Femoroacetabular impingement (FAI) results from a morphological deformity of the hip and is associated with osteoarthritis (OA). Increased bone mineral density (BMD) is observed in the antero-superior acetabulum rim where impingement occurs. It is hypothesized that the repeated abnormal contact leads to damage of the cartilage layer, but could also cause a bone remodelling response according to Wolff's Law. Thus the goal of this study was to assess the relationship between bone metabolic activity measured by PET and BMD measured in CT scans. Five participants with asymptomatic cam deformity, three patients with uni-lateral symptomatic cam FAI and three healthy controls were scanned in a 3T PET-MRI scanner following injection with [18F]NaF. Bone remodelling activity was quantified with Standard Uptake Values (SUVs). SUVmax was analyzed in the antero-superior acetabular rim, femoral head and head-neck junction. In these same regions, BMD was calculated from CT scans using the calibration phantom included in the scan. The relationship between SUVmax and BMD from corresponding regions was assessed using the coefficient of determination (R. 2. ) from linear regression. High bone activity was seen in the cam deformity and acetabular rim. SUVmax was negatively correlated with BMD in the antero-superior region of the acetabulum (R. 2. =0.30, p=0.08). SUVmax was positively correlated with BMD in the antero-superior head-neck junction of the femur (R. 2. =0.359, p=0.067). Correlations were weak in other regions. Elevated bone turnover was seen in patients with a cam deformity but the relationship to BMD was moderate. This study demonstrates a pathomechanism of hip degeneration associated with FAI deformities, consistent with Wolff's law and the proposed mechanical cause of hip degeneration in FAI. [18F]-NaF PET SUV may be a biomarker of degeneration, especially in early stages of degeneration, when joint preservation surgery is likely to be the most successful

Odontoid fracture of the second cervical vertebra (C2) is the most common spinal fracture type in elderly patients. However, very little is known about the biomechanical fracture mechanisms, but could play a role in fracture prevention and treatment. This study aimed to investigate the biomechanical competence and fracture characteristics of the odontoid process. A total of 42 human C2 specimens (14 female and 28 male, 71.5 ± 6.5 years) were scanned via quantitative computed tomography, divided in 6 groups (n = 7) and subjected to combined quasi-static loading at a rate of 0.1 mm/s until fracturing at inclinations of −15°, 0° and 15° in sagittal plane, and −50° and 0° in transverse plane. Bone mineral density (BMD), specimen height, fusion state of the ossification centers, stiffness, yield load, ultimate load, and fracture type according to Anderson and d'Alonzo were assessed. While the lowest values for stiffness, yield, and ultimate load were observed at load inclination of 15° in sagittal plane, no statistically significant differences could be observed among the six groups (p = 0.235, p = 0.646, and p = 0.505, respectively). Evaluating specimens with only clearly distinguishable fusion of the ossification centers (n = 26) reveled even less differences among the groups for all mechanical parameters. BMD was positively correlated with yield load (R² = 0.350, p < 0.001), and ultimate load (R² = 0.955, p < 0.001), but not with stiffness (p = 0.070). Type III was the most common fracture type (23.5%). These biomechanical outcomes indicate that load direction plays a subordinate role in traumatic fractures of the odontoid process in contrast to BMD which is a strong determinant of stiffness and strength. Thus, odontoid fractures appear to result from an interaction between load magnitude and bone quality

We have developed a novel technique to analyse bone, using imaging mass cytometry (IMC) without the constraints of using immunofluorescent histochemistry. IMC can measure the expression of over 40 proteins simultaneously, without autofluorescence. We analysed mitochondrial respiratory chain (RC) protein deficiencies in human bone which are thought to contribute to osteoporosis with increasing age. Osteoporosis is characterised by reduced bone mineral density (BMD) and fragility fractures. Humans accumulate mitochondrial mutations and RC deficiency with age and this has been linked to the changing phenotype in advancing age and age-related disease. Mitochondrial mutations are detectable from the age of 30 onwards, coincidently the age BMD begins to decline. Mitochondria contain their own genome which accumulates somatic variants at around 10 times the rate of nuclear DNA. Once these mutations exceed a threshold, RC deficiency and cellular dysfunction occur. The PolgD257A/D257A mouse model expresses a proof-reading deficient version of PolgA, a mtDNA polymerase. These mice accumulate mutations 3-5 times higher than wild-type mice showing enhanced levels of age-related osteoporosis and RC deficiency in osteoblasts. Bone samples were analysed from young and old patients, developing a protocol and analysis framework for IMC in bone tissue sections to analyse osteoblasts in-situ for RC deficiency. Samples from the femoral neck of 10 older healthy volunteers aged 40 – 85 were compared with samples from young patients aged 1-19. We have identified RC complex I defect in osteoblasts from 6 of the older volunteers, complex II defects in 2 of the older volunteers, complex IV defect in just 1 older volunteer, and complex V defect in 4 of the older volunteers. These observations are consistent with the PolgD257A/D257A mouse-model and suggest that RC deficiency, due to age-related pathogenic mitochondrial DNA mutations, may play a significant role in the pathogenesis of human age-related osteoporosis

