties of osteonal and interstitial regions have not been investigated in juvenile bone and compared to adult bone in a combined dataset. In this work, cortical bone samples obtained from fibulae of 13 juveniles patients (4 to 18 years old) during corrective surgery and from 17 adult donors (50 to 95 years old) were analyzed. Microindentation was used to assess the mechanical properties of the extracellular matrix, quantitative microradiography was used to measure the degree of bone mineralization (DMB), and Fourier transform infrared microspectroscopy was used to evaluate the physicochemical modifications of bone composition (organic versus mineral matrix). Juvenile and adult osteonal and interstitial regions were analyzed for DMB, crystallinity, mineral to organic matrix ratio, mineral maturity, collagen maturity, carbonation, indentation modulus, indicators of yield strain and tissue ductility using a mixed model. We found that the intrinsic properties of the juvenile bone were not all inferior to those of the adult bone. Mechanical properties were also differently explained in juvenile and adult groups. The study shows that different intrinsic properties should be used in case of juvenile bone investigation.

3D analysis of the osteonal and interstitial tissue in human radii cortical bone.

Human cortical bone has a complex hierarchical structure that is periodically remodelled throughout a lifetime. This microstructure dictates the mechanical response of the tissue under a critical load. If only some structural features, such as the different porosities observed in bone, are primarily studied, then investigations may not fully consider the osteonal systems in three-dimensions (3D). Currently, it is difficult to differentiate osteons from interstitial tissue using standard 3D characterization methods. Synchrotron radiation micro-computed tomography (SR-µCT) in the phase contrast mode is a promising method for the investigation of osteons. In the current study, SR-µCT imaging was performed on cortical bone samples harvested from eight human radii (female, 50-91 y.o.). The images were segmented to identify Haversian canals, osteocyte lacunae, micro-cracks, as well as osteons. The significant correlation between osteonal and Haversian canal volume fraction highlights the role of the canals as sites where bone remodelling is initiated. The results showed that osteocyte lacunae morphometric parameters depend on their distance to cement lines, strongly suggesting the evolution of biological activity from the beginning to the end of the remodelling process. Thus, the current study provides new data on 3D osteonal morphometric parameters and their relationships with other structural features in humans.

Anisotropic elastic properties of human femoral cortical bone and relationships with composition and microstructure in elderly.

The strong dependence between cortical bone elasticity at the millimetre-scale (mesoscale) and cortical porosity has been evidenced by previous studies. However, bone is an anisotropic composite material made by mineral, proteins and water assembled in a hierarchical structure. Whether the variations of structural and compositional properties of bone affect the different elastic coefficients at the mesoscale is not clear. Aiming to understand the relationships between bone elastic properties and compositions and microstructure, we applied state-of-the-art experimental modalities to assess these aspects of bone characteristics. All elastic coefficients (stiffness tensor of the transverse isotropic bone material), structure of the vascular pore network, collagen and mineral properties were measured in 52 specimens from the femoral diaphysis of 26 elderly donors. Statistical analyses and micromechanical modeling showed that vascular pore volume fraction and the degree of mineralization of bone are the most important determinants of cortical bone anisotropic mesoscopic elasticity. Though significant correlations were observed between collagen properties and elasticity, their effects in bone mesoscopic elasticity were minor in our data. This work also provides a unique set of data exhibiting a range of variations of compositional and microstructural cortical bone properties in the elderly and gives strong experimental evidence and basis for further development of biomechanical models for human cortical bone. STATEMENT OF SIGNIFICANCE: This study reports the relationships between microstructure, composition and the mesoscale anisotropic elastic properties of human femoral cortical bone in elderly. For the first time, we provide data covering the complete anisotropic elastic tensor, the microstructure of cortical vascular porosity, mineral and collagen characteristics obtained from the same or adjacent samples in each donor. The results revealed that cortical vascular porosity and degree of mineralization of bone are the most important determinants of bone anisotropic stiffness at the mesoscale. The presented data gives strong experimental evidence and basis for further development of biomechanical models for human cortical bone.

Influence of loading condition and anatomical location on human cortical bone linear micro-cracks.

