Porphyromonas gingivalis (P. gingivalis), a major pathogenic bacterium of chronic periodontitis and central player in the onset and subsequent progression of periodontitis, can cause alveolar bone resorption. The osteoblast dysfunction induced by P. gingivalis infection is a crucial pathological process causing bone loss. However, the comprehensive responses of osteoblasts, especially metabolism processes involved in osteoblast dysfunction under P. gingivalis invasion are largely unknown. In the present study, to profile the molecules switched in osteoblast dysfunction caused by P. gingivalis infection, the effect of P. gingivalis invasion on osteoblast differentiation was assessed and investigated through transcriptomics and metabolomics approaches. We found that P. gingivalis infection dramatically impaired osteoblast function. P. gingivalis invasion disrupted homeostasis of phosphorus (Pi)/calcium (Ca) and induced robust oxidative stress, cell apoptosis and massive activation of inflammatory response in osteoblasts. Notably, the exposure to P. gingivalis induced the inactivation of endocrines pathways, involved in bone formation, which is characterized by downregulated genes and less accumulated metabolites in "Parathyroid hormone synthesis, secretion and action", its downstream "Wnt signaling pathway" and related Pi/Ca transport. Furthermore, we found that disrupted purine metabolism produced less ATP in P. gingivalis-infected osteoblasts and the reduced ATP may directly inhibit phosphorus transport. Collectively, these results provide a new insight into the molecular changes in P. gingivalis-infected osteoblasts in a comprehensive way.

Maintained bone health is critical for independent living when aging. Currently, multimodal exercise regimes including weight-bearing exercises with impact are prescribed as optimal for maintaining bone health, while there is less consensus on the effects of resistance training at different intensities upon bone. Here we examined whether bone health was positively influenced by 1 year of supervised resistance training at two different intensities.

The correlation between serum vitamin D and mortality in patients with osteopenia or osteoporosis remains unclear. Therefore, this study examined the relationship between serum 25-hydroxy vitamin D [(25(OH)D] and mortality in patients with osteopenia or osteoporosis.

Nonlinear homogenised finite element (hFE) models can accurately predict stiffness and strength of ultra-distal sections of the radius and tibia using in vivo HR-pQCT images. Recent findings showed good stiffness prediction at these distal sections but a limited ability to reproduce experimental strain localisation. The coarseness of voxel-based meshes reduces the computational effort at the cost of heavily simplifying the underlying geometry of the cortex, the gradient of material properties, and the resulting strain distribution. To overcome these limitations, we present a comprehensive approach to generating fully automated, smooth, and structured hexahedral meshes for HR-pQCT scans at the distal radius and tibia. This study used three datasets to validate the proposed hFE pipeline and its short-term repeatability: ex vivo 2nd generation HR-pQCT images of 21 human radii and 25 human tibiae, and 208 in vivo images from same-day repeated scans on 39 individuals. Results show high accuracy in predicting stiffness (tibia: R=0.94, radius: R=0.88) and yield force (tibia: R=0.93, radius: R=0.95). Mesh sensitivity analysis reveals stabilisation within a ± 3 % error margin. Dice similarity coefficients between mesh and scanned image were >0.99, and good element quality was achieved across the validation datasets (tibia: S-ICN=0.809, radius: S-ICN=0.764). Along with the improved volumetric representation of distal cortical and trabecular bone geometry and the good element quality, the new pipeline shows gains in computational performance: 11.70±1.49 min for triple-stack tibia images and 11.00±0.97 min for double-stack radius images, respectively. Generating structured meshes with consistent element-to-element correspondence facilitates seamless comparison between patient models or in longitudinal settings, providing an additional clinical information.

To evaluate the impact of prior teriparatide (TPTD) treatment on the effectiveness of romosozumab (ROMO) in postmenopausal osteoporosis.

Finite element analysis (FEA) is a widely used tool to predict bone biomechanics in orthopaedics for prevention, treatment, and implant design. Subject-specific FEA models are more accurate than generic adult-scaled models, especially for a paediatric population, due to significant differences in bone geometry and bone mineral density. However, creating these models can be time-consuming, costly and requires medical imaging. To address these limitations, population-based models have been successful in characterizing bone shape and density variation in adults. However, children are not small adults and need their own population-based model to generate accurate and accessible musculoskeletal geometry and bone mineral density in a paediatric population. Therefore, this study aimed to create a biomechanical research tool to predict the personalized shape and density of the paediatric femur using a statistical shape and density model for a population of children aged from 4 to 18 years old. Femur morphology and bone mineral density were extracted from 330 CT scans of children. Variations in shape and density were captured using Principal Component Analysis (PCA). Principal components were correlated to demographic and linear bone measurements to create a predictive statistical shape-density model, which was used to predict femoral shape and density. A leave-one-out analysis showed that the shape-density model can predict the femur geometry with a root mean square error (RMSE) of 1.78 ± 0.46 mm and the bone mineral density with a normalized RMSE ranging from 8.9 % to 13.5 % across various femoral regions. These results underscore the model's potential to reflect real-world physiological variations in the paediatric femur. This statistical shape and density model has the potential for clinical application in rapidly generating personalized computational models using partial or no medical imaging data.