Quantitative ultrasound (QUS) is a promising tool to estimate bone structure characteristics and predict fragile fracture. The aim of this pilot cross-sectional study was to evaluate the performance of a multi-channel residual network (MResNet) based on ultrasonic radiofrequency (RF) signal to discriminate fragile fractures retrospectively in postmenopausal women. Methods. RF signal and speed of sound (SOS) were obtained using an axial transmission QUS at one‐third distal radius for 246 postmenopausal women. Based on the involved RF signal, we conducted a MResNet, which combines multi-channel training with original ResNet, to classify the high risk of fragility fractures patients from all subjects. The bone mineral density (BMD) at lumber, hip and femoral neck acquired with DXA was recorded on the same day. The fracture history of all subjects in adulthood were collected. To assess the ability of the different methods in the discrimination of fragile fracture, the odds ratios (OR) calculated using binomial logistic regression analysis and the area under the receiver operator characteristic curves (AUC) were analyzed. Results. Among the 246 postmenopausal women, 170 belonged to the non-fracture group, 50 to the vertebral group, and 26 to the non-vertebral fracture group. MResNet was discriminant for all fragile fractures (OR = 2.64; AUC = 0.74), for Vertebral fracture (OR = 3.02; AUC = 0.77), for non-vertebral fracture (OR = 2.01; AUC = 0.69). MResNet showed comparable performance to that of BMD of hip and lumbar with all types of fractures, and significantly better performance than SOS all types of fractures. Conclusions. the MResNet model based on the ultrasonic RF signal can significantly improve the ability of QUS device to recognize previous fragile fractures. Moreover, the performance of the proposed model modified by age, weight, and height is further optimized. These results open perspectives to evaluate the risk of fragile fracture applying a deep learning model to analyze ultrasonic RF signal

Stand-alone anterior lumbar interbody fusion (ALIF) provides the opportunity to avoid supplemental posterior fixation. This may reduce morbidity and complication rate, which is of special interest in patients with reduced bone mineral density (BMD). This study aims to assess immediate biomechanical stability and radiographic outcome of a stand-alone ALIF device with integrated screws in specimens of low BMD. Eight human cadaveric spines (L4-sacrum) were instrumented with SynFix-LR™ (DePuy Synthes) at L5/S1. Quantitative computed tomography was used to measure BMD of L5 in AMIRA. Threshold values proposed by the American Society of Radiology 80 and 120 mg CaHa/mL were used to differentiate between Osteoporosis, Osteopenia, and normal BMD. Segmental lordosis, anterior and posterior disc height were analysed on pre- and postoperative radiographs (Fig 1). Specimens were tested intact and following instrumentation using a flexibility protocol consisting of three loading cycles to ±7.5 Nm in flexion-extension, lateral bending, and axial rotation. The ranges of motion (ROM) of the index level were assessed using an optoelectronic system. BMD ranged 58–181mg CaHA/mL. Comparison of pre- and postoperative radiographs revealed significant increase of L5/S1 segmental lordosis (mean 14.6°, SD 5.1, p < 0.001) and anterior disc height (mean 5.8mm, SD 1.8, p < 0.001), but not posterior disc height. ROM of 6 specimens was reduced compared to the intact state. Two specimens showed destructive failure in extension. Mean decrease was most distinct in axial rotation up to 83% followed by flexion-extension. ALIF device with integrated screws at L5/S1 significantly increases segmental lordosis and anterior disc height without correlation to BMD. Primary stability in the immediate postoperative situation is mostly warranted in axial rotation. The risk of failure might be increased in extension for some patients with reduced lumbar BMD, therefore additional posterior stabilization could be considered. For any figures or tables, please contact the authors directly

Nuclear factor erythroid 2–related factor 2 (Nrf2) is a crucial transcription factor to maintain cellular redox homeostasis, but is also affecting bone metabolism. As the association between Nrf2 and osteoporosis in elderly females is not fully elucidated, our aim was to shed light on the potential contribution of Nrf2 to the development of age-dependent osteoporosis using a mouse model. Female wild-type (WT, n=18) and Nrf2-knockout (KO, n=12) mice were sacrificed at different ages (12 weeks=young mature adult, and 90 weeks=old), morphological cortical and trabecular properties of femoral bone analyzed by micro-computed tomography (µCT), and compared to histochemistry. Mechanical properties were derived from quasi-static compression tests and digital image correlation (DIC) used to analyze full-field strain distribution. Bone resorbing cells and aromatase expression by osteocytes were evaluated immunohistochemically and empty osteocyte lacunae counted in cortical bone. Wilcoxon rank sum test was used for data comparison and differences considered statistically significant at p<0.05. When compared to old WT mice, old Nrf2-KO mice revealed a significantly reduced trabecular bone mineral density (BMD), cortical thickness (Ct.Th), cortical area (Ct.Ar), and cortical bone fraction (Ct.Ar/Tt.Ar). Surprisingly, these parameters were not different in skeletally mature young adult mice. Metaphyseal trabeculae were thin but present in all old WT mice, while no trabecular bone was detectable in 60% of old KO mice. Occurrence of empty osteocyte lacunae did not differ between both groups, but a significantly higher number of osteoclast-like cells and fewer aromatase-positive osteocytes were found in old KO mice. Furthermore, female Nrf2-KO mice showed an age-dependently reduced fracture resilience when compared to age-matched WT mice. Our results confirmed lower bone quantity and quality as well as an increased number of bone resorbing cells in old female Nrf2-KO mice. Additionally, aromatase expression in osteocytes of old Nrf2-KO mice was compromised, which may indicate a chronic lack of estrogen in bones of old Nrf2-deficient mice. Thus, chronic Nrf2 loss seems to contribute to age-dependent progression of female osteoporosis