Human cortical bone fracture toughness depends on the anatomical locations under quasi-static loading. Recent results also showed that under fall-like loading, cortical bone fracture toughness is similar at different anatomical locations in the same donor. While cortical bone toughening mechanisms are known to be dependent on the tissue architecture under quasi-static loading, the fracture mechanisms during a fall are less studied. In the current study, the structural parameters of eight paired femoral diaphyses, femoral necks and radial diaphyses were mechanically tested under quasi-static and fall-like loading conditions (female donors, 70 ±â€¯14 y.o., [50-91 y.o.]). Synchrotron radiation micro-CT imaging was used to quantify the amount of micro-cracks formed during loading. The volume fraction of these micro-cracks was significantly higher within the specimens loaded under a quasi-static condition than under a loading representative of a fall. Under fall-like loading, there was no difference in crack volume fraction between the different paired anatomical locations. This result shows that the micro-cracking toughening mechanism depends both on the anatomical location and on the loading condition.

3D micro structural analysis of human cortical bone in paired femoral diaphysis, femoral neck and radial diaphysis.

Human bone is known to adapt to its mechanical environment in a living body. Both its architecture and microstructure may differ between weight-bearing and non-weight-bearing bones. The aim of the current study was to analyze in three dimensions, the morphology of the multi-scale porosities on human cortical bone at different locations. Eight paired femoral diaphyses, femoral necks, and radial diaphyses were imaged using Synchrotron Radiation µCT with a 0.7 µm isotropic voxel size. The spatial resolution facilitates the investigation of the multiscale porosities of cortical bone, from the osteonal canals system down to the osteocyte lacunar system. Our results showed significant differences in the microstructural properties, regarding both osteonal canals and osteocytes lacunae, between the different anatomical locations. The radius presents significantly lower osteonal canal volume fraction and smaller osteonal canals than the femoral diaphysis or neck. Osteocytes lacunae observed in the radius are significantly different in shape than in the femur, and lacunar density is higher in the femoral neck. These results show that the radius, a non-weight-bearing bone, is significantly different in terms of its microstructure from a weight-bearing bone such as the femur. This implies that the cortical bone properties evaluated on the femoral diaphysis, the main location studied within the literature, cannot be generalized to other anatomical locations.

Relationships between human cortical bone toughness and collagen cross-links on paired anatomical locations.

Human cortical bone fracture processes depend on the internal porosity network down to the lacunar length scale. Recent results show that at the collagen scale, the maturation of collagen cross-links may have a negative influence on bone mechanical behavior. While the effect of pentosidine on human cortical bone toughness has been studied, the influence of mature and immature enzymatic cross-links has only been studied in relation to strength and work of fracture. Moreover, these relationships have not been studied on different paired anatomical locations. Thus, the aim of the current study was to assess the relationships between both enzymatic and non-enzymatic collagen cross-links and human cortical bone toughness, on four human paired anatomical locations. Single Edge Notched Bending toughness tests were performed for two loading conditions: a quasi-static standard condition, and a condition representative of a fall. These tests were done with 32 paired femoral diaphyses, femoral necks and radial diaphyses (18 women, age 81 ±â€¯12 y.o.; 14 men, age 79 ±â€¯8 y.o.). Collagen enzymatic and non-enzymatic crosslinks were measured on the same bones. Maturation of collagen was defined as the ratio between immature and mature cross-links (CX). The results show that there was a significant correlation between collagen cross-link maturation and bone toughness when gathering femoral and radial diaphyses, but not when considering each anatomical location individually. These results show that the influence of collagen enzymatic and non-enzymatic cross-links is minor when considering human cortical bone crack propagation mechanisms.

Erratum: One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties, osteocyte survival and lacunae volume in mature mice skeletons.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

One-month spaceflight compromises the bone microstructure, tissue-level mechanical properties, osteocyte survival and lacunae volume in mature mice skeletons.

The weightless environment during spaceflight induces site-specific bone loss. The 30-day Bion-M1 mission offered a unique opportunity to characterize the skeletal changes after spaceflight and an 8-day recovery period in mature male C57/BL6 mice. In the femur metaphysis, spaceflight decreased the trabecular bone volume (-64% vs. Habitat Control), dramatically increased the bone resorption (+140% vs. Habitat Control) and induced marrow adiposity invasion. At the diaphysis, cortical thinning associated with periosteal resorption was observed. In the Flight animal group, the osteocyte lacunae displayed a reduced volume and a more spherical shape (synchrotron radiation analyses), and empty lacunae were highly increased (+344% vs. Habitat Control). Tissue-level mechanical cortical properties (i.e., hardness and modulus) were locally decreased by spaceflight, whereas the mineral characteristics and collagen maturity were unaffected. In the vertebrae, spaceflight decreased the overall bone volume and altered the modulus in the periphery of the trabecular struts. Despite normalized osteoclastic activity and an increased osteoblast number, bone recovery was not observed 8 days after landing. In conclusion, spaceflight induces osteocyte death, which may trigger bone resorption and result in bone mass and microstructural deterioration. Moreover, osteocyte cell death, lacunae mineralization and fatty marrow, which are hallmarks of ageing, may impede tissue maintenance and repair.

Strain rate influence on human cortical bone toughness: A comparative study of four paired anatomical sites.

Bone fracture is a major health issue worldwide and consequently there have been extensive investigations into the fracture behavior of human cortical bone. However, the fracture properties of human cortical bone under fall-like loading conditions remains poorly documented. Further, most published research has been performed on femoral diaphyseal bone, whereas it is known that the femoral neck and the radius are the most vulnerable sites to fracture. Hence, the aim of this study is to provide information on human cortical bone fracture behavior by comparing different anatomical sites including the radius and the femoral neck acquired from 32 elderly subjects (50 - 98 y.o.). In order to investigate the intrinsic fracture behavior of human cortical bone, toughness experiments were performed at two different strain rates: standard quasi-static conditions, and a higher strain rate representative of a fall from a standing position. The tests were performed on paired femoral neck, femoral, tibial and radius diaphyseal samples. Linear elastic fracture toughness and the non-linear J-integral method were used to take into account both the elastic and non-elastic behavior of cortical bone. Under quasi-static conditions, the radius presents a significantly higher toughness than the other sites. At the higher strain rate, all sites showed a significantly lower toughness. Also, at the high strain rate, there is no significant difference in fracture properties between the four anatomical sites. These results suggest that regardless of the anatomical site (femur, femoral neck, tibia and radius), the bone has the same fracture properties under fall loading conditions. This should be considered in biomechanical models under fall-like loading conditions.

Pore network microarchitecture influences human cortical bone elasticity during growth and aging.

Cortical porosity is a major determinant of bone strength. Haversian and Volkmann׳s canals are׳seen' as pores in 2D cross-section but fashion a dynamic network of interconnected channels in 3D, a quantifiable footprint of intracortical remodeling. Given the changes in bone remodeling across life, we hypothesized that the 3D microarchitecture of the cortical pore network influences its stiffness during growth and ageing. Cubes of cortical bone of 2 mm side-length were harvested in the distal 1/3 of the fibula in 13 growing children (mean age±SD: 13±4 yrs) and 16 adults (age: 75±13 yrs). The cubes were imaged using desktop micro-CT (8.14µm isotropic voxel size). Pores were segmented as a solid to assess pore volume fraction, number, diameter, separation, connectivity and structure model index. Elastic coefficients were derived from measurements of ultrasonic bulk compression and shear wave velocities and apparent mass density. The pore volume fraction did not significantly differ between children and adults but originates from different microarchitectural patterns. Compared to children, adults had 42% (p=0.033) higher pore number that were more connected (Connective Density: +205%, p=0.001) with a 18% (p=0.007) lower pore separation. After accounting for the contribution of pore volume fraction, axial elasticity in traction-compression mode was significantly correlated with better connectivity in growing children and with pore separation among adults. The changes in intracortical remodeling across life alter the distribution, size and connectedness of the channels from which cortical void fraction originates. These alterations in pore network microarchitecture participate in changes in compressive and shear mechanical behavior, partly in a porosity-independent manner. The assessment of pore volume fraction (i.e., porosity) provides only a limited understanding of the role of cortical void volume fraction in its mechanical properties.