Cortical remodeling during menopause, rheumatoid arthritis, glucocorticoid and bisphosphonate therapy

Bone mass, bone geometry and its changes are based on trabecular and cortical bone remodeling. Whereas the effects of estrogen loss, rheumatoid arthritis (RA), glucocorticoid (GC) and bisphosphonate (BP) on trabecular bone remodeling have been well described, the effects of these conditions on the cortical bone geometry are less known. The present review will report current knowledge on the effects of RA, GC and BP on cortical bone geometry and its clinical relevance. Estrogen deficiency, RA and systemic GC lead to enhanced endosteal bone resorption. While in estrogen deficiency and under GC therapy endosteal resorption is insufficiently compensated by periosteal apposition, RA is associated with some periosteal bone apposition resulting in a maintained load-bearing capacity and stiffness. In contrast, BP treatment leads to filling of endosteal bone cavities at the epiphysis; however, periosteal apposition at the bone shaft seems to be suppressed. In summary, estrogen loss, RA and GC show similar effects on endosteal bone remodeling with an increase in bone resorption, whereas their effect on periosteal bone remodeling may differ. Despite over 50 years of GC therapy and over 25 years of PB therapy, there is still need for better understanding of the skeletal effects of these drugs as well as of inflammatory disease such as RA on cortical bone remodeling.

Image-based vs. mesh-based statistical appearance models of the human femur: Implications for finite element simulations.

Statistical appearance models have recently been introduced in bone mechanics to investigate bone geometry and mechanical properties in population studies. The establishment of accurate anatomical correspondences is a critical aspect for the construction of reliable models. Depending on the representation of a bone as an image or a mesh, correspondences are detected using image registration or mesh morphing. The objective of this study was to compare image-based and mesh-based statistical appearance models of the femur for finite element (FE) simulations. To this aim, (i) we compared correspondence detection methods on bone surface and in bone volume; (ii) we created an image-based and a mesh-based statistical appearance models from 130 images, which we validated using compactness, representation and generalization, and we analyzed the FE results on 50 recreated bones vs. original bones; (iii) we created 1000 new instances, and we compared the quality of the FE meshes. Results showed that the image-based approach was more accurate in volume correspondence detection and quality of FE meshes, whereas the mesh-based approach was more accurate for surface correspondence detection and model compactness. Based on our results, we recommend the use of image-based statistical appearance models for FE simulations of the femur.

Strength indices of the proximal femur and shaft in prepubertal female gymnasts

Introduction/Purpose: The role of impact loading activity on bone mass is well established; however, there are little data on the effects of exercise on bone geometry and indices of bone strength. The primary purpose of this study was to compare indices of bone strength at the proximal femur (PF) between elite premenarcheal gymnasts (N = 30) and age-matched controls (N = 30). Methods: Structural properties of the proximal femur were derived from the hip analyses program and included measurement of subperiosteal width, endosteal diameter, cross-sectional area, bone mineral density, cross-section moment of inertia (CSMI), and section modulus (Z). These parameters were measured for two regions of the PF: the narrow neck (NN), and the shaft (S). In addition, a strength index (S-SI) was calculated at the shaft by dividing the Z at the shaft by the femur length. A secondary purpose was to compare bone mineral content (BMC) values at the total body, lumbar spine, and three sites at the PF (neck, trochanter, and total) between the groups. All dependent values were compared adjusting for height and weight using an ANCOVA procedure and for relative lean body mass post hoc. Results: The gymnasts had significantly greater size-adjusted strength indices (CSMI, Z, and SI) at the NN and S. Gymnasts also had significantly greater size-adjusted BMC at all sites investigated. However, these differences disappeared when adjusted for relative lean body mass. Conclusion: When adjusted for body size, gymnasts had significantly greater indices of both axial strength and bending strength at the NN region of the PF and S, as well as a greater bone SI at the femoral shaft. These differences may be related to greater relative lean body mass attained in gymnastics training.