Objectives. Several genome-wide association studies (GWAS) of bone mineral density (BMD) have successfully identified multiple susceptibility genes, yet isolated susceptibility genes are often difficult to interpret biologically. The aim of this study was to unravel the genetic background of BMD at pathway level, by integrating BMD GWAS data with genome-wide expression quantitative trait loci (eQTLs) and methylation quantitative trait loci (meQTLs) data. Method. We employed the GWAS datasets of BMD from the Genetic Factors for Osteoporosis Consortium (GEFOS), analysing patients’ BMD. The areas studied included 32 735 femoral necks, 28 498 lumbar spines, and 8143 forearms. Genome-wide eQTLs (containing 923 021 eQTLs) and meQTLs (containing 683 152 unique methylation sites with local meQTLs) data sets were collected from recently published studies. Gene scores were first calculated by summary data-based Mendelian randomisation (SMR) software and meQTL-aligned GWAS results. Gene set enrichment analysis (GSEA) was then applied to identify BMD-associated gene sets with a predefined significance level of 0.05. Results. We identified multiple gene sets associated with BMD in one or more regions, including relevant known biological gene sets such as the Reactome Circadian Clock (GSEA p-value = 1.0 × 10. -4. for LS and 2.7 × 10. -2. for femoral necks BMD in eQTLs-based GSEA) and insulin-like growth factor receptor binding (GSEA p-value = 5.0 × 10. -4. for femoral necks and 2.6 × 10. -2. for lumbar spines BMD in meQTLs-based GSEA). Conclusion. Our results provided novel clues for subsequent functional analysis of bone metabolism, and illustrated the benefit of integrating eQTLs and meQTLs data into pathway association analysis for genetic studies of complex human diseases. Cite this article: W. Wang, S. Huang, W. Hou, Y. Liu, Q. Fan, A. He, Y. Wen, J. Hao, X. Guo, F. Zhang. Integrative analysis of GWAS, eQTLs and meQTLs data suggests that multiple gene sets are associated with bone mineral density. Bone Joint Res 2017;6:572–576

Total Hip Replacement (THR) is one of the most successful operations in all of medicine, however surgeons just rely on their experience and expertise when choosing between cemented or cementless stem, without having any quantitative guidelines. The aim of this project is to provide clinicians with some tools to support in their decision making. A novel method based on bone mineral density (BMD) measurements and assessments was developed 1) to estimate the periprosthetic fracture risk (FR) while press-fitting cementless stem; 2) to evaluate post-operative bone remodeling in terms of BMD changes after primary THR. Data for 5 out of over 70 patients (already involved in a previous study. 1. ) that underwent primary THA in Iceland were selected for developing novel methods to assess intra-operative FR and bone mineral density (BMD) changes after the operation. For each patient three CT images were acquired (Philips Brilliance 64 Spiral-CT, 120 kVp, slice thickness: 1 mm, slice increment: 0.5 mm): pre-op, 24 hours and 1 year post-operative. Pre-op CT scan was used to create 3D finite element model (Materialise Mimics) of the proximal femur. The material properties were assigned based on Hounsfield Units. Different strategies were analyzed for simulating the press-fitting operation, developing what has already been done in prior study. 1. In the finite element simulation (Ansys Workbench), a pressure (related to the implant hammering force of 9.25 kN. 2. ) was applied around the femur's hollow for the stem and the distribution of maximum principal elastic strain over the bone was calculated. Assuming a critical failure value. 3. of 7300 με, the percentage of fractured elements was calculated (i.e. FR). Post 24 hours and Post 1 year CT images were co-registrated and compared (Materialise Mimics) in order to assess BMD changes. Successively, volumes of bone lost and bone gained were calculated and represented in a 3D model. Age and gender should not be taken as unique indicators to choose between implants typologies, since also three dimensional BMD distribution along with volume of cortical bone influence the risk of periprosthetic fractures. Highest FR values were experienced in the calcar-femorale zone and in similar location on the posterior side. BMD loss volume fractions after 1 year were usually higher than BMD gain ones. Consistently with prior studies. 4. , BMD loss was mainly concentrated around the proximal end (lesser trochanter area, outer bone). If present, BMD gain occurred at the distal end (below stem's tip) or proximally (lesser trochanter area, interface contact with the stem). The use of clinical data for BMD assessments serves as an important tool to develop a quantitative method which will support surgeons in their decisions, guiding them to the optimal implant for the patient. Knowing the risk of fracture if choosing a cementless stem and being aware of how the bone will remodel around the stem in one year's time can eventually lead to reduction in revisions and increased quality of life for the patient. Further work will target analysis of a larger cohort of patients and validate FE models

Introduction and Objective. Type 2 diabetes mellitus (T2DM), and the often concurrent obesity, causes metabolic changes that affect many organs and tissues, including bone. Despite a normal or even higher bone mineral density (BMD), T2DM has often been associated with a higher fracture risk, indicating a compromised bone quality. In this work, we use a novel congenic leptin receptor-deficient BioBreeding Diabetes Resistant rat (BBDR.cg.lepr.cp) to investigate the impact of T2DM and obesity on bone morphology and architecture at the microscale. Materials and Methods. Two different anatomical locations, i.e., femur and cranium, were studied combining micro-computed X-ray tomography (micro-CT) with scanning electron microscopy (SEM). Micro-CT data were examined using advanced image analysis tools in three-dimensions (3D). Results. Both parietal bones and femurs were smaller, i.e., thinner and shorter, respectively, in diabetic animals compared to healthy controls. Image analysis of the sagittal suture revealed a reduced suture width and length in diabetic animals, suggesting an altered bone apposition rate. Histomorphometry analysis from micro-CT data highlighted differences in microstructure of both trabecular and cortical femur between diabetic and healthy rats. In particular, bone volume fraction (BV/TV) was lower in the T2DM group, while trabecular spacing (Tb.Sp) was increased, overall indicating a higher porosity in diabetic trabecular bone. SEM revealed the presence of extended portions of hyper-mineralized cartilage in the distal femur of the diabetic animals. Conclusions. Micro-CT analyses, combined with SEM imaging, suggest that T2DM impacts bone growth and remodelling, in turn leading to differences in the structural organization at the microscale

Abstract. Objectives. Current therapies for osteoporosis are limited to generalised antiresorptive or anabolic interventions, which do not target specific regions to improve skeletal health. Moreover, the adaptive changes of separate and combined pharmacological and biomechanical treatments in the ovariectomised (OVX) mouse tibia has not been studied yet. Therefore, this study combines micro- computed tomography (micro-CT) imaging and computational modelling to evaluate the efficacies of treatments in reducing bone loss. Methodology. In vivo micro-CT (10.4µm/voxel) images of the right tibiae of N=18 female OVX C57BL/6 mice were acquired at weeks 14, 16, 18, 20 and 22 of age for 3 groups: mechanical loading (ML), parathyroid hormone (PTH) or combined therapies (PTHML). All mice received either injection of PTH (100μg/kg/day, 5days/week) or vehicle from week 18. The right tibiae were mechanically loaded in vivo at week 19 and 21 with a 12N peak load, 40 cycles/day and 3 days/week. Bone adaptation was quantified through spatial changes in bone mineral density (BMD) and strain distribution was obtained from micro-CT-based finite element models. Results. Densitometric parameters improved for all treatment between week 18–20 (10–21%), with the strongest benefits due to loading in the proximal regions (16–35%). At week 22, PTHML treatment induced 23–76% higher bone apposition in the proximal tibia than either monotherapy. Compared to the OVX control, all treatments reduced periosteal resorption at weeks 18–20 and 20–22 (20–87%). However, resorption in weeks 20–22 were 29–55% higher than weeks 18–20, increasing the strain in the proximal tibia. Synergistic effects of PTH and ML were observed on the periosteal surface of proximal tibia, but additive effects were seen predominately on the distal and lateral tibia. Conclusions. ML had a more dominant effect in improving bone health. PTH enhances bone's osteogenic response to ML additively and synergistically in a site- and time-dependent manner

Osteoporosis is a common disorder characterized by low bone mass and reduced bone quality that affects the bone strength negatively and leads to increased risk of fracture. Bone mineral density (BMD) has been the standard instrument for the diagnosis of osteoporosis and the determination of fracture risk. Despite the approximation of the bone mass, BMD does not provide information about the bone structure. Trabecular bone score (TBS), which provides an indirect evaluation of skeletal microarchitecture, is calculated from dual X-ray absorptiometry and a simple and noninvasive method that may contribute to the prediction of osteoporotic fractures in addition to the measure of bone density. The goal of this study was to determine the mean TBS values in healthy postmenopausal women and the overall association between TBS and demographic features, bone mineral density of the lumbar spine and femoral neck and bone mineral density to body mass index ratio (BMD/BMI) of the lumbar spine. Fifty-three postmenopausal healthy women participated. The bone mineral density of the lumbar spine and femoral neck were measured dual X-ray absorptiometry. Anteroposterior lumbar spine acquisitions were used to calculate TBS for L1-L4. Age, height, weight, BMI and the ratio of BMD to BMI, which was considered to be a simple tool for assessing fracture risk in especially obese individuals, were calculated. The relationship between TBS and other variables was examined using Spearman's rank correlation coefficients. Mean BMD of the lumbar spine and the femoral neck were 0.945 ± 0.133 and 0.785 ± 0.112 g/cm2, respectively (Table 1). Mean TBS was 1.354 ± 0.107. There was a significant positive moderate correlation between TBS and total lumbar BMD/BMI ratio (r=0.595, pTBS values of postmenopausal women were negatively correlated with age and BMI and positively with bone mineral density and BMD/BMI ratio. The ratio between lumbar BMD and BMI presented a stronger correlation with TBS than that of BMD with TBS. Because of the better correlation, the BMD/BMI ratio may be used as a simple tool for the assessment of the risk of fractures. Further investigation may be needed to evaluate the factors influencing exercise intervention on TBS on this population of patients

Objectives. The aim of the current study was to assess whether calcaneal broadband ultrasound attenuation (BUA) can predict whole body and regional dual-energy x-ray absorptiometry (DXA)-derived bone mass in healthy, Australian children and adolescents at different stages of maturity. Methods. A total of 389 boys and girls across a wide age range (four to 18 years) volunteered to participate. The estimated age of peak height velocity (APHV) was used to classify children into pre-, peri-, and post-APHV groups. BUA was measured at the non-dominant heel with quantitative ultrasonometry (QUS) (Lunar Achilles Insight, GE), while bone mineral density (BMD) and bone mineral content (BMC) were examined at the femoral neck, lumbar spine and whole body (DXA, XR-800, Norland). Associations between BUA and DXA-derived measures were examined with Pearson correlations and linear regression. Participants were additionally ranked in quartiles for QUS and DXA measures in order to determine agreement in rankings. Results. For the whole sample, BUA predicted 29% of the study population variance in whole body BMC and BMD, 23% to 24% of the study population variance in lumbar spine BMC and BMD, and 21% to 24% of the variance in femoral neck BMC and BMD (p < 0.001). BUA predictions were strongest for the most mature participants (pre-APHV R. 2. = 0.03 to 0.19; peri-APHV R. 2. = 0.05 to 0.17; post-APHV R. 2. = 0.18 to 0.28) and marginally stronger for girls (R. 2. = 0.25-0.32, p < 0.001) than for boys (R. 2. = 0.21-0.27, p < 0.001). Agreement in quartile rankings between QUS and DXA measures of bone mass was generally poor (27.3% to 38.2%). Conclusion. Calcaneal BUA has a weak to moderate relationship with DXA measurements of bone mass in children, and has a tendency to misclassify children on the basis of quartile rankings. Cite this article: B. K. Weeks, R. Hirsch, R. C. Nogueira, B. R. Beck. Is calcaneal broadband ultrasound attenuation a valid index of dual-energy x-ray absorptiometry-derived bone mass in children? Bone Joint Res 2016;5:538–543. DOI: 10.1302/2046-3758.511.BJR-2016-0116.R1

To date, the fixation of proximal humeral fractures with angular stable locking plates is still insufficient with mechanical failure rates of 18% to 35%. The PHILOS plate (DePuy Synthes, Switzerland) is one of the most used implants. However, this plate has not been demonstrated to be optimal; the closely symmetric plate design and the largely heterogeneous bone mineral density (BMD) distribution of the humeral head suggest that the primary implant stability may be improved by optimizing the screw orientations. Finite element (FE) analysis allows testing of various implant configurations repeatedly to find the optimal design. The aim of this study was to evaluate whether computational optimization of the orientation of the PHILOS plate locking screws using a validated FE methodology can improve the predicted primary implant stability. The FE models of nineteen low-density (humeral head BMD range: 73.5 – 139.5 mg/cm3) left proximal humeri of 10 male and 9 female elderly donors (mean ± SD age: 83 ± 8.8 years) were created from high-resolution peripheral computer tomography images (XtremeCT, Scanco Medical, Switzerland), using a previously developed and validated computational osteosynthesis framework. To simulate an unstable mal-reduced 3-part fracture (AO/OTA 11-B3.2), the samples were virtually osteotomized and fixed with the PHILOS plate, using six proximal screws (rows A, B and E) according to the surgical guide. Three physiological loading modes with forces taken from musculoskeletal models (AnyBody, AnyBody Technology A/S, Denmark) were applied. The FE analyses were performed with Abaqus/Standard (Simulia, USA). The average principal compressive strain was evaluated in cylindrical bone regions around the screw tips; since this parameter was shown to be correlated with the experimental number of cycles to screw cut-out failure (R2 = 0.90). In a parametric analysis, the orientation of each of the six proximal screws was varied by steps of 5 in a 5×5 grid, while keeping the screw head positions constant. Unfeasible configurations were discarded. 5280 simulations were performed by repeating the procedure for each sample and loading case. The best screw configuration was defined as the one achieving the largest overall reduction in peri-screw bone strain in comparison with the PHILOS plate. With the final optimized configuration, the angle of each screw could be improved, exhibiting significantly smaller average bone strain around the screw tips (range of reduction: 0.4% – 38.3%, mean ± SD: 18.49% ± 9.56%). The used simulation approach may help to improve the fixation of complex proximal humerus fractures, especially for the target populations of patients at high risk of failure

Introduction and Objective. Individuals with type 2 diabetes (T2D) have a 3-fold increased risk of bone fracture compared to non-diabetics, with the majority of fractures occurring in the hip, vertebrae and wrists. However, unlike osteoporosis, in T2D, increased bone fragility is generally not accompanied by a reduction in bone mineral density (BMD). This implies that T2D is explained by poorer bone quality, whereby the intrinsic properties of the bone tissue itself are impaired, rather than bone mass. Yet, the mechanics remain unclear. The objective of this study is to (1) assess the fracture mechanics of bone at the structural and tissue level; and (2) investigate for changes in the composition of bone tissue along with measuring total fluorescent advanced glycation end products (fAGEs) from the skin, as T2D progresses with age in Zucker diabetic fatty (ZDF (fa/fa)) and lean Zucker (ZL (fa/+)) rats. Materials and Methods. Right ulnae and skin sections were harvested from ZDF (fa/fa) (T2D) and ZL (fa/+) (Control) rats at 12 and 46 weeks (wks) of age (n = 8, per strain and age) and frozen. Right ulnae were thawed for 12 hrs before micro-CT (μCT) scanning to assess the microstructure and measure BMD. After scanning, ulnae were loaded until failure via three-point bending. Fourier transform-infrared microspectroscopy (FTIR) was used to measure various bone mineral- and collagen-related parameters such as, mineral-to-matrix ratio and nonenzymatic cross-link ratio. Finally, fAGEs were measured from skin sections using fluorescence spectrometry and an absorbance assay, reported in units of ng quinine/ mg collagen. Results. At 12 and 46 wks bone size was significantly smaller in length (p < 0.01), cortical area (p < 0.001) and cross-sectional moment of inertia (p < 0.001) in T2D rats compared to age-matched controls. A slight reduction in BMD was observed in T2D rats compared to controls at both ages, however, this was not significant. Structural properties of T2D bone were significantly altered at 12 and 46 wks, with bending rigidity increasing approximately 2.5-fold and 1.5-fold in control and T2D rats with age, respectively (p < 0.0001). Similarly, yield and ultimate moment significantly reduced in T2D rats with age in comparison to controls (p < 0.0001). Energy absorbed to failure was significantly reduced in T2D rats at 46 weeks of age compared to controls (p < 0.01). The amount of energy absorbed to failure increased approximately 1.4-fold from 12 to 46 wks in control rats, however, in T2D rats a reduction was seen with age, although not significant. At 12 wks, there was no significant deficits in tissue material properties, whereas, at 46 wks a significant reduction in yield stress, yield strain and ultimate stress was observed for T2D rats in comparison to controls (p < 0.05). Conclusions. These findings show that longitudinal growth is impaired as early as 12 wks of age and by 46 wks bone size is significantly reduced in T2D rats compared to controls. The reduction in T2D structural properties is likely attributed to the bone geometry deficits. At 12 wks of age, the tissue material properties are not altered in T2D bone versus controls. However, at 46 wks, bone strength is reduced in T2D, leading to the conclusion that tissue properties are altered as the disease progresses

SL-PLUS MIA stem (Smith & Nephew Orthopaedics AG) is a modified implant of Zweymuller type SL-PLUS standard stem (Smith & Nephew Orthopaedics AG). We constructed finite element (FE) models and analysed equivalent stresses in the femur. In addition, we measured bone mineral density (BMD) in the femur by dual-energy X-ray absorptiometry (DEXA) after THA. The purpose of this study was to investigate the equivalent stress and to compare the results of the FE analyses with changes in BMD after THA. Twenty-one patients (18 women and 3 men) who underwent primary cementless THA with SL-PLUS MIA or SL-PLUS formed the basis of this study. Eleven patients received SL-PLUS MIA and ten patients received SL-PLUS. Zones were defined according to Gruen's system (zones 1∼7). Computed-tomography (CT) images of the femur were taken before and at 1 week after THA. FE models of the femur and prosthesis were obtained from CT data by Mechanical Finder (Research Center of Computational Mechanics Inc., Tokyo, Japan), software that creates FE models showing individual bone shape and density distribution. Equivalent stresses were analysed in zones 1 to 7 and compared to the DEXA data. FE studies revealed that there was no significant difference in equivalent stress between SL-PLUS MIA and SL-PLUS. BMD was maintained after THA in zones 3, 4, and 5, whereas BMD decreased in zones 2, 6, and 7. In zone 1, BMD decreased in SL-PLUS MIA stem group by 14%, while BMD was maintained in SL-PLUS standard stem

