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The majority of patients with osteogenesis imperfecta (OI) have mutations in the COL1A1 or COL1A2 gene, which has consequences for the composition of the bone matrix and bone architecture. The mutations result in overmodified collagen molecules, thinner collagen fibres and hypermineralization of bone tissue at a bone matrix level. Trabecular bone in OI is characterized by a lower trabecular number and connectivity as well as a lower trabecular thickness and volumetric bone mass. Cortical bone shows a decreased cortical thickness with less mechanical anisotropy and an increased pore percentage as a result of increased osteocyte lacunae and vascular porosity.Most OI patients have mutations at different locations in the COL1 gene. Disease severity in OI is probably partly determined by the nature of the primary collagen defect and its location with respect to the C-terminus of the collagen protein. The overall bone biomechanics result in a relatively weak and brittle structure. Since this is a result of all of the above-mentioned factors as well as their interactions, there is - considerable variation between patients, and accurate prediction on bone strength in the individual patient with OI is difficult.Current treatment of OI focuses on adequate vitamin-D levels and interventions in the bone turnover cycle with bisphosphonates. Bisphosphonates increase bone mineral density, but the evidence on improvement of clinical status remains limited. Effects of newer drugs such as antibodies against RANKL and sclerostin are currently under investigation.This paper was written under the guidance of the Study Group Genetics and Metabolic Diseases of the European Paediatric Orthopaedic Society.

International audience; This article reports on a complete left human humerus from the Cussac Cave (Dordogne, France), dating to the Gravettian, or Mid-Upper Palaeolithic. This humerus is characterised by a very marked retroversion, significant intracortical porosity, an unusual morphology and orientation of the medial epicondyle, and a marked depression at the bottom of the olecranon fossa. These morphological features could be related to mechanical stimuli, but this is just an assumption given the absence of control data for many factors (e.g. age-at-death, sex, body mass, degree of asymmetry). Nevertheless, the description of this new discovery contributes significantly to our understanding of the range of variation of known Late Pleistocene skeletal morphology.; This article reports on a complete left human humerus from the Cussac Cave (Dordogne, France), dating to the Gravettian, or Mid-Upper Palaeolithic. This humerus is characterised by a very marked retroversion, significant intracortical porosity, an unusual morphology and orientation of the medial epicondyle, and a marked depression at the bottom of the olecranon fossa. These morphological features could be related to mechanical stimuli, but this is just an assumption given the absence of control data for many factors (e.g. age-at-death, sex, body mass, degree of asymmetry). Nevertheless, the description of this new discovery contributes significantly to our understanding of the range of variation of known Late Pleistocene skeletal morphology. Keywords Mid-upper palaeolithic • Morphometry • Biomechanics • Cross section • MicrotomographyAU: "Microct" has been changed to "Microtomography". Please confirm Résumé Cette étude porte un humérus gauche complet issu de la grotte de Cussac (Dordogne, France), daté du Gravettien (ou Paléolithique supérieur moyen). Cet humérus est caractérisé par une rétroversion extrêmement marquée, une importante porosité intracorticale, une morphologie et une orientation particulière de l'épicondyle médial, ainsi que par la présence d'une dépression profonde au fond de la fosse olécranienne Merci de vérifier. Ces caractéristiques morphologiques pourraient être associées à des contraintes biomécaniques, mais cela reste une hypothèse en l'absence de contrôle pour de nombreux facteurs (par exemple : âge au décès, sexe, masse corporelle, degré d'asymétrie). Cette étude contribue néanmoins de façon significative à l'enrichissement de nos connaissances de l'étendue de la variation morphologique connue pour le Pléistocène récent.

At this moment, no method is available to objectively estimate the temperature to which skeletal remains have been exposed during a fire. Estimating this temperature can provide crucial information in a legal investigation. Exposure of bone to heat results in observable and measurable changes, including a change in colour. To determine the exposure temperature of experimental bone samples, heat related changes in colour were systemically studied by means of image analysis. In total 1138 samples of fresh human long bone diaphysis and epiphysis, varying in size, were subjected to heat ranging from room temperature to 900 °C for various durations and in different media. The samples were scanned with a calibrated flatbed scanner and photographed with a Digital Single Lens Reflex camera. Red, Green, Blue values and Lightness, A-, and B-coordinates were collected for statistical analysis. Cluster analysis showed that discriminating thresholds for Lightness and B-coordinate could be defined and used to construct a model of decision rules. This model enables the user to differentiate between seven different temperature clusters with relatively high precision and accuracy. The proposed decision model provides an objective, robust and non-destructive method for estimating the exposure temperature of heated bone samples.

The majority of patients with osteogenesis imperfecta (OI) have mutations in the COL1A1 or COL1A2 gene, which has consequences for the composition of the bone matrix and bone architecture. The mutations result in overmodified collagen molecules, thinner collagen fibres and hypermineralization of bone tissue at a bone matrix level. Trabecular bone in OI is characterized by a lower trabecular number and connectivity as well as a lower trabecular thickness and volumetric bone mass. Cortical bone shows a decreased cortical thickness with less mechanical anisotropy and an increased pore percentage as a result of increased osteocyte lacunae and vascular porosity. Most OI patients have mutations at different locations in the COL1 gene. Disease severity in OI is probably partly determined by the nature of the primary collagen defect and its location with respect to the C-terminus of the collagen protein. The overall bone biomechanics result in a relatively weak and brittle structure. Since this is a result of all of the above-mentioned factors as well as their interactions, there is considerable variation between patients, and accurate prediction on bone strength in the individual patient with OI is difficult. Current treatment of OI focuses on adequate vitamin-D levels and interventions in the bone turnover cycle with bisphosphonates. Bisphosphonates increase bone mineral density, but the evidence on improvement of clinical status remains limited. Effects of newer drugs such as antibodies against RANKL and sclerostin are currently under investigation. This paper was written under the guidance of the Study Group Genetics and Metabolic Diseases of the European Paediatric Orthopaedic Society. Cite this article: Nijhuis WH, Eastwood DM, Allgrove J, Hvid I, Weinans HH, Bank RA, Sakkers RJ. Current concepts in osteogenesis imperfecta: bone structure, biomechanics and medical management.

Osteocytes and their lacunocanalicular network have been identified as the regulator of bone quality and function by exerting extensive influence over metabolic processes, mechanical adaptation, and mineral homeostasis. Recent research has shown that osteocyte apoptosis leads to a decrease in bone quality and increase in bone fragility mediated through its effects on remodeling. The purpose of this study is to investigate variation in cortical bone osteocyte lacunar density with respect to major factors including sex, age, and intracortical porosity to establish both regional and systemic trends. Samples from the midshaft femur, midshaft rib and distal one-third diaphysis of the radius were recovered from 30 modern cadaveric individuals (15 males and 15 females) ranging from 49 to 100 years old. Thick ground undecalcified histological (80 μm) cross-sections were made and imaged under bright field microscopy. Osteocyte lacunar density (Ot.Lc.N/B.Ar) and intracortical porosity (%Po.Ar) were quantified. No significant sex differences in Ot.Lc.N/B.Ar or %Po.Ar were found in any element. Linear regressions demonstrated a significant decrease in osteocyte lacunar density (Ot.Lc.N/B.Ar) and increase in intracortical porosity (%Po.Ar) with age for the sex-pooled sample in the femur (R2 = 0.208, 0.297 respectively) and radius (R2 = 0.108, 0.545 respectively). Age was unable to significantly predict osteocyte lacunar density or intracortical porosity in the rib (R2 = 0.058, 0.114 respectively). Comparisons of regression coefficients demonstrated a systemic trend in the decrease in osteocyte lacunar density (Ot.Lc.N/B.Ar) and increase in intracortical porosity (%Po.Ar) with age. In each element, intracortical porosity was significantly negatively correlated with lacunar density for which the radius demonstrated the strongest relationship (r = − 0.746). Using pore number (Po.N) as a proxy for available vascularity to support the osteocyte population, Po.N was able to predict 61.8% of variation in osteocyte lacunar number (Ot.Lc.N) in the rib. The femur and radius also demonstrated significant relationships between these variables (R2 = 0.560 and 0.397 respectively). The results from this study indicate that although the femur, radius and rib may be experiencing systemically influenced declines in osteocyte lacunar density, there may be differential effects at each anatomical site potentially due to age related changes in mechanical loading. With decreasing osteocyte lacunar density in each element, intracortical porosity increased with likely direct impacts on gross bone strength. This study provides a foundation upon which to build interpretations of osteocyte lacunar density values and their effect on differential fracture risk for aging individuals., Highlights • Ot.Lc.N/B.Ar demonstrate no significant sex differences in cortical bone. • Ot.Lc.N/B.Ar decreases and %Po.Ar increases with age at each skeletal site. • Systemic trends in rate of change with age in Ot.Lc.N/B.Ar and %Po.Ar were found. • Osteocyte lacunar density was inversely correlated with intracortical porosity.

Employing computer vision (CV) and optimized pulse-coupled neural networks (PCNN), this work automatically quantifies the geometrical attributes of intracortical bone porosity (namely lacunae and canaliculi (L-C), Haversian canals, and resorption cavities). Fifty pathological slides of cortical bone (× 20 magnification) were prepared from middiaphysis of bovine forelegs collected fresh from butcher. Biopsies were subdivided into sectors encircling arcs (θ of 10°) and radial distances (R) originating from the bone's geometric center toward posterior regions and spanning 3.3 mm. Microscopically, each pore is classified according to whether it belonged to primary or secondary osteon. Globally, each pore is assigned as being located in anterior or posterior regions. For each pore, area and major/minor axes lengths were determined as raw measures from which derived geometric measures, namely, area fraction (AF) and aspect ratio (AR), were derived. Said measures were plotted versus R (for different angles). Plots of AF and AR trends were found to vary linearly along the radial distance. Area fractions (%) significantly decreased linearly with R (p 0.01) in the anterior region. In the posterior region, area fraction values are flat versus R. These findings are indicative of maturing osteons at the outer cortex with predominately near circular-shaped pores. Graphical abstract (Left) Grids of slides (magnified at 20X) of intra-cortical bone showing Lacunar-canalicular porosity (LCP). Areas marked with the dotted square represent a group of 25 images. The dashed line is a hand-drawn line that demarcates the anterior and posterior regions and the solid line is the best-fit arc radii (R =16.4 mm) of the dashed demarcation line. (Right) Images rotated in the polar coordinate system with their respective angles and radii shown.

article i nfo Vertebral fractures and trabecular bone loss are hallmarks of osteoporosis. However, 80% of fractures are non- vertebral and 70% of all bone loss is cortical and is produced by intracortical remodeling. The resulting cortical porosity increases bone fragility exponentially. Denosumab, a fully human anti-RANKL antibody, reduces the rate of bone remodeling more than alendronate. The aim of this study was to quantify the effects of denosumab and alendronate on cortical and trabecular bone. Postmenopausal women, mean age 61 years (range 50 to 70), were randomized double blind to placebo (n = 82), alendronate 70 mg weekly (n = 82), or denosumab 60 mg every 6 months(n = 83) for 12 months.Porosityof the compact-appearing cortex(CC), outer and inner cortical transitional zones (OTZ, ITZ), and trabecular bone volume/total volume (BV/TV) of distal radius were quantified in vivo from high-resolution peripheral quantitative computed tomography scans. Denosumab reduced remod- eling more rapidly and completely than alendronate, reduced porosity of the three cortical regions at 6 months, more so by 12 months relative to baseline and controls, and 1.5- to 2-fold more so than alendronate. The respec- tive changes at 12 months were (mean (95% CI)); CC: −1.26% (−1.61, −0.91) versus −0.48% (−0.96, 0.00), p = 0.012; OTZ: −1.97% (−2.37, −1.56) versus −0.81% (−1.45, −0.17), p = 0.003; and ITZ: −1.17% (−1.38, −0.97) versus −0.78% (−1.04, −0.52), p = 0.021. Alendronate reduced porosity of the three cortical regions at 6 months relative to baseline and controls but further decreased porosity of only the ITZ at 12 months. By 12 - months, CC porosity was no different than baseline or controls, OTZ porosity was reduced only relative to baseline, not controls, while ITZ porosity was reduced relative to baseline and 6 months, but not controls. Each treatment increased trabecular BV/TV volume similarly: 0.25% (0.19, 0.30) versus 0.19% (0.13, 0.30), p = 0.208. The greater reduction in cortical porosity by denosumab may be due to greater inhibition of intracortical remodeling. Head to head studies are needed to determine whether differences in porosity result in differing fracture outcomes.

Intracortical bone remodeling is persistent throughout life, leading to age related increases in osteon population density (OPD). Intracortical porosity also increases with age in many mammals including humans, contributing to bone fragility and fracture risk. Unbalanced bone resorption and formation during disuse (e.g., physical inactivity) also increases intracortical porosity. In contrast, hibernating bears are a naturally occurring model for the prevention of both age-related and disuse osteoporoses. Intracortical bone remodeling is decreased during hibernation, but resorption and formation remain balanced. Black bears spend 0.25-7 months in hibernation annually depending on climate and food availability. We found longer hibernating bears demonstrate lower OPD and higher cortical bone mineralization than bears with shorter hibernation durations, but we surprisingly found longer hibernating bears had higher intracortical porosity. However, bears from three different latitudes showed age-related decreases in intracortical porosity, indicating that regardless of hibernation duration, black bears do not show the disuse- or age-related increases in intracortical porosity which is typical of other animals. This ability to prevent increases in intracortical porosity likely contributes to their ability to maintain bone strength during prolonged periods of physical inactivity and throughout life. Improving our understanding of the unique bone metabolism in hibernating bears will potentially increase our ability to develop treatments for age- and disuse-related osteoporoses in humans.

Numerical models commonly account for elastic inhomogeneity in cortical bone using power-law scaling relationships with various measures of tissue density, but limited experimental data exists for anatomic variation in elastic anisotropy. A recent study revealed anatomic variation in the magnitude and anisotropy of elastic constants along the entire femoral diaphysis of a single human femur (Espinoza Orías et al., 2009). The objective of this study was to confirm these trends across multiple donors while also considering possible confounding effects of the anatomic quadrant, apparent tissue density, donor age, and gender. Cortical bone specimens were sampled from the whole femora of 9 human donors at 20%, 50%, and 80% of the total femur length. Elastic constants from the main diagonal of the reduced fourth-order tensor were measured on hydrated specimens using ultrasonic wave propagation. The tissue exhibited orthotropy overall and at each location along the length of the diaphysis (p0.0001). Elastic anisotropy increased from the mid-diaphysis toward the epiphyses (p0.05). The increased elastic anisotropy was primarily caused by a decreased radial elastic constant (C(11)) from the mid-diaphysis toward the epiphyses (p0.05), since differences in the circumferential (C(22)) and longitudinal (C(33)) elastic constants were not statistically significant (p0.29). Anatomic variation in intracortical porosity may account for these trends, but requires further investigation. The apparent tissue density was positively correlated with the magnitude of each elastic constant (p0.0001, R(2)0.46), as expected, but was only weakly correlated with C(33)/C(11) (p0.05, R(2) = 0.04) and not significantly correlated with C(33)/C(22) and C(11)/C(22).

The patterns of bone modeling and mineral mobilization (skeletal homeostasis) among mammals other than humans and laboratory rodents are still poorly known. In this study we assessed the pattern of bone formation and bone resorption in the femur of a wild population of Cape dune molerats,Bathyergus suillus(n= 41) (Bathyergidae), a solitary subterranean mammal with a marked extended longevity among rodents, and which also lives in a naturally deficient state of vitamin D. In order to determine ontogenetic and sex effects on histomorphometric parameters of transversal undecalcified bone sections, two-way ANOVA, linear mixed-effects model and regression statistical analyses were performed. During ontogeny,B. suillusincreased their cross sectional area, cortical area and cortical thickness, and most importantly, they showed scarce endosteal bone resorption which resulted in a retained medullary cavity size during ontogeny. This resulted in a positively imbalanced bone modeling, where bone formation considerably surpasses bone loss by almost 100-fold in adulthood. This differs markedly from other terrestrial mammals with relatively thin cortical walls. Regarding bone loss and remodeling, three main processes involving intracortical resorption were observed: modeling-related bone loss in early postnatal growth; secondary osteon formation occurring in both sexes; and subendosteal secondary reconstruction observed only in females. The latter is accompanied by females having six-fold more relative bone loss than males, which is evidenced by the development of enlarged resorption cavities (RCs) distributed circumferentially around the medullary cavity. Males have smaller, more circular and randomly distributed RCs. In general, our data indicate no age-related decline in mineral content inB. suillus, and provides strong support for a pattern of sexual dimorphism in skeletal homeostasis, similar to that occurring in humans and other mammals, with females losing more bone throughout aging as compared to males due to reproductive factors. Interestingly as well, despite the high mechanical loads experienced during burrow construction, bone remodeling inB. suillusis kept at very low levels throughout their lifespan, and dense Haversian tissue never forms. This study represents the first comprehensive assessment of skeletal homeostasis in a subterranean mammal, and it enables a better understanding of the complex processes governing the acquisition and maintenance of bone properties in this species with extraordinary fossorial adaptations.

International audience; Cortical bone and the surrounding soft tissues are attenuating and heterogeneous media, which might affect the signals measured with axial transmission devices. This work aims at evaluating the effect of the heterogeneous acoustic absorption in bone and in soft tissues on the bone ultrasonic response. Therefore, a two-dimensional finite element time-domain method is derived to model transient wave propagation in a three-layer medium composed of an inhomogeneous transverse isotropic viscoelastic solid layer, sandwiched between two viscous fluid layers. The model couples viscous acoustic propagation in both fluid media with the anisotropic viscoelastic response of the solid. A constant spatial gradient of material properties is considered for two values of bone thicknesses (0.6 and 4 mm). In the studied configuration, absorption in the surrounding fluid tissues does not affect the results, whereas bone viscoelastic properties have a significant effect on the first arriving signal (FAS) velocity. For a thin bone, the FAS velocity is governed by the spatially averaged bone properties. For a thick bone, the FAS velocity may be predicted using a one-dimensional model.

Bone modeling and remodeling is the final common pathway expressing all genetic and environmental factors that influence the attainment and maintenance of bone’s material and structural strength. Modeling and remodeling require a surface, and during growth this cellular machinery fashions bone’s external size, shape, and internal architecture by depositing bone on, and removing bone from, both its periosteal (external) and endosteal (internal) envelopes. Bone is distributed and redistributed to achieve strength commensurate with its loading requirements. Advancing age is associated with: (1) a reduction in the volume of bone resorbed by each basic multicellular unit (BMU); (2) an even greater reduction in the volume of bone formed by each BMU so that each remodeling event, whether adaptive or reparative, removes bone from the bone; (3) increased remodeling (number of BMUs) on the three (endocortical, intracortical, and trabecular) components of its endosteal envelope in midlife in women and late in life in both sexes; and (4) reduced bone formation on the periosteal envelope. The net effect is cortical thinning, increased intracortical porosity, trabecular thinning, and loss of connectivity. While remodeling intensity on an envelope determines structure (e.g., trabecular perforations), the surface area of the envelope determines remodeling intensity, and, so, structure. High remodeling on trabecular surfaces decreases as trabeculae (with their surface) are lost. Conversely, remodeling on the endocortical and intracortical envelopes increases their surface area, so remodeling intensity increases and bone loss becomes predominantly cortical. Understanding bone structural strength and its decay and the effects of genetic factors, exercise, nutrition, and drug therapy on bone requires thinking outside and inside these envelopes; their absolute and relative movements during growth and aging determine bone structure and its strength.

Disuse typically uncouples bone formation from resorption, leading to bone loss which compromises bone mechanical properties and increases the risk of bone fracture. Previous studies suggest that bears can prevent bone loss during long periods of disuse (hibernation), but small sample sizes have limited the conclusions that can be drawn regarding the effects of hibernation on bone structure and strength in bears. Here we quantified the effects of hibernation on structural, mineral, and mechanical properties of black bear (Ursus americanus) cortical bone by studying femurs from large groups of male and female bears (with wide age ranges) killed during pre-hibernation (fall) and post-hibernation (spring) periods. Bone properties that are affected by body mass (e.g. bone geometrical properties) tended to be larger in male compared to female bears. There were no differences (p > 0.226) in bone structure, mineral content, or mechanical properties between fall and spring bears. Bone geometrical properties differed by less than 5% and bone mechanical properties differed by less than 10% between fall and spring bears. Porosity (fall: 5.5 ± 2.2%, spring: 4.8 ± 1.6%) and ash fraction (fall: 0.694 ± 0.011, spring: 0.696 ± 0.010) also showed no change (p > 0.304) between seasons. Statistical power was high (>72%) for these analyses. Furthermore, bone geometrical properties and ash fraction (a measure of mineral content) increased with age and porosity decreased with age. These results support the idea that bears possess a biological mechanism to prevent disuse and age-related osteoporoses.

Compact bone makes up approximately 80% of the human skeleton by mass; but there are little data available on the effects of increased bone turnover on compact bone mechanical and material properties. This study addresses this question by measuring intracortical remodeling, resorption cavity number, and porosity in an ovariectomized (OVX) sheep model, and measures changes in biomechanical properties. Thirty-eight sheep were divided into two groups. Group 1 were controls (n = 19), and Group 2 were ovariectomized (OVX; n = 19). Fluorochrome dyes were administered intravenously to both groups at five time points over 12 months post-OVX to label sites of bone turnover. At 12 months post-OVX all animals were euthanized. Samples were harvested from the left metatarsal and were analyzed for intracortical bone turnover at five time points, the number of resorption cavities, and the level of intracortical porosity. The effects of these parameters on bone biomechanical properties were then measured. Bone turnover was increased in the OVX group at 6, 9, and 12 months (p < 0.05). Resorption was also higher in the OVX group at 12 months (p < 0.05). Furthermore, porosity was significantly increased in the OVX group at 12 months (p < 0.05). Stiffness and yield strength were reduced in the OVX group compared to controls (p = 0.05). Ultimate compressive strength and work to fracture did not differ between groups. These findings provide new insights into the mechanisms and effects of increased bone turnover on bone material and microstructural properties.

It has been proposed that bone damageability (i.e. bone's susceptibility to formation of damage) increases with the elevation or suppression of bone turnover. Suppression of turnover via bisphosphonates increases local bone mineralization, which theoretically should increase the susceptibility of bone to microcrack formation. Elevation of bone turnover has also been proposed to increase bone microdamage through an increase in bone intracortical porosity and local stresses and strains. The goal of this paper was to investigate the above proposals, i.e., whether or not increases to mineral content and porosity increase bone in-service damageability. To do this, we measured in vivo diffuse damage area (Df.Dm.Ar, %) and microcrack density (Cr.Dn) (cracks/mm(2)) in the same specimen from human cortical bone of the midshaft of the proximal femur obtained from cadavers with an age range of eight decades and examined their relationships with porosity, mineralization and age. Results of this study showed that Cr.Dn and Df.Dm.Ar increased with a decrease in bulk mineralization. This finding does not appear to support the proposal that damage accumulation increases with low bone turnover that results in increases mineralization. It was proposed however that the negative correlation between damage accumulation and mineralization may be attributed to highly mineralized regions of bone existing with under-mineralized regions resulting in an overall decrease in average bone mineralization. It was also found that microdamage accumulates with increasing porosity which does appear to support the proposal that elevated bone turnover that results in increased porosity can accelerate microdamage accumulation. Finally, it was shown that linear microcracks and Df.Dm.Ar accumulate with age differently, but because they correlate with each other, one may be the precursor for the other.

Cortical bone porosity is a major determinant of strength, stiffness, and fracture toughness of cortical tissue. The goal of this work was to investigate changes in spatial distribution and microstructure of cortical porosity associated with aging in men and women. The specific aims were to: 1) develop an automated technique for spatial analysis of cortical microstructure based on HR-pQCT data, and; 2) apply this technique to explore sex- and age-specific spatial distribution and microstructure of porosity within the cortex. We evaluated HR-pQCT images of the distal tibia from a cross-sectional cohort of 145 individuals, characterizing detectable pores as being in the endosteal, midcortical, or periosteal layers of the cortex. Metrics describing porosity, pore number, and pore size were quantified within each layer and compared across sexes, age groups, and cortical layers. The elderly cohort (65-78 years, n=22) displayed higher values than the young cohort (20-29 years, n=29) for all parameters both globally and within each layer. While all three layers displayed significant age-related porosity increases, the greatest difference in porosity between the young and elderly cohort was in the midcortical layer (+344%, p

We examined the time course effects of continuous PTH on cortical bone and mechanical properties. PTH increased cortical bone turnover and induced intracortical porosity with no deleterious effect on bone strength. Withdrawal of PTH increased maximum torque to failure and stiffness with no change in energy absorbed. Introduction: The skeletal response of cortical bone to parathyroid hormone (PTH) is complex and species dependent. Intermittent administration of PTH to rats increases periosteal and endocortical bone formation but has no known effects on intracortical bone turnover. The effects of continuous PTH on cortical bone are not clearly established. Materials and Methods: Eighty-four 6-month-old female Sprague-Dawley rats were divided into three control, six PTH, and two PTH withdrawal (WD) groups. They were subcutaneously implanted with osmotic pumps loaded with vehicle or 40 μg/kg BW/day human PTH(1-34) for 1, 3, 5, 7, 14, and 28 days. After 7 days, PTH was withdrawn from two groups of animals for 7 (7d-PTH/7d-WD) and 21 days (7d-PTH/21d-WD). Histomorphometry was performed on periosteal and endocortical surfaces of the tibial diaphysis in all groups. μCT of tibias and mechanical testing by torsion of femora were performed on 28d-PTH and 7d-PTH/21d-WD animals. Results and Conclusions: Continuous PTH increased periosteal and endocortical bone formation, endocortical osteoclast perimeter, and cortical porosity in a time-dependent manner, but did not change the mechanical properties of the femur, possibly because of addition of new bone onto periosteal and endocortical surfaces. Additionally, withdrawal of PTH restored normal cortical porosity and increased maximum torque to failure and stiffness. We conclude that continuous administration of PTH increased cortical porosity in rats without having a detrimental effect on bone mechanical properties.

This study was designed to study the individual or combined effects of estrogen and bipedal stance "exercise" on the lumbar vertebral body (LVB) and femoral neck (FN). At 6 months of age, six rats were sacrificed as baseline controls and all the others were either bilateral sham-ovariectomized or ovariectomized (OVX). Groups of OVX rats were housed in normal height cage (NC, 28 cm) or raised height cages (RC, 33 cm) and received biweekly s.c. injections of 10 microg/kg 17 beta estradiol (E2) or vehicle for 4 and 8 weeks. Histomorphometric measurements were performed on the undecalcified mid-transverse sections of the 4th LVB and FN. Ovariectomy alone induced cancellous bone loss by 21% and 39% in the LVB and FN, respectively; intracortical porosity area of the FN increased by 108% while total bone area did not change significantly because of the periosteal expansion following OVX. E2 alone partially prevented cancellous bone loss in the LVB and FN and prevented increased intracortical porosity area in the FN by reducing eroded surface and activation frequency. RC alone partially prevented the decrease of cancellous bone in the LVB and FN by reducing the bone-eroded surface but increased wall width. E2 plus RC completely preserved cancellous bone by having an additive effect on reducing eroded surface and activation frequency. RC helped to partially prevent decreased periosteal bone formation after estrogen administration. In conclusion, apart from inducing cancellous bone loss in the LVB and FN, OVX also increased intracortical remodeling in the FN. Estrogen prevented the overall activation of remodeling space induced by OVX. Apart from having similar effects as estrogen on remodeling space, RC induced positive bone balance within each remodeling unit. Combination treatment increased total bone mass beyond that of sham-control level by having an additive effect on lowering bone remodeling and increasing wall in both the LVB and FN.

The purpose of this study was to describe the age-specific distribution of midfemoral intracortical porosity throughout the cortical width in males and females. Microradiography and an automated image analysis system were used to study midfemoral cortical bone specimens from 163 white people, including 77 males and 86 females, in a recent anthropological collection covering a broad age range. In each specimen, porosity (percentage of the cortical bone area occupied by pores), pore number, and pore size were measured throughout the entire cortex and in three cortical subregions of equal width labeled the periosteal, midcortical, and endosteal subregions. For each gender, relationships linking age to porosity, pore number, and mean pore size were assessed using regression analysis. In addition, age- and site-related changes in these three variables were tested for significance using two-way analysis of variance (ANOVA). Age explained 52% of the porosity variance in females and 13.5% in males. In each gender, there were significant age- and site-related differences in porosity, pore number, and pore size. In adults aged 60 years or younger, both pore size and pore number increased with increasing age, whereas in adults older than 60 years, pore size continued to increase but pore number decreased. In males, the age-related changes in pore size and pore number were proportionally similar in the three cortical subregions. In females, in contrast, the changes predominated in the endosteal subregion and resulted in significant cortical thinning.

To determine whether computed tomography (CT) can be used to quantify age- and site-related changes in cortical bone mineral density (cBMD) at the middiaphyseal femur and whether cBMD differences are related to intracortical porosity.Cortical bone specimens from 163 femurs were studied with CT and microradiography. Femurs were from 77 males and 86 females in a white anthropologic collection covering a broad age spectrum. In each sample, the cBMD was measured in the entire cortical width and in periosteal, midcortical, and endosteal subregions of interest. Age- and site-related changes in cBMD were tested for significance by using a two-way analysis of variance for both sexes. By using linear regression, cBMD was compared with porosity in the entire cortical width and in each subregion.There were significant age-related differences in cBMD (P.001 in females, P =.008 in males). In addition, cBMD values were significantly different between the three cortical subregions (P.001 for both sexes), decreasing from the periosteum to the midcortex to the endosteum. The cBMD values were closely related to porosity, and porosity contributed to 71.6% of the variance in cBMD in the overall population.CT is effective in the measurement of age- and site-related changes in cBMD. Decreases in cBMD are closely correlated with increased cortical porosity.

In vivo microcracks in cortical bone are typically observed within more highly mineralized interstitial tissue, but postmortem investigations are inherently limited to cracks that did not lead to fracture which may be misleading with respect to understanding fracture mechanisms. We hypothesized that the one fatigue microcrack which initiates fracture is located spatially adjacent to elevated intracortical porosity but not elevated mineralization. Therefore, the spatial correlation between intracortical porosity, elevated mineralization, and fatigue microdamage was investigated by combining, for the first time, sequential, nondestructive, three-dimensional micro-computed tomography (micro-CT) measurements of each in cortical bone specimens subjected to compressive fatigue loading followed by a tensile overload to fracture. Fatigue loading resulted in significant microdamage accumulation and compromised mechanical properties upon tensile overload compared to control specimens. The microdamage that initiated fracture upon tensile overload was able to be identified in all fatigue-loaded specimens using contrast-enhanced micro-CT and registered images. Two-point (or pair) correlation functions revealed a spatial correlation between microdamage at the fracture initiation site and intracortical porosity, but not highly mineralized tissue, confirming the hypothesis. This difference was unique to the fracture initiation site. Intracortical porosity and highly mineralized tissue exhibited a significantly lower and higher probability, respectively, of being located spatially adjacent to all sites of microdamage compared to the fracture initiation site. Therefore, the results of this study suggest that human cortical bone is tolerant of most microcracks, which are generally compartmentalized within the more highly mineralized interstitial tissue, but a single microcrack of sufficient size located in spatial proximity to intracortical porosity can compromise fracture resistance.

With aging and in disease, the changes in bone microstructure and geometry influence the mechanical properties of cortical bone, however, the level of interaction between the two is not known. Here, we investigate the interaction between the changes in microstructural and geometrical properties of the aging male tibia in proximal and distal middiaphysis. The microstructural measurements include variables related to the size and density of osteons and intracortical porosity. The macroscopic geometrical properties include variables related to bone surfaces (periosteal and endosteal) and cross section (area, moment of inertia). Site-specific correlations were found between the microstructural and geometrical properties along the bone length and at different bone surfaces. In contrast to the proximal middiaphysis of male tibia, where no correlation existed, significant (p

This study employs regression analysis to explore population and sex differences in the pattern of age-associated bone loss, as reflected by histomorphometric variables that are measures of intracortical and endocortical bone remodeling. A comparison of an African American sample from the Washington Park Cemetery in St. Louis, Missouri, and a European American rib sample composed of cadavers, autopsies, and forensic cases from Missouri reveals the existence of complex age-associated patterns for differences in measures of intracortical remodeling and cortical area. Females from the two samples express similar bone dimensions and dynamics. The African American females appear to lose more bone than their male counterparts, but this difference is absent in the European American sample. When age-associated patterns are considered, it is in the younger cohorts that African Americans exhibit greater relative cortical area than European Americans, but this is reversed in the older ages, when the latter group manifests greater bone mass. The European American males consistently differ in the slopes and intercepts for the variables compared to the other groups, and differences are highly significant with African American females, with the former group maintaining bone mass while the latter exhibit a more rapid bone loss. Achieving larger relative cortical area due to smaller endosteal area, coupled with better bone quality due to lower intracortical porosity early in life, may be a mechanism by which African Americans, especially females, maintain adequate bone mass in older ages, which buffers them from bone loss and related fragility fractures despite higher rates of intracortical remodeling and endosteal expansion later in life. These results suggest that both genetic and environmental factors are responsible for the differences in bone remodeling and bone mass observed between these samples.

International audience; AbstractThe ultrasonic axial transmission technique allows for investigating skeletal sites such as the cortical layer of long bones (radius, tibia, phalanges). Using synchrotron radiation microCT, we investigated, in vitro, the relationships between 1-MHz axial transmission SOS measurements at the radius and site-matched measurements of C.Th, POR, MIN, and vBMD.INTRODUCTION:The ultrasonic axial transmission technique allows for investigating skeletal sites such as the cortical layer of long bones (radius, tibia, phalanges).MATERIALS AND METHODS:Using synchrotron radiation microCT, we investigated, in vitro, the relationships between 1-MHz axial transmission speed of sound (SOS) measurements at the radius and site-matched measurements of cortical thickness (C.Th), intracortical porosity (POR), tissue mineralization (MIN), and volumetric BMD (vBMD). SOS measurements were based on bidirectional axial transmission and were performed with a 1-MHz proprietary probe on 39 excised human radii.RESULTS:The highest correlations between SOS values and bone parameters (R(2)(SOS/POR) = 0.28, p < 10(-3); R(2)(SOS/MIN) = 0.38, p < 10(-4); R(2)(SOS/vBMD) = 0.57, p < 10(-3)) were found for bone parameters assessed in a 1-mm-thick periosteal region of the cortex rather than throughout the whole cortex. The observed moderate correlation between SOS and C.Th values (R(2)(SOS/C.Th) = 0.20, p < 10(-2)) disappeared when controlled for other variables. The two best multilinear predictive models, including either BMD alone or the pair of dependent variables MIN and POR (all assessed in the periosteal cortex), were equally accurate in predicting SOS values (R(2)(SOS/(POR,MIN)) = 0.59, p < 10(-5); R(2)(SOS/vBMD) = 0.57, p < 10(-5)).CONCLUSION:For the first time, the respective adjusted contributions of POR (-24 m/s%(-1)) and tissue mineralization (+3.5 m/s/mg/cm(-3)) to SOS values were assessed. These results suggest potential sensitivity of axial transmission SOS values to changes in cortical bone status under different pathological conditions or treatments affecting POR and/or tissue mineralization.

Bone is characterised by age-related morphological and histological changes. We have previously established an automated method of recording bone morphometry and histology from entire transverse sections of cortical bone. Our aim was to determine whether data acquired using this automated system were useful in the prediction of age. Ninety-six specimens of human femoral middiaphysis were studied from subjects aged 21–92 y. Equations predicting specimen age were constructed using macroscopic data (total subperiosteal area (TSPA), periosteal perimeter (PP), endosteal perimeter (EP), cortical bone area (CA) and moments of area) and microscopic data (the number, size and diversity of pores and intracortical porosity) together with sex, height and weight. Both TSPA and PP were independent predictors of age but the number of pores was not a significant predictor of age in any equation. The age predicted by these equations was inaccurate by more than 8 y in over half the subjects. We conclude that we could not predict age at a clinically acceptable level using data from our automated system. This most likely reflects an insensitivity to regional age-related changes in bone histology because we recorded data from each entire cortex. Automated bone measurement according to cortical region might be more useful in the prediction of age. The inclusion of TSPA together with PP as independent predictors of age raises the possibility that a future measure of periosteal shape at the femoral diaphysis could also be helpful in the prediction of age. The accuracy reached with the relatively simple methods described here is sufficient to encourage the development of image-analysis systems for the automatic detection of more complex features.

The high importance of intracortical porosity for mechanical strength of cortical bone has been established. The contribution of other parameters of microstructure such as osteon dimensions for strength is in discussion. The aim of this study was to evaluate the predictive value of microcomputed tomography (µCT) for porosity and other microstructural parameters of cortical bone in cortical bone biopsies. Femoral cortical bone specimens from the middiaphysis of 24 patients were harvested during the procedure of total hip replacement at the location where normally one hole (O 4.5 mm) for the relief of the intramedullary pressure is placed.In vitro intracortical porosity and bone mineral density (BMD) measurements by µCT were compared with structural parameters assessed in histological sections of the same specimens. A strong correlation was found between intracortical porosity measured by µCT and histological porosity (r=0.95,P

The matrix of human cortical bone is arranged around a network of vascular spaces (hereafter referred to as “pores”). Our aim was to investigate age-related differences in human cortical porosity (total pore area divided by cortical bone area), pore size and number, and surface to volume ratios, while adjusting for sex, height, and weight. Ninety-six specimens of entire transverse sections of human femoral diaphysis, from subjects aged 21–92 years, were examined. We used our established automated image acquisition and analysis system which measures pores from entire sections of multiple specimens of bone. Over 400,000 pores were recorded. Results showed a greater porosity in older bone (p < 0.01) but marked variation in porosity for any given age. The cohort median, of the specimen medians, of pore cross-sectional area was 2050 μm2. Older specimens did not have more pores than younger specimens but had a greater proportion of larger pores (p < 0.05) and greater intraspecimen variation in pore size (p < 0.001). The pore surface to bone matrix volume ratio was a median 2.3 mm2/mm3. This varied more than 4-fold between individuals but did not relate to age. No simple relationships were found between any of the measured parameters and either sex, height, or weight, even after adjustment for age. We conclude that the greater porosity in older specimens is due to greater pore size rather than a larger number of pores. Age, however, explains little of the inter-individual variation in the parameters studied.

Complete cross-sections from the femoral midshaft of 180 individuals of known height and weight, aged 21-97 y, from a modern Australian population were examined using automatic video image analysis to quantify total subperiosteal porosity (TSPP). More specifically, the aim was to investigate whether age changes were similar in both sexes in (1) total subperiosteal area (TSPA), cortical area (CA) and medullary area (MA), (2) intracortical porosity (ICP), and (3) the respective contributions to TSPP made by MA and intracortical void area (ICVA). Our findings indicated that both sexes showed a significantly greater height normalised TSPA in the 70s as compared with the 20s. Males had consistently larger bones with a greater height normalised CA. In both sexes CA showed a tendency to increase till the 7th decade and then to decline, more so in females. MA approximately trebled in females and doubled in males over the age range studied. Although ICP also increased, from 4-6% in young adults to over 9% in the elderly, it showed a significant difference between the sexes only in the 3rd decade, being greater in males at this stage. By contrast, TSPP became significantly greater in females (from that recorded in the 3rd decade) by the time they reached the 50s, while in males this did not occur till the 80s. It increased from approximately 25% in young adults of both sexes to approximately 50% in females and approximately 37% in males in their 80s. However, in the elderly there was great variability in both sexes in the appearance of bones from individuals of similar chronological age. Some bones differed little from those in younger subjects, others showed greatly increased ICP, still others displayed reduced cortical widths with low ICP. The femoral midshaft resembles other skeletal sites in that age changes in TSPP are more marked in females than males.

pathogenesis of age-related bone loss show that most bone loss with age is cortical, not trabecular, and is the result of intracortical remodelling on the surfaces of the myriads of haversian canals traversing the cortex. These excavated canals increase in number, size and coalesce, particularly in the cortex adjacent to the marrow space leaving a layer of chaotically connected cortical remnants that look like trabeculae. Half of the total bone loss that occurs during ageing is produced during the process of formation of cortical remnants; indeed, the ratio of the thickness of the layer of cortical remnants to the thickness of the entire cortical mass (proportion compact remnants; PCR) appears to be a more reliable indicator of age-related bone loss than the cortical thickness. The calculation of porosity in the compactappearing cortex without including porosity produced by cortical remnants underestimates the true age related increase in porosity by three-fold. Moreover, the true decline with age is underestimated fourfold when cortical remnants are erroneously included in the trabecular compartments as is commonly done in standard bone structure analyses. Thus, overlooking intracortical porosity producing cortical remnants has resulted in a significant underestimation of agerelated cortical decay and loss.Contrary to prevailing notions, most bone loss is cortical, occurs by intracortical remodelling, causes most structural decay, and occurs after 60 years of age, not in the decade after menopause. Intracortical remodelling is a neglected target for preventing and reversing bone fragility in old age.

Cortical bone grafts were implanted for six months in mature dogs using an osteoperiosteal 3-cm defect in the ulna to evaluate their respective morphometric and physical values compared with autografts. The bone-grafting material included fresh auto- and allografts, frozen and thimerosal preserved allografts, and partially demineralized bone allografts. The grafts were evaluated by roentgenograms, microradiograms, photon absorptiometry, porosity, fluorescence labeling measurements, and torsional loading at failure. Autografts achieved a better union score than the allografts, but intracortical bone porosity, percentage of cumulative new bone, and mineral apposition rate were not variables with statistical significance. Lamellar bone was found earlier and in greater quantity in autografts. Within the graft, new bone was deposited at a slower rate than in the recipient bone. Autografts showed less peripheral resorption and a greater torsional resistance than allografts. Photon absorptiometry demonstrated that nondemineralized allografts underwent a substantial loss of peripheral bone. This marked reduction in the outer diameter of the graft had more influence on torsional resistance than did the intracortical porosity of the graft. Demineralized allografts were osteoinductive in only 28% of the cases and appeared to respond in an all-or-nothing pattern. Frozen and thimerosal preserved allografts were the most acceptable substitutes to autografts.

Micromovement has been shown to promote the healing of experimental fractures, but its role in the clinical management of fractures with soft-tissue injury is less certain. In a 2-mm transverse osteotomy of the ovine tibia held in an instrumented external fixator, axial interfragmentary displacement was quantified in vivo for six weeks after osteotomy. Group I (n = 11) had an axial fixation stiffness of 460 N/mm and Group II (n = 12) had a stiffness of 238 N/mm. With a 25% difference in micromovement, a fourfold change in corticomedullary blood flow was observed at two weeks after osteotomy (p < 0.01). Although by six weeks mechanical properties in torsion were similar, there were marked differences in the periosteal cross-sectional perimeter, area, and intracortical porosity that complemented the hemodynamic changes. The early vascular response is very sensitive to the initial mechanical environment, and appears to precede and determine the organization of osteogenesis. Further understanding of this relationship may prove to be of direct clinical relevance in the augmentation of healing of devascularized diaphyseal fractures.

The authors measured osteon dimensions and number in specimens of cortical bone obtained from the medial femoral neck (calcar) from nine female patients treated with hemiarthroplasty for femoral neck fractures, and from 12 (seven women, five men) age-matched cadavers without fractures. Specimens from the same location in 14 (seven women, seven men) younger patients treated with total hip arthroplasty (THA) for osteoarthrosis were also studied. There were fewer osteons per unit area and the osteons and their Haversian canals were bigger in the fracture group than in the nonfracture or osteoarthritic groups. Patients with femoral neck fractures also exhibited a decreased Singh index and an increased intracortical porosity compared with age-matched normal controls. By contrast, the osteoarthritic group showed no difference in osteon or Haversian dimensions, osteon number per unit area, Singh index, or in porosity compared with the nonfracture group. These morphometric differences found in the cortical bone of the medial femoral neck may play a role in the incidence of fractures.