Osteoporosis is a prevalent systemic metabolic disease, and an imbalance in the adipogenic and osteogenic differentiation of mesenchymal stem cells (MSCs) plays a crucial role in its pathogenesis. Thus, elucidating the mechanisms that regulate MSC lineage allocation is urgently needed. METTL9 was recently characterized as a novel N1-histidine methyltransferase that performs a wide range of functions. however, the role of METTL9 in the imbalance of MSC differentiation in osteoporosis remains unclear. In this study, we found that METTL9 expression was downregulated in osteoporosis, and further adipogenic functional experiments revealed that METTL9 negatively regulated the adipogenic differentiation of MSCs both in vitro and in vivo. Mechanistically, METTL9 mediated methylation of SLC39A7 at the His45 and His49 residues suppressed ferroptosis through the endoplasmic reticulum (ER) stress regulatory protein kinase R-like endoplasmic reticulum kinase (PERK)/ATF4 signaling pathway and the downstream protein SLC7A11. Moreover, SLC7A11 transported cystine for intracellular glutathione synthesis, eliminating intracellular reactive oxygen species (ROS) and inhibiting MSC adipogenic differentiation. Additionally, METTL9 overexpression significantly alleviated bone loss in ovariectomy (OVX) model mice. In summary, our results suggest that the METTL9/SLC39A7 axis may be a promising diagnostic and therapeutic target for osteoporosis.

In laying hens, maintaining optimal bone health and development from the early stages is crucial, as it directly affects their egg-laying efficiency, overall welfare and productivity. Studies have shown that grape polyphenols from Vitis vinifera enhance bone health in both humans and animals. Still, the mechanisms behind this effect remain unclear, given the diversity of grape polyphenols and their varying mechanisms of action. The objective of this study was to investigate the effect of a standardized dry grape extract (SDGE) on bone quality and metabolome of future laying hens reared in commercial conditions. Therefore, 36300 day-old pullets were randomly divided into two barns on the same farm site. Both received the same diet, with the addition of 30 mg/kg of SDGE (Nor-Grape®, Nor-Feed, France) from day 1 until week 17 in the supplemented group (SDGE). At the end of the supplementation period, several bone quality parameters were analyzed on 50 individuals per group. Additionally, non-targeted metabolomics on plasma and bones were performed to uncover the impact of SDGE supplementation on pullet's metabolome. Results demonstrated that keel bone deformity tended to improve following SDGE supplementation (P = 0.10). Moreover, SDGE intake significantly increased bone dry and mineral content, compared to the control group (P < 0.05) and tended to increase calcium (Ca) (P = 0.074) and phosphorus (P) content (P = 0.055). On the other hand, non-targeted metabolomics on plasma samples revealed an impact on fatty acids and glycerophospholipid metabolisms while bone samples analysis uncovered pathways related to sphingolipid and estrogen mediated signaling pathways. Overall, this study suggests novel mechanisms related to estrogen signaling through lipid metabolism in SDGE supplemented pullets and highlights that nutritional intervention with SDGE in early developmental stage of future laying hens improves their bone health prior to entry into the laying phase, thus proving a useful tool in bone health management.

Few studies have explored the association between the triglyceride-glucose (TyG) index and lumbar bone mineral density (BMD) across different skeletal sites in individuals with osteoporotic fractures (OPFs). The objective of this research was to investigate the relationship between the TyG index and lumbar BMD in individuals with OPFs. Conducted at the Affiliated Kunshan Hospital of Jiangsu University between January 2017 and March 2024, this retrospective cross-sectional study involved 950 OPFs patients requiring hospitalization or surgery. In this study, lumbar BMD the dependent variable, while the TyG index served as the independent variable. Generalized estimating equations (GEE) were used to evaluate the association between the TyG index and lumbar BMD levels. The generalized additive model (GAM) was employed to explore non-linear associations. In the all-adjusted models, a positive association was found between the TyG index and lumbar BMD among the patients with OPFs (β = 0.027; 95% confidence interval [CI] 0.011-0.042; P-value < 0.001). Similar results were observed across the four quantiles of the TyG index, Q4 (β = 0.045; 95% confidence interval [CI] 0.019-0.072; P-value < 0.001). A highly uniform pattern was noted across these findings. The evidence-based discovery of the relationship between the TyG index and lumbar BMD could inform clinical practices, particularly in the assessment and management of bone health in patients with OPFs.