To prevent bone loss, OPG/RANK/RANKL signalling pathway is a key in keeping the balance between the action of osteoblasts and osteoclasts. Aim of this study is to assess the influence of long-term nicotine exposure on bone mineral density (BMD) scores, RANKL and OPG levels of plasma and RANKL and OPG immunoreactivities of tissue in rats. In this study, totally 36 Swiss Albino rats (70±10 g) were used in three groups. Whereas normal drinking water was given for the control group (n:12), 0.4 mg/kg/day and 6.0 mg/kg/day nicotine was added to drinking water for low-dose nicotine (LDN) group (n:12) and high-dose nicotine (HDN) group (n:12), respectively for 12 months. At the end of 12. th. month, BMD scores were measured via X-ray absorptiometry and then bone turnover was assessed via measuring both RANKL, OPG levels in plasma and RANKL, OPG immunoreactivities in tail vertebrae of all rats. Lumbar spine and femoral regions BMD scores of the control group and the nicotine groups were not significantly difference. In HDN group, OPG levels of plasma were found significantly higher when compared with the control and LDN groups (p=0.001) unlike RANKL levels of plasma. RANKL and OPG immunoreactivities of tissue were found significantly lower in both LDN and HDN groups (p<0.001, p=0.004, respectively) in comparison to control group. No correlation was found between plasma levels and tissue immunoreactivities of RANKL and OPG. As a result, this study indicates that nicotine is not primarily responsible for the decline of BMD frequently seen in smokers

Introduction. Excessive bone mass and microarchitecture loss exacerbate the risk of osteoporotic fracture, a skeletal disorder attributable to disability in the elder. Excessive marrow adipose development at the expense of osteoblastic bone acquisition is a prominent feature of aging-induced osteoporotic skeletons. MicroRNA-29a (miR-29a) modulates osteogenic and adipogenic commitment of mesenchymal progenitor cells. The purposes of this study were to test if miR-29a overexpression changed bone mass or microstructure in aged skeletal tissues. Materials/Methods. Transgenic mice that overexpressed miR-29a in osteoblasts driven by osteocalcin promoter (miR-29aTg) were generated. Littermates without carrying construct of interest were used as wild-type mice (WT). 3- and 12-month-old mice were designated into young and aged groups respectively. Bone mineral density (BMD), cortical, trabecular microarchitecture and morphometric profiles were quantified with ultrahigh resolution μCT system. Primary bone-marrow mesenchymal stem cells (BMMSCs) were incubated in osteogenic and adipogenic conditions. Expressions of osteogenic and adipogenic marker were quantified with RT-PCR. Results. Skeletons in the aged WT group showed 65% decrease in BMD in association with 72% reduction in miR-29a expression and 2.3-fold elevation in marrow fat volume as compared with those in young WT group. The young miR-29aTg mice showed 35–48% increases in serum osteocalcin and bone alkaline phosphatase levels concomitant with 22–35% increases in BMD, trabecular BV/TV, Tb.Th, Tb.N, and cortical morphology than those of young WT mice. Intriguing analyses are that miR-29aTg mice exhibited mild responses to the aging provocation of BMD loss, trabecular, cortical microstructure deterioration, and fatty marrow histopathology. In vitro, primary BMMSCs in miR-29aTg mice showed significant increases in osteogenic gene expression and mineralized matrices as probed with von Kossa staining, whereas adipogenic gene expression and adipocyte formation were evidently reduced as evidenced by fluorescence Nile Red. Conclusion. miR-29a overexpression in osteoblasts facilitates skeletal tissue anabolism. High osteogenic lineage commitment of bone-marrow mesenchymal progenitor cells contributes to high bone mass and microstructure phenotypes promoted by miR-29a signaling. Analyses shed a new light on the miR-29a signaling protection against the aging escalation of osteoporosis pathogenesis

Introduction. Glenoid loosening, still a main complication for shoulder arthroplasty, was suggested to be related implant design, surgical aspects, and also bone quality. However, typical studies of fixation do not account for heterogeneity in bone morphology and density which were suggested to affect fixation failure. In this study, a combination of cyclic rocking horse tests on cadaver specimens and microCT-based finite element (microFE) analysis of specimens of a wide range of bone density were used to evaluate the effects of periprosthetic bone quality on the risks of loosening of anatomical keeled or pegged glenoid implants. Methods. Six pairs of cadaveric scapulae, scanned with a quantitative computer tomography (QCT) scanner to calculate bone mineral density (BMD), were implanted with either cemented anatomical pegged or keeled glenoid components and tested under constant glenohumeral load while a humeral head component was moved cyclically in the inferior and superior directions. Edge displacements were measured after 1000, 4000 and 23000 test cycles, and tested for statistical differences with regards to changes or implant design. Relationships were established between edge displacements and QCT-based BMD below the implant. Four other specimens were scanned with high-resolution peripheral QCT (82µm) and implanted with the same 2 implants to generate virtual models. These were loaded with constant glenohumeral force, varying glenohumeral conformity and superior or inferior load shifts while internal stresses at the cement-bone and implant-cement interfaces were calculated and related to apparent bone density in the periprosthetic zone. Results. Mean displacements at the inferior and superior edges showed no statistical difference between keeled and pegged designs (p>0.05). Compression and distraction were however statistically different from the initial reference measurement at even 1000 and 4000 cycles for both implant designs (p<0.05). For both implant designs, superior and inferior distractions were generally highest at each measurement time in specimens where BMD below the lifting edge was lower, showing a trend of increased distraction with decreased BMD. Moreover, the microFE models predicted higher bone and cement stresses for specimens of lower apparent bone density. Finally, highest peak stresses were located at the cement-bone interface, which seemed the weaker part of the fixation. Discussion. With this combined experimental and numerical study, it was shown that implant distraction and stresses in the cement layer are greater in glenoids of lower bone density for both implant designs. This indicates that fixation failure will most likely occur in bone of lower density, and that fixation design itself may play a secondary role. These results have important impact for understanding the mechanisms of glenoid component failure, a common complication of total shoulder arthroplasty

Background. Trabecular metal (TM) cones are designed to fill up major bone defects in total knee arthroplasty. Tibial components can be implanted in combination with a stem, but it is unclear if this is necessary after reconstruction with a TM cone. Implanting a stem may give extra stability, but may also have negative side-effects. Aim of this study was to investigate stability and strain distribution of a tibial plateau reconstruction with a TM cone while the tibal component is implanted with and without a stem, and whether prosthetic stability was influenced by bone mineral density (BMD). Methods. Tibial revision arthroplasties were performed after reconstruction of an AORI 2B bone defect with TM cones. Plateaus were implanted in seven pairs of cadaveric tibiae; of each pair, one was implanted with and the other without stem. All specimens were loaded to one bodyweight alternating between the medial and lateral tibia plateau. Implant-bone micro motions, bone strains, BMD and correlations were measured and/or calculated. Results. Tibial components without a stem showed only more varus tilt (difference in median 0.14 degrees (P<0.05), but this was not considered clinically relevant. Strain distribution did not differ. BMD had only an effect on the anterior/posterior tilt ρ:-0.72 (P<0.01). Conclusions. Tibial components, with or without a stem, which are implanted after reconstruction of major bone defects using TM cones produce very similar biomechanical conditions in terms of stability and strain distribution. Additional stem extension of the tibial component may not be required after reconstruction of major bone defects using TM cones. Level of evidence. IIb. Disclosures. The department of Orthopaedics, University of Groningen, University Medical Center Groningen has received direct funding from the Anna Fonds (Oegstgeest, NL). Zimmer (Warsaw, IN, USA) has provided the instrumentation and tools for this study. The department of Orthopaedics, University of Groningen, University Medical Center Groningen receives research institutional support from InSpine (Schiedam, NL) and Stryker (Kalamazoo, Mich. USA). One of the authors (ALB) will be and has been paid as a consultant by Zimmer (Warsaw, IN, USA) for purposes of education and training in knee arthroplasty

The pathogenesis of falling bone mineral density (BMD) as a universal feature of advancing age is poorly understood. 1. Frequently culminating in the development of osteoporosis, the process is attributable to more than 500,000 fragility fractures occurring every year in the UK Such injuries are associated with great levels of morbidity, mortality and a £3.5 billion cost to the healthcare economy. 2. . With age, humans are known to accumulate somatic mitochondrial DNA (mtDNA) mutations in mitotic and post mitotic tissue, and stem cell precursors. 3. Compelling evidence in recent years, particularly that provided by animal models suggests that these mutations are intrinsic to the ageing process. 4–6. We provide evidence for the first time that mitochondrial dysfunction contributes significantly to the failure of bone homeostasis and falling BMD. We have utilised a mouse model that accumulates mtDNA mutations at 3–5 times the rate of normal mice, consequently ageing and developing osteoporosis prematurely. 7. , to clearly demonstrate that osteoblasts are vulnerable to mtDNA mutations. We have developed a new quadruple immunofluorescent assay to show that mitochondrial respiratory chain dysfunction occurs in osteoblasts as a consequence (p < 0.0001). We show that this mitochondrial dysfunction is associated with reduced BMD in female and male mice by 7 (p = 0.003) and 11 (p = 0.0003) months of age respectively. Using osteoblasts derived from mesenchymal stem cells extracted from male and female mice with mitochondrial dysfunction aged 4, 7 and 11 months, we demonstrate a vastly reduced capacity to produce new mineralised bone in vitro when compared to wild type cell lines (p < 0.0001). Exercise was found to have no beneficial effect on osteoblast and whole bone phenotype in this mouse model. It is likely that mtDNA mutations accumulating over a longer time period in human ageing have significantly detrimental effects on bone biology and diminishing BMD