Genome-wide association with bone mass and geometry in the Framingham Heart Study

BACKGROUND:Osteoporosis is characterized by low bone mass and compromised bone structure, heritable traits that contribute to fracture risk. There have been no genome-wide association and linkage studies for these traits using high-density genotyping platforms.METHODS:We used the Affymetrix 100K SNP GeneChip marker set in the Framingham Heart Study (FHS) to examine genetic associations with ten primary quantitative traits: bone mineral density (BMD), calcaneal ultrasound, and geometric indices of the hip. To test associations with multivariable-adjusted residual trait values, we used additive generalized estimating equation (GEE) and family-based association tests (FBAT) models within each sex as well as sexes combined. We evaluated 70,987 autosomal SNPs with genotypic call rates [greater than or equal to]80%, HWE p [greater than or equal to] 0.001, and MAF [greater than or equal to]10% in up to 1141 phenotyped individuals (495 men and 646 women, mean age 62.5 yrs). Variance component linkage analysis was performed using 11,200 markers.RESULTS:Heritability estimates for all bone phenotypes were 30-66%. LOD scores [greater than or equal to]3.0 were found on chromosomes 15 (1.5 LOD confidence interval: 51,336,679-58,934,236 bp) and 22 (35,890,398-48,603,847 bp) for femoral shaft section modulus. The ten primary phenotypes had 12 associations with 100K SNPs in GEE models at p < 0.000001 and 2 associations in FBAT models at p < 0.000001. The 25 most significant p-values for GEE and FBAT were all less than 3.5 x 10-6 and 2.5 x 10-5, respectively. Of the 40 top SNPs with the greatest numbers of significantly associated BMD traits (including femoral neck, trochanter, and lumbar spine), one half to two-thirds were in or near genes that have not previously been studied for osteoporosis. Notably, pleiotropic associations between BMD and bone geometric traits were uncommon. Evidence for association (FBAT or GEE p < 0.05) was observed for several SNPs in candidate genes for osteoporosis, such as rs1801133 in MTHFR; rs1884052 and rs3778099 in ESR1; rs4988300 in LRP5; rs2189480 in VDR; rs2075555 in COLIA1; rs10519297 and rs2008691 in CYP19, as well as SNPs in PPARG (rs10510418 and rs2938392) and ANKH (rs2454873 and rs379016). All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:The FHS 100K SNP project offers an unbiased genome-wide strategy to identify new candidate loci and to replicate previously suggested candidate genes for osteoporosis.

The effects of repetitive loading on bone mass and geometry in young male tennis players : a quantative study using magnetic resonance imaging

Pre- and early puberty seem to be the most opportune times for exercise to  improve bone strength in girls, but few studies have addressed this issue in boys. This study investigated the site-, surface-, and maturity-specific exercise-induced changes in bone mass and geometry in young boys. The osteogenic effects of loading were analyzed by comparing the playing and nonplaying humeri of 43 male pre-, peri-, and postpubertal competitive tennis players 10-19 yr of age. Total bone area, medullary area, and cortical area were determined at the mid (40-50%) and distal humerus (60-70%) of both arms using MRI. Humeral bone mass (BMC) was derived from a whole body DXA scan. In prepubertal boys, BMC was 17% greater in the playing compared with nonplaying arm (p < 0.001), which was accompanied by a 12-21% greater cortical area, because of greater periosteal expansion than medullary expansion at the midhumerus and periosteal expansion associated with medullary contraction at the distal humerus. Compared with prepuberty, the side-to-side differences in BMC (27%) and cortical area (20-33%) were greater in peripuberty (p < 0.01). No differences were found between peri- and postpuberty despite longer playing history in the postpubertal players.The osteogenic response to loading was greater in peri- compared with prepubertal boys, which is in contrast with our previous findings in girls and may be caused by differences in training history. This suggests that the window of opportunity to improve bone mass and size through exercise may be longer in boys than in girls.

Typical accuracy and quality control of a process for creating CT-Based virtual bone models

A pragmatic method for assessing the accuracy and precision of a given processing pipeline required for converting computed tomography (CT) image data of bones into representative three dimensional (3D) models of bone shapes is proposed. The method is based on coprocessing a control object with known geometry which enables the assessment of the quality of resulting 3D models. At three stages of the conversion process, distance measurements were obtained and statistically evaluated. For this study, 31 CT datasets were processed. The final 3D model of the control object contained an average deviation from reference values of −1.07±0.52 mm standard deviation (SD) for edge distances and −0.647±0.43 mm SD for parallel side distances of the control object. Coprocessing a reference object enables the assessment of the accuracy and precision of a given processing pipeline for creating CTbased 3D bone models and is suitable for detecting most systematic or human errors when processing a CT-scan. Typical errors have about the same size as the scan resolution.

Influences of age and mechanical stability on volume, microstructure, and mineralization of the fracture callus during bone healing : Is osteoclast activity the key to age-related impaired healing?

Earlier studies have shown that the influence of fixation stability on bone healing diminishes with advanced age. The goal of this study was to unravel the relationship between mechanical stimulus and age on callus competence at a tissue level. Using 3D in vitro micro-computed tomography derived metrics, 2D in vivo radiography, and histology, we investigated the influences of age and varying fixation stability on callus size, geometry, microstructure, composition, remodeling, and vascularity. Compared were four groups with a 1.5-mm osteotomy gap in the femora of Sprague–Dawley rats: Young rigid (YR), Young semirigid (YSR), Old rigid (OR), Old semirigid (OSR). Hypothesis was that calcified callus microstructure and composition is impaired due to the influence of advanced age, and these individuals would show a reduced response to fixation stabilities. Semirigid fixations resulted in a larger ΔCSA (Callus cross-sectional area) compared to rigid groups. In vitro μCT analysis at 6 weeks postmortem showed callus bridging scores in younger animals to be superior than their older counterparts (pb0.01). Younger animals showed (i) larger callus strut thickness (pb0.001), (ii) lower perforation in struts (pb0.01), and (iii) higher mineralization of callus struts (pb0.001). Callus mineralization was reduced in young animals with semirigid fracture fixation but remained unaffected in the aged group. While stability had an influence, age showed none on callus size and geometry of callus. With no differences observed in relative osteoid areas in the callus ROI, old as well as semirigid fixated animals showed a higher osteoclast count (pb0.05). Blood vessel density was reduced in animals with semirigid fixation (pb0.05). In conclusion, in vivo monitoring indicated delayed callus maturation in aged individuals. Callus bridging and callus competence (microstructure and mineralization) were impaired in individuals with an advanced age. This matched with increased bone resorption due to higher osteoclast numbers. Varying fixator configurations in older individuals did not alter the dominant effect of advanced age on callus tissue mineralization, unlike in their younger counterparts. Age-associated influences appeared independent from stability. This study illustrates the dominating role of osteoclastic activity in age-related impaired healing, while demonstrating the optimization of fixation parameters such as stiffness appeared to be less effective in influencing healing in aged individuals.

Primary stability of two uncemented acetabular components of different geometry : hemispherical or peripherally enhanced?

Objective This study compared the primary stability of two commercially available acetabular components from the same manufacturer, which differ only in geometry; a hemispherical and a peripherally enhanced design (peripheral self-locking (PSL)). The objective was to determine whether altered geometry resulted in better primary stability. Methods Acetabular components were seated with 0.8 mm to 2 mm interference fits in reamed polyethylene bone substrate of two different densities (0.22 g/cm3 and 0.45 g/cm3). The primary stability of each component design was investigated by measuring the peak failure load during uniaxial pull-out and tangential lever-out tests. Results There was no statistically significant difference in seating force (p = 0.104) or primary stability (pull-out p = 0.171, lever-out p = 0.087) of the two components in the low-density substrate. Similarly, in the high-density substrate, there was no statistically significant difference in the peak pull-out force (p = 0.154) or lever-out moment (p = 0.574) between the designs. However, the PSL component required a significantly higher seating force thanthe hemispherical cup in the high-density bone analogue (p = 0.006). Conclusions Higher seating forces associated with the PSL design may result in inadequate seating and increased risk of component malpositioning or acetabular fracture in the intra-operative setting in high-density bone stock. Our results, if translated clinically, suggest that a purely hemispherical geometry may have an advantage over a peripherally enhanced geometry in high density bone stock.

Sex-specific compromised bone healing in female rats might be associated with a decrease in mesenchymal stem cell quantity

Introduction The clinically known importance of patient sex as a major risk factor for compromised bone healing is poorly reflected in animal models. Consequently, the underlying cellular mechanisms remain elusive. Because mesenchymal stem cells (MSCs) are postulated to regulate tissue regeneration and give rise to essential differentiated cell types, they may contribute to sex-specific differences in bone healing outcomes. Methods We investigated sex-specific variations in bone healing and associated differences in MSC populations. A 1.5 mm osteotomy gap in the femora of 8 male and 8 female 12-month-old Sprague-Dawley rats was stabilized by an external fixator. Healing was analyzed in terms of biomechanical testing, bridging and callus size over time (radiography at 2, 4, and 6 weeks after surgery), and callus volume and geometry by μCT at final follow-up. MSCs were obtained from bone marrow samples of an age-matched group of 12 animals (6 per gender) and analyzed for numbers of colony-forming units (CFUs) and their capacity to differentiate and proliferate. The proportion of senescent cells was determined by β-galactosidase staining. Results Sex-specific differences were indicated by a compromised mechanical competence of the callus in females compared with males (maximum torque at failure, p = 0.028). Throughout the follow-up, the cross-sectional area of callus relative to bone was reduced in females (p ≤ 0.01), and the bridging of callus was delayed (p 2weeks = 0.041). μCT revealed a reduced callus size (p = 0.003), mineralization (p = 0.003) and polar moment of inertia (p = 0.003) in female animals. The female bone marrow contained significantly fewer MSCs, represented by low CFU numbers in both femora and tibiae (p femur = 0.017, p tibia = 0.010). Functional characteristics of male and female MSCs were similar. Conclusion Biomechanically compromised and radiographically delayed bone formation were distinctive in female rats. These differences were concomitant with a reduced number of MSCs, which may be causative for the suboptimal bone healing.

Comparison of mechanical and ultrasound elastic modulus of ovine tibial cortical bone

Finite element models of bones can be created by deriving geometry from anx-ray CT scan. Material properties such as the elastic modulus can then be applied using either a single or set of homogeneous values, or individual elements can have local values mapped onto them. Values for the elastic modulus can be derived from the CT density values using an elasticityversus density relationship. Many elasticity–density relationships have been reported in the literature for human bone. However, while ovine in vivo models are common in orthopaedic research, no work has been done to date on creating FE models of ovine bones. To create these models and apply relevant material properties, an ovine elasticity-density relationship needs to be determined. Using fresh frozen ovine tibias the apparent density of regions of interest was determined from a clinical CT scan. The bones were the sectioned into cuboid samples of cortical bone from the regions of interest. Ultrasound was used to determine the elastic modulus in each of three directions – longitudinally, radially and tangentially. Samples then underwent traditional compression testing in each direction. The relationships between apparent density and both ultrasound, and compression modulus in each directionwere determined. Ultrasound testing was found to be a highly repeatable non-destructive method of calculating the elastic modulus, particularly suited to samples of this size. The elasticity-density relationships determined in the longitudinal direction were very similar between the compression and ultrasound data over the density range examined.A clear difference was seen in the elastic modulus between the longitudinal and transverse directions of the bone samples, and a transverse elasticity-density relationship is also reported.

Effects of strain artefacts arising from a pre-defined callus domain in models of bone healing mechanobiology

Iterative computational models have been used to investigate the regulation of bone fracture healing by local mechanical conditions. Although their predictions replicate some mechanical responses and histological features, they do not typically reproduce the predominantly radial hard callus growth pattern observed in larger mammals. We hypothesised that this discrepancy results from an artefact of the models’ initial geometry. Using axisymmetric finite element models, we demonstrated that pre-defining a field of soft tissue in which callus may develop introduces high deviatoric strains in the periosteal region adjacent to the fracture. These bone-inhibiting strains are not present when the initial soft tissue is confined to a thin periosteal layer. As observed in previous healing models, tissue differentiation algorithms regulated by deviatoric strain predicted hard callus forming remotely and growing towards the fracture. While dilatational strain regulation allowed early bone formation closer to the fracture, hard callus still formed initially over a broad area, rather than expanding over time. Modelling callus growth from a thin periosteal layer successfully predicted the initiation of hard callus growth close to the fracture site. However, these models were still susceptible to elevated deviatoric strains in the soft tissues at the edge of the hard callus. Our study highlights the importance of the initial soft tissue geometry used for finite element models of fracture healing. If this cannot be defined accurately, alternative mechanisms for the prediction of early callus development should be investigated.

The dependence of computed tomography number to relative electron density conversion on phantom geometry and its impact on planned dose

A computed tomography number to relative electron density (CT-RED) calibration is performed when commissioning a radiotherapy CT scanner by imaging a calibration phantom with inserts of specified RED and recording the CT number displayed. In this work, CT-RED calibrations were generated using several commercially available phantoms to observe the effect of phantom geometry on conversion to electron density and, ultimately, the dose calculation in a treatment planning system. Using an anthropomorphic phantom as a gold standard, the CT number of a material was found to depend strongly on the amount and type of scattering material surrounding the volume of interest, with the largest variation observed for the highest density material tested, cortical bone. Cortical bone gave a maximum CT number difference of 1,110 when a cylindrical insert of diameter 28 mm scanned free in air was compared to that in the form of a 30 × 30 cm2 slab. The effect of using each CT-RED calibration on planned dose to a patient was quantified using a commercially available treatment planning system. When all calibrations were compared to the anthropomorphic calibration, the largest percentage dose difference was 4.2 % which occurred when the CT-RED calibration curve was acquired with heterogeneity inserts removed from the phantom and scanned free in air. The maximum dose difference observed between two dedicated CT-RED phantoms was ±2.1 %. A phantom that is to be used for CT-RED calibrations must have sufficient water equivalent scattering material surrounding the heterogeneous objects that are to be used for calibration.

Insight into differences in nanoindentation properties of bone.

Nanoindentation provides the ideal framework to determine mechanical properties of bone at the tissue scale without being affected by the size, shape, and porosity of the bone. However, the values of tissue level mechanical properties vary significantly between studies. Since the differences in the bone sample, hydration state, and test parameters complicate direct comparisons across the various studies, these discrepancies in values cannot be compared directly. The objective of the current study is to evaluate and compare mechanical properties of the same bones using a broad range of testing parameters. Wild type C56BL6 mice tibiae were embedded following different processes and tested in dry and rehydrated conditions. Spherical and Berkovich indenter probes were used, and data analysis was considered within the elasto-plastic (Oliver-Pharr), viscoelastic and visco-elastic-plastic frameworks. The mean values of plane strain modulus varied significantly depending on the hydration state, probe geometry and analysis method. Indentations in dry bone analyzed using a visco-elastic-plastic approach gave values of 34 GPa. After rehydrating the same bones and indenting them with a spherical tip and utilizing a viscoelastic analysis, the mean modulus value was 4 GPa, nearly an order of magnitude smaller. Results suggest that the hydration state, probe geometry and the limitations and assumptions of each analysis method influence significantly the measured mechanical properties. This is the first time that such a systematic study has been carried out and it has been concluded that the discrepancies in the mechanical properties of bone measured by nanoindentation found in the literature should not be attributed only to the differences between the bones themselves, but also to the testing and analysis protocols.