To investigate the association between the cumulative exposure to triglyceride-glucose index (cumTyG index) and fragility fractures in the general population.

Accurate 3D characterization of osteocyte lacunae is important when investigating the role of osteocytes under various physiological and pathological conditions but remains a challenge. With the continued development of laboratory X-ray micro-computed tomography, an increasing number of studies employ these techniques beyond traditional bone morphometry to quantify osteocyte lacunae. However, there is a lack of knowledge on the effect of measurement parameters on the image quality and resolution and in turn the osteocyte lacunar quantification. Herein, we have examined the interplay between scan parameters and the resultant lacunar quantification in terms of lacunar size, shape, and density by comparison with a synchrotron benchmark dataset. We summarize our conclusions in a guide for use of μ-CT for osteocyte lacunar quantification: (1) Identification of the measurement requirements to address the research questions. (2) Collection and preparation of suitable sample(s) that fulfills these requirements. (3) Experimental considerations including determination of the required voxel size, in turn dictating the maximum FOV and by extension the maximum size of the sample(s). The experimental parameters chosen should ensure optimal image contrast, sufficient signal to noise, angular sampling etc. Usually, it is advisable to measure as well as possible within the limits of time, budget, data storage and analysis capabilities. (4) Data analysis and reporting of the results, including visual examination of the data at multiple steps in the analysis, to ensure correct feature identification and suitable reporting approaches. (5) Cross study comparisons, which may be unsuitable if the experimental conditions and analysis strategies are not comparable.

Diabetes mellitus is a global disease that results in various complications, including diabetic osteoporosis. Prior studies have indicated a correlation between low levels of nicotinamide adenine dinucleotide (NAD) and diabetes-related complications. Nicotinamide riboside (NR), a widely utilized precursor vitamin of NAD, has been demonstrated to enhance age-related osteoporosis through the Sirt1/FOXO/β-catenin pathway in osteoblast progenitors. However, the impact of NR on bone health in diabetes mellitus remains unclear. In this study, we assessed the potential effects of NR on bone in diabetic mice. NR was administered to high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetic mice (T2DM), and various parameters, including metabolic indicators, bone quality, bone metabolic markers, and RNA sequences, were measured. Our findings confirmed that HFD/STZ-induced T2DM impaired bone microstructures, resulting in bone loss. NR effectively ameliorated insulin resistance, improved bone microarchitecture, and bone quality, reduced bone resorption, enhanced the Forkhead box O (FOXO) signaling pathway, mitigated the nuclear factor kappa B (NF-kB) signaling pathway, and ameliorated the disorder of the oxidative phosphorylation process (OXPHOS) in diabetic mice. In conclusion, NR demonstrated the capacity to alleviate T2DM-induced bone loss through the modulation of OXPHOS in type 2 diabetic mice. Our results underscore the potential of NR as a therapeutic target for addressing T2DM-related bone metabolism and associated diseases. Further cell-based studies under diabetic conditions, such as in vitro cultures of key cell types (e.g., osteoblasts and osteoclasts), are necessary to validate these findings.

Fracture risk is increased in longstanding type 2 diabetes (T2D). High-resolution peripheral quantitative CT scans have demonstrated higher cortical porosity in T2D complicated by microvascular disease (MVD). We investigated if cortical bone resorption is followed by inadequate bone formation in individuals with T2D complicated by MVD.

Comorbid diabetes and chronic kidney disease create a complex disease state with multi-faceted impacts on bone health, primarily reduced bone mass and tissue quality. To reduce fracture risk in this growing population, interventions are needed that target both bone mass and quality. Romosozumab (Romo) is an FDA-approved sclerostin inhibitor that has been shown to increase bone mass and strength in a murine model of combined diabetes and CKD (DKD), while Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone mechanical properties by increasing bone bound water content. We aimed to test whether combined RAL and Romo treatment could improve bone quality in our murine model of DKD more than either treatment alone. Using a previously established streptozotocin- and adenine-diet-induced model, male, C57BL/6J mice were randomly divided into four treatment groups and given daily subcutaneous injections of 100 μL vehicle (phosphorus buffered saline, PBS) or 0.5 mg/kg RAL. In addition, two groups were also given a weekly dose of Romo (10 mg/kg). Overall, Romo increased whole-bone strength and RAL improved tissue-level mechanical properties. Combined RAL-Romo treatment led to significantly higher cortical and trabecular bone mass compared to untreated controls. These morphological improvements created corresponding improvements in cortical bending strength and vertebral trabecular compression strength. These results suggest that combined RAL-Romo treatment provides both mass and quality improvements to DKD bone.

Postmenopausal women are at increased risk of fractures due to reduced bone mineral density (BMD) and impaired physical function. While fracture risk assessment tools like FRAX include clinical factors and BMD, they exclude functional measures such as balance and muscle strength, which are critical for fall prevention. This study aimed to evaluate the correlation between two functional tests- the 30-Second Sit to Stand Test (30STS) and the One Leg Stance Test (OLST)- and fracture risk, independent of BMD in postmenopausal women aged 50-70.

The tibia is one of the most common sites for bone stress injury (BSI) in active individuals. BSIs are thought to occur in response to damage accumulation from repetitive loading below the tissue's yield limit. The effect of fatigue on musculoskeletal biomechanics and tibial bone strain during athletic movements remains unclear. In this study, participant-specific finite element (FE) and musculoskeletal models in 10 collegiate-basketball players were used to analyze the effect of acute performance fatigue on joint kinematics and torques, ground reaction forces (GRFs), and the magnitude and distribution of tibial bone strains during select basketball maneuvers. Participants were fatigued by performing repeated exercises wearing a weighted vest until their vertical jump height decreased by 20 %. Fatigue reduced the vertical GRF during midstance of a jump task, and lowered hip and knee peak extension torques and ankle plantarflexion. However, fatigue had limited impact on tibial bone strain magnitude and distribution during jumping. In contrast, there was a shift in peak strain timing following fatigue during a lateral cut task and reduced strain at various times of stance during sprinting. The results suggest that fatigue was induced and, if anything, reduced tibial bone strain. As increased bone strain is thought to be associated with increased BSI risk, the reduced strain observed in the current study suggests that fatigue may actually be partly protective, possibly as a result of reduced muscle activation and force production.

Romosozumab is an anti-sclerostin antibody that increases bone formation and decreases bone resorption, and it became available for patients at high risk of osteoporotic fractures in Japan in 2019. The aim of this study was to clarify the clinical effects, safety, and predictors of the effectiveness of 12 months of romosozumab therapy following daily or weekly administration of teriparatide. The study had an observational pre-post design and included 171 female patients. Romosozumab was administered at a dose of 210 mg subcutaneously every 4 weeks for 12 months following daily or weekly administration of teriparatide. The incidence of new fractures, safety, and changes in bone mineral density (BMD) and bone turnover markers were recorded. New fractures occurred in 3 cases (2.2 %). Four patients (2.3 %) with secondary osteoporosis experienced cardiovascular events, which were fatal in 1 patient (0.6 %). The percent changes in BMD at the spine and total hip at 12 months from baseline were + 7.9 % and + 2.4 %, respectively. The percent change in spine BMD did not significantly differ according to whether daily or weekly teriparatide was given as previous treatment. Romosozumab following teriparatide showed greater effectiveness in patients with primary osteoporosis, high P1NP level at 1 month, and low percent changes in TRACP-5b after 12 months of treatment. Romosozumab after treatment with daily or weekly teriparatide was relatively safe and more effective in patients with primary osteoporosis than in those with secondary osteoporosis.

Long term glucocorticoid treatment in Duchenne Muscular Dystrophy (DMD) is associated with a high incidence of fragility fractures. This systematic review aims to assess the current evidence for pharmacological and non-pharmacological treatment for osteoporosis in children and adults with DMD.

This paper presents a review of the potential role of the endoplasmic reticulum/Golgi complex and intracellular vesicles in mediating events leading to or associated with vertebrate tissue mineralization. The possible importance of these organelles in this process is suggested by observations that calcium ions accumulate in the tubules and lacunae of the endoplasmic reticulum and Golgi. Similar levels of calcium ions (approaching millimolar) are present in vesicles derived from endosomes, lysosomes and autophagosomes. The cellular level of phosphate ions in these organelles is also high (millimolar). While the source of these ions for mineral formation has not been identified, there are sound reasons for considering that they may be liberated from mitochondria during the utilization of ATP for anabolic purposes, perhaps linked to matrix synthesis. Published studies indicate that calcium and phosphate ions or their clusters contained as cargo within the intracellular organelles noted above lead to formation of extracellular mineral. The mineral sequestered in mitochondria has been documented as an amorphous calcium phosphate. The ion-, ion cluster- or mineral- containing vesicles exit the cell in plasma membrane blebs, secretory lysosomes or possibly intraluminal vesicles. Such a cell-regulated process provides a means for the rapid transport of ions or mineral particles to the mineralization front of skeletal and dental tissues. Within the extracellular matrix, the ions or mineral may associate to form larger aggregates and potential mineral nuclei, and they may bind to collagen and other proteins. How cells of hard tissues perform their housekeeping and other biosynthetic functions while transporting the very large volumes of ions required for mineralization of the extracellular matrix is far from clear. Addressing this and related questions raised in this review suggests guidelines for further investigations of the intracellular processes promoting the mineralization of the skeletal and dental tissues.

Osteoporosis is the most common bone metabolic unbalance, leading to fragility fractures, which are known to be associated with structural changes in the bone. Cortical bone accounts for 80 % of the skeleton mass and undergoes remodeling throughout life, leading to changes in its thickness and microstructure. Although many studies quantified the different cortical bone structures using CT techniques (3D), they are often realised on a small number of samples. Therefore, the work presented here proposes a method to quantify cortical bone microstructure using 2D histology, shows its application on a set of 94 samples and compares to 3D methods. Fresh frozen human femur pairs from 47 donors aged between 57 and 96 years were obtained from the Medical University of Vienna. Bone samples were cut from 3 sites: proximal part of the diaphysis, inferior and superior segments of the neck. The samples were stained with toluidine blue and imaged under light microscopy. After manual segmentation of a few regions of interest by multiple operators, a convolutional neural network was trained in combination with a random forest for automatic segmentation. The segmentation analysis compares morphology and structure distribution of Haversian canals, osteocyte lacunae, and cement lines with literature, between anatomical sites, sex, left and right sides, and relation to ageing. Morphological analysis of the segmentation gives results similar to the literature. Comparison between male and female donors shows no significant differences. There is no significant difference between left and right femur on paired samples but significant differences are observed between anatomical locations. The structures' relative amounts do not present significant changes with age but only weak tendencies. Nevertheless, a strong correlation was observed between osteocyte lacunae density and bone areal fraction. This study presents a full process to stain and automatically segment digital cortical bone images. Its application to a large sample set of proximal femora provides strong statistics on the cortical bone structures morphology and distribution. Similarities observed between sides and sexes together with differences observed between sites could indicate that mechanical loading might be a main driver for bone microstructure. Additionally, the relationship between osteocyte lacunae density and bone areal fraction could suggest that bone porosity is regulated by osteocyte survival.

Osteoarthritis (OA) is associated with sclerosis, a thickening of the subchondral bone plate, yet little is known about bone adaptations around full-thickness cartilage defects in severe knee OA, particularly beneath bone-on-bone wear grooves. This high-resolution micro-computed tomography (microCT) study aimed to quantify subchondral bone microstructure relative to cartilage defect location, distance from the joint space, and groove depth. Ten tibial plateaus with full-thickness cartilage defects were microCT-scanned to determine defect location and size. Wear groove depth was estimated as the thickness from its deepest point to a surface interpolated from the defect edges. Two 5 × 5 mm specimens were sampled from three regions (defect, edge, and cartilage-covered areas) and two from the contralateral condyle, then scanned at higher resolution. Bone density profiles were analyzed as a function of distance from the joint space to identify cortical and trabecular regions of interest and and compute their respective bone density and microstructure. Cortical bone beneath defects was four times thicker under wear grooves than beneath cartilage. Bone density profiles significantly differed between the three specimen types at depths up to 5 mm. Below defects, cortical porosity was 85 % higher, and trabecular density 14 % higher, than in cartilage-covered specimens. Some trabecular spaces were filled with woven bone-like tissue, forming a new cortical layer. These changes were confined to the defect region and ceased abruptly at the defect edge. No correlation was found between bone microstructural indices and the estimated groove depth. Our findings suggest an ongoing migration of the cortical layer during formation of the groove from its original position into the underlying trabecular bone, a process we termed "trabecular corticalization." Under deeper wear grooves, the new cortical layer exhibited large pores connecting bone marrow to the joint space, suggesting physiological limits to corticalization. These results highlight specific bone adaptations beneath cartilage defects in severe OA and provide insights into the progression of subchondral bone changes under bone-on-bone contact areas.

The objective of this retrospective, database study was to characterize the rate, magnitude and timeline of increases in parathyroid hormone (PTH) levels post-denosumab (DMAb) vs. zoledronic acid (ZA) injection in patients with osteoporosis and near normal baseline PTH. Included were osteoporotic females, ≥50 years, initiating treatment with 60 mg DMAb or 5 mg ZA. PTH levels within 6-months post-DMAb or 12-months post-ZA injection were extracted from the electronic database of a 4.5 million-member health maintenance organization. The indication for PTH measurements was unknown. Exclusion criteria were creatinine >2 mg/dL, vitamin D < 50 nmol/L or parathyroid hormone level > 1.5 × upper limit of normal (ULN). Among 3317 women, 1992 received DMAb and 1325 ZA. The DMAb group was older (73.3 ± 8.5 vs. 69.8 ± 8.6 years, p < 0.001) and more patients treated with DMAb compared with patients treated with ZA had prior non-vertebral fractures (7.7 % vs. 5.2 %, p < 0.01) and had previously been treated with osteoporosis medication (56.3 % vs. 50.3 %, p < 0.001). Among the patients, 14.9 % had at least one post-treatment PTH > 1.5 ULN. Of 7273 post-treatment PTH tests, 62.6 % were within normal limits, while 24.8 % were mildly elevated at 1.01-1.5 ULN. Two-months after both treatments, >1.5 ULN PTH levels peaked at ∼20 %. Elevated PTH was associated with eGFR < 60 mL/min/1.73 m and comorbidities. In conclusion, most PTH levels post-DMAb or ZA in osteoporotic patients with baseline PTH < 1.5 ULN, were within normal range. PTH increased to >1.5 ULN in 14.9 % of patients; peaking in the first 2-months post-treatment and declining thereafter. Elevated PTH may be related to anti-resorptive effects and is not medication specific. PTH measurements in the first few months post-DMAb and ZA therapy should be limited.

This study aimed to assess the global burden of injuries due to low bone mineral density (BMD) among adults aged 55 and above from 1990 to 2021, focusing on mortality and disability-adjusted life years (DALYs) and analyzing trends across sexes, age groups, and sociodemographic index (SDI) regions.

Bone tissue is a biological composite material with a complex hierarchical structure that could continuously adjust its internal structure to adapt to the alterations in the external load environment. The fluid flow within bone is the main route of osteocyte metabolism, and the pore pressure as well as the fluid shear stress generated by it are important mechanical stimuli perceived by osteocytes. Owing to the irregular multiscale structure of bone tissue, the fluid stimulation that lacunar-canalicular network (LCN) in different regions of the tissue underwent remained unclear. In this study, we constructed a multiscale conduction model of fluid flow stimulus signals in bone tissue based on the poroelasticity theory. We analyzed the fluid flow behaviors at the macro-scale (whole bone tissue), macro-meso scale (periosteum, interstitial bone, osteon and endosteum), and micro-scale (lacunar-osteocyte-canalicular) levels. We explored how fluid stimulation at the tissue level correlated with that at the cellular level in cortical bone and characterized the distributions of the pore pressure, fluid velocity and fluid shear stress that the osteocytes experienced across the entire tissue structure. The results showed that the initial conditions of intramedullary pressure had a significant impact on the pore pressure of Haversian systems, but had a relatively small influence on the fluid velocity. The osteocyte which were located at different positions in the bone tissue received very distinct fluid stimuli. Osteocytes in the vicinity of the Haversian Canals experienced higher fluid shear stress stimulation. When the permeability of the LCN was within the range from 10 m to 10 m, the distribution of pressure, fluid velocity and fluid shear stress within the osteon near the periosteum and endosteum was significantly different from that in other parts of the bone. However, when the permeability was less than 10 m, such a difference did not exist. Particularly, the flow velocity at the lacunae was markedly higher than that in the canaliculi. Meanwhile, the pore pressure and fluid shear stress were conspicuously lower than those in the canaliculi. In this study, we considered the interconnections of different biofunctional units at different scales of bone tissue, construct a more complete multiscale model of bone tissue, and propose that osteocytes at different locations receive different fluid stimuli, which provides a reference for a deeper understanding of bone mechanotransduction.