Damage to the keel bone in commercial laying hens represent one of the greatest welfare issues in laying hens. This study aims to identify the DNA markers and candidate genes for bone strength and density traits in a Rhode Island Red laying hen population. We conducted genome-wide association studies (GWAS) on bone quality traits using a sample of 925 Rhode Island Red laying hens genotyped with a genotyping array consisting of 60 000 DNA markers. With a univariate linear mixed model, we identified 52 suggestive genetic markers located within 28 candidate genes that are associated with the humerus, keel, and tibia strength and density. We also found overlaps between the GWAS results for medullary bone score and tibia strength and density with published quantitative trait loci (QTL) for eggshell effective layer thickness and abdominal fat weight, respectively. Heritability estimates for the humerus stiffness, tibia stiffness, medullary bone score and minor bone diameter ranged from 0.21 to 0.34. Annotation term enrichment analysis of genes within 2 Megabases of suggestive markers found that mTOR signalling pathway, tryptophan metabolism, TGF-β signalling pathway, and apoptosis were significantly enriched. These loci do not overlap previously published associations, and thus appear to be novel.

This focused review concentrates on eight topics of high importance for Gaucher disease (GD) clinicians and researchers: 1) The consideration of GD as distinct types rather than a spectrum. A review of the literature clearly supports the view that there are distinct types of GD. Type 1 is characterized by the absence of primary neuronopathic involvement, while types 2 and 3 are characterized by progressive primary neuronopathic disease. 2) Neurologic and neuronopathic manifestations. A growing body of evidence indicates that the peripheral nervous system may be involved in GD type 1 and that there may also be signs and symptoms of central nervous system (CNS) disease in this group. However, GD type 1 is characterized by the absence of primary neuronopathic disease, whereas GD types 2 and 3 are characterized by progressive, albeit variable, primary neuronopathic disease. Abnormalities in saccadic eye movements have been suggested as being diagnostic for neuronopathic GD, but they may also occur in GD type 1 and in other inflammatory diseases. 3) The importance of whole GBA1 sequencing. This approach is superior to exome sequencing because of potential effects of deep intronic variants on gene expression. It also has the capacity to detect variant alleles that might be missed with gene panels. 4) Monoclonal gammopathy of undetermined significance (MGUS). The risks of MGUS, multiple myeloma, and non-Hodgkin's lymphoma are elevated in patients with GD compared to the general population and strong evidence indicates that lyso-Gb1 stimulates the formation of monoclonal immunoglobulins (M-protein) in patients with GD and MGUS. 5) Pulmonary involvement in GD. Pulmonary complications can be identified through spirometry in up to 45 % of patients with GD type 1 and 55 % of those with GD type 3. Limited evidence exists that enzyme replacement therapy (ERT) reduces the severity of these complications in patients with GD type 1. 6) Gaucheromas. These may occur in patients with GD types 1 or 3, but there is little detailed information about their inception, mechanisms underlying growth, cellular organization, and biochemical activities, and no definitive guidance for their management. Gaucheromas behave like benign (i.e. non-metastasizing) neoplasms, and it may be reasonable to classify them as such. 7) Bone and joint involvement. Dual-energy X-ray absorptiometry scans alone are insufficient for monitoring all changes in bone that may occur in patients with GD. Quantitative magnetic resonance imaging (MRI) techniques using Dixon quantitative chemical shift imaging have provided results that correlate with GD severity scores, bone complications, and biomarkers for GD bone involvement. Thoracic kyphosis is a common complication of GD types 1 and 3, and there is very limited information regarding the effects of ERT or substrate synthesis inhibition therapy (SSIT) on this condition. 8) Treatment initiation, selection, combination, and switching. Prompt initiation of treatment in pediatric patients is important as GD can lead to impaired growth, lower peak bone mass, and delayed puberty. These adverse outcomes can often be ameliorated or prevented with timely treatment. Either ERT or eliglustat, a SSIT agent, is suitable as first-line treatment of adults with GD. Studies of switching from ERT to eliglustat, or between different ERT products, have indicated that changing treatment is safe, although efficacy outcomes vary. A critical remaining issue is the lack of treatments capable of reaching the CNS to slow or halt the progression of neuronopathic disease in patients with GD type 2 or 3 and potentially reduce the risk of Parkinson's disease in GD type 1 patients and heterozygotes for GBA1 variants.

Adipose tissue is the primary site of energy storage in the body and a key regulator of metabolism. However, different adipose depots exhibit distinct molecular and phenotypic characteristics that have yet to be fully unraveled. While initially considered inert, bone marrow adipocytes (BMAs) have been recognized as key regulators of bone homeostasis, and more recently bone pathologies, although many unknowns remain. In this review, we summarize the current knowledge on BMAs, focusing on their distinct characteristics, functional significance in bone physiology and metabolism, as well as their emerging role in cancer pathogenesis. We present and discuss the current methodologies for investigating BMA-cancer interactions, encompassing both in vitro 3D culture systems and in vivo models, and their limitations in accurately replicating the phenotypes and biological processes of the human species. We highlight the imperative for advancing towards humanized models to better mimic the complexities of human physiology and disease progression. Finally, therapeutic strategies targeting metabolism or BMA-secreted factors, such as anti-cholesterol drugs, hold considerable promise in cancer treatment. We present the synergistic avenue of combining conventional cancer therapies with agents targeting adipocyte signaling to amplify treatment efficacy. Developing preclinical models that more faithfully replicate human pathological and physiological processes will lead to more accurate mechanistic understanding of the role of BMAs in bone metastasis and lead to more relevant preclinical drug screening.

Bone marrow is a complex tissue featuring distinct cellular organization and diverse cell types. Bone marrow adipose tissue (BMAT) is a dynamic component crucial for tissue function and disease processes. This study explores differences between bone marrow-derived mesenchymal stem cells (BM-MSCs) and BMAT-derived mesenchymal stem cells (BMAT-MSCs), isolated from the same cavity, examining their differentiation potential and secretory profiles. BM-MSCs and BMAT-MSCs both exhibit classical mesenchymal characteristics, with over 90 % positivity for markers such as CD105 and CD29. Notably, BMAT-MSCs display significantly higher differentiation potential than BM-MSCs, with enhanced osteogenic and adipogenic capabilities, as indicated by increased calcium accumulation and lipid storage. In Fanconi anemia (FA) and acute myeloid leukemia (AML), osteogenic potential is limited, indicating impaired differentiation under these pathological conditions. Gene expression analysis of adipogenic molecules and metabolic regulators revealed significant differences in expression profile between BM- and BMAT-MSCs, particularly during adipogenic differentiation, indicating distinct characteristics that were more notable in FAs and AMLs. Furthermore, metabolomic profiling of BM plasma, using GC-MS for in-vivo niche reflection, and lipid analysis via LC-qTOF-MS show significant lipidomic alterations in patient samples, highlighting metabolic dysregulation and lipid remodeling. Lipid-mediated signaling and membrane composition changes appear integral to disease mechanisms. In conclusion, this study highlights the distinctive molecular and metabolomic profiles and adaptive mechanisms of BM- and BMAT-MSCs in bone marrow pathologies.

Recent discoveries have shown that systemic manipulations, such as parabiosis, blood exchange, and young plasma transfer, can counteract many hallmarks of aging. This rejuvenation effect has been attributed to circulatory factors produced by cells from both hematopoietic and non-hematopoietic lineages. However, the specific involvement of bone marrow (BM) or hematopoietic cells in producing such factors and their effects on aging is still unclear. We developed a model of aged mice with transplanted young or old BM cells and assessed the impact on the aging process, specifically on energy metabolism and bone remodeling parameters. The donor BM cell engraftment in the aged mice was confirmed by flow cytometry using a transplanted cell-specific marker (green fluorescent protein). Energy metabolism was assessed using Oxymax indirect calorimetry system after 3 months of transplantation. Tibiae and L3-L4 vertebrae were analyzed using micro-CT, a three-point bending test and bone histomorphometry. Moreover, bone marrow proteome was assessed using proteomics, and blood serum/plasma was collected and analyzed using the Luminex assay. Our results showed that while the effect on energy metabolism was insignificant, rejuvenating the BM through young bone marrow transplantation reversed age-associated low bone mass traits in old mice. Specifically, young bone marrow transplantation improved bone trabecular microarchitecture both in tibiae and vertebrae of old mice and increased the number of osteoblasts and osteoclasts compared to old bone marrow transplantation. In conclusion, young bone marrow cells may represent a future therapeutic strategy for age-related diseases such as osteoporosis. The findings of this study provide important insights into our understanding of aging.

To explore the associations between hormones, metabolic markers, and low bone mass in perimenopausal and postmenopausal women.

A total of 198 women were enrolled in this study. The correlations between hormones, metabolic markers, and BMD were analyzed. Risk factors for bone loss were identified. Receiver operating characteristic (ROC) curves were used to display the predictive power of these risk factors.

The years since menopause and the levels of glucose (GLU), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were inversely correlated with BMD, while estrogen and testosterone were positively correlated with BMD. Age (odds ratio [OR] 1.232; 95% confidence interval [CI] 1.106-1.372; p < 0.001), GLU (OR 1.848; 95% CI 1.116-3.059; p = 0.017), and FSH (OR 1.089; 95% CI 1.003-1.182; p = 0.042) were identified as risk factors for bone loss. Age (AUC = 0.884, 95% CI 0.833-0.935), FSH (AUC = 0.824, 95% CI 0.760-0.888), and GLU (AUC = 0.683, 95% CI 0.599-0.768) demonstrated significant discrimination capability for bone loss. The combined application of these factors resulted in a better prediction effect (AUC = 0.930, 95% CI 0.893-0.967).

Age, FSH, and GLU were found to be specific risk factors for bone loss. The utilization of these factors offers compelling predictive power for bone loss in perimenopausal and postmenopausal women.

Chemical shift encoded-based water-fat separation magnetic resonance imaging (CSE-MRI) is an emerging noninvasive tool for the assessment of bone and muscle composition. This study aims to examine both the predictive value and the longitudinal change of proton density fat fraction (PDFF) and T2* in the paraspinal muscles (PSM) in patients with and without the development of an incidental vertebral compression fracture (VCFs) after 6 months of follow-up.

Patients (N=56) with CT and 3T CSE-MRI of the lumbar spine at baseline and CSE-MRI at 6 months follow-up were included in this retrospective study. Patients who, on average, developed an incidental VCF one year after baseline MRI (VCF: N=14, 9 males, 66.8 ± 7.9 years) were frequency matched by age and sex to patients without VCFs (non-VCF) at baseline and follow-up (non-VCF: N=42, 27 males, 64.6 ± 13.3 years). Mean PDFF, T2*, and cross-sectional area (CSA) values from the autochthonous PSM of the thoracolumbar spine (T11-L4) and opportunistic CT-based bone mineral density (BMD) measurements were obtained for each individual. The associations between baseline measurements, longitudinal changes in PDFF, T2*, CSA of the PSM and the occurrence of VCFs at follow-up were evaluated using linear and logistic multivariable regression models. ROC analyses were used to assess cutoff values for predicting the development of VCFs.

No significant difference in PDFF of the PSM was found between the VCF and non-VCF group at baseline (VCF/non-VCF 8.5 ± 13.8% vs. 5.0 ± 4.6%; p=0.53). In multivariable linear regression models adjusted for sex, age and baseline BMD, PDFF values of the PSM increased significantly over 6 months in the VCF group (2.4 ± 2.8% vs. -1.0 ± 2.3%, p<0.001), while T2* values of the PSM showed a significant decrease (p ≤ 0.01). ROC analyses identified a PDFF increase of 0.2% in the PSM as the optimal cutoff value to distinguish between patients with and without VCF (AUC 0.86, 95% CI [0.74-0.98], p<0.001).

Longitudinal PDFF-based assessment of the PSM composition may be a useful indicator for the prediction of the development of vertebral compression fractures.

Subsequent vertebral fracture (SVF) is a common and refractory complication after percutaneous vertebral augmentation (PVA) for osteoporotic vertebral compression fracture (OVCF). Computed tomography (CT)-based Hounsfeld units (HU) and magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score can evaluate osteoporosis quantitatively, hyperlipidemia(HLP) might affect measurement result of VBQ score. The primary objective of this study is to compare the predictive capabilities of HU and VBQ for SVF, and to clarify the impact of hyperlipidemia on the predictive abilities. This study included consecutive 341 patients with OVCF who were treated with PVA from March 1, 2020, to December 31, 2022. A multivariate logistic regression analysis was used to determine the relationship between HU and VBQ and SVF. ROC curves were plotted to calculate area under curve (AUC), and hoc analysis and Youden index was used to determine cut-off values of HU and VBQ. Compared with the non-SVF group, VBQ (4.69 ± 0.35 vs. 4.14 ± 0.41, P < 0.001) was higher and HU (58.2 ± 13.81 vs. 81.2 ± 16.68, P < 0.001) was lower in the SVF group. On multivariate logistic regression analysis, higher VBQ (odds ratio (OR) = 23.47,P < 0.001) and lower HU (OR = 0.93,P < 0.001) are independent predictors for SVF. The AUC using VBQ for predicting SVF was 0.84, the cut-off was 4.28. The AUC using HU for predicting SVF was 0.85, the cut-off was 64.40. In the HLP group, the AUC of VBQ was comparable with that of HU for SVF prediction, however, the sensitivity was lower in the HLP group (0.50 vs. 0.83). Furthermore, the AUC value of VBQ with HLP was lower than that of VBQ without HLP (0.78 vs. 0.90, P = 0.017). These findings demonstrated that both VBQ and HU can accurately predict the occurrence of SVF after PVA. HLP might cause a false increase of VBQ value, using HU could better assess bone quality and predict SVF occurrence when HLP is present.

TGF-β1 is the most abundant cytokine in bone, in which it serves as a vital factor to interdict adipogenesis and osteogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, how TGF-β1 concurrently manipulates differentiation into these two distinct lineages remains elusive.

Treatments with ligands or inhibitors followed by biochemical characterization, reporter assay, quantitative PCR and induced differentiation were applied to MSC line or primary BM-MSCs for signaling dissection. In vivo adipogenesis and ex vivo culture of bone explants were used to verify the functions of different SMAD complexes. Ingenuity Pathway Analysis, and analysis of transcriptomic datasets from human BM-MSCs in combination with hierarchical clustering and STRING assay were used to decipher the interplaying co-repressors. Mouse models of chronic and acute bone loss followed by biochemical assays and micro-computed tomography demonstrated the bone effects when functionally blocking the critical co-repressor HDAC1.

Distinct from the TGF-β1 inhibition on adipogenesis through canonical SMAD2/3 signaling, we clarified that TGF-β1 suppresses osteogenesis by inducing the formation of previously unidentified mixed SMADs mainly composed of SMAD1 and SMAD2, in which SMAD2 recruits more TGF-β1-induced co-repressors including HDAC1, TGIF1 and ATF3, whereas SMAD1 allows directing the whole transcriptional suppression complex to the cis-elements of osteogenic genes. Depletion of the cross-activation to the mixed SMADs dismantled specifically the TGF-β1 suppression on osteogenesis without affecting its inhibition on adipogenesis. Such phenomena can be reproduced via knockdown of co-repressors such as Hdac1 or addition of HDAC1 inhibitors in TGF-β1-treated MSCs. In either the chronic or the acute bone loss model, we demonstrated that the TGF-β signaling was augmented in the bone niche during osteolysis, whereas administration of HDAC1 inhibitors significantly improved bone quality.

This study identifies a new signal valve through which TGF-β1 can inhibit osteogenesis specifically. Functional interruption of this valve can tilt the seesaw balance of BM-MSC differentiation towards osteogenesis, highlighting the interplaying co-repressors, such as HDAC1, as promising therapeutic targets to combat diverse degenerative orthopedic diseases.

Limited whole genome sequencing (WGS) studies in Asian populations result in a lack of representative reference panels, thus hindering the discovery of ancestry-specific variants. Here, we present the South and East Asian reference Database (SEAD) panel ( https://imputationserver.westlake.edu.cn/ ), which integrates WGS data for 11,067 individuals from various sources across 17 Asian countries. The SEAD panel, comprising 22,134 haplotypes and 88,294,957 variants, demonstrates improved imputation accuracy for South Asian populations compared to 1000 Genomes Project, TOPMed, and ChinaMAP panels, with a higher proportion of well-imputed rare variants. For East Asian populations, SEAD shows concordance comparable to ChinaMAP, but outperforming TOPMed. Additionally, we apply the SEAD panel to conduct a genome-wide association study for total hip (Hip) and femoral neck (FN) bone mineral density (BMD) traits in 5369 genotyped Chinese samples. The single-variant test suggests that rare variants near SNTG1 are associated with Hip BMD (rs60103302, MAF = 0.0092, P = 1.67 × 10-7), and variant-set analysis further supports the association (Pslide_window = 9.08 × 10-9, Pgene_centric = 5.27 × 10-8). This association was not reported previously and can only be detected by using Asian reference panels. Preliminary in vitro experiments for one of the rare variants identified provide evidence that it upregulates SNTG1 expression, which could in turn inhibit the proliferation and differentiation of preosteoblasts.

The dual-energy spectral CT (DEsCT) employs material decomposition (MD) technology, opening up novel avenues for the opportunistic assessment of bone status. Radiomics, a powerful tool for elucidating the structural and textural characteristics of bone, aids in the detection of mineral loss. Therefore, this study aims to compare the efficacy of bone status assessment using both bone density measurements and radiomics models derived from MD images and to further explore the clinical value of radiomics models.

Retrospective data were collected from 307 patients who underwent both quantitative computed tomography (QCT) and full-abdomen DEsCT scans at our institution. Based on QCT measurements, patients were divided into three categories: normal bone mineral density (BMD), osteopenia, and osteoporosis. Using the abdominal DEsCT data, six types of MD images were reconstructed, including HAP (Water), HAP (Fat), Ca (Water), Ca (Fat), Fat (Ca), and Fat (HAP). Patients were randomly divided into a training cohort (n = 214) and a validation cohort (n = 93) at a ratio of 7:3. Focusing on the L1 to L3 vertebrae, density values from the six MD images were measured. Six density value models and six radiomics models were constructed using a random forest (RF) classifier. The performance of these models in assessing bone status was evaluated using the receiver operating characteristic (ROC) curves, and the DeLong test was employed to compare performance differences between the models.

The macro-area under the curve (AUC) values for the density value models based on HAP (Water), HAP (Fat), Ca (Water), and Ca (Fat) MD images were 0.870, 0.870, 0.847, and 0.765, respectively, which outperformed those of Fat (Ca) (AUC = 0.623) and Fat (HAP) (AUC = 0.618) density value models. In the comparison of radiomics models, the trends of model performance were consistent with the density value models across the six MD images. However, the models based on HAP (Water), Ca (Water), HAP (Fat), Ca (Fat), Fat (Ca), and Fat (HAP) images exhibited superior performance than those of the density value models with the corresponding MD images, with values of 0.946, 0.941, 0.934, 0.926, 0.831, and 0.824, respectively.

Bone status assessment can be accurately conducted using density values from HAP (Water), HAP (Fat), Ca (Water), and Ca (Fat) MD images. However, radiomics models derived from MD images surpass traditional density measurement methods in evaluating bone status, highlighting their superior diagnostic potential.

Bone marrow adipose tissue (BMAT) accrues in osteoporosis, whereas its contribution to the progression of bone resorption remains insufficiently understood. To understand the mechanisms that promote BMAT expansion in osteoporosis, in the present study, we performed extensive analysis of the spatiotemporal pattern of BMAT expansion during the progression of bone resorption in TgRANKL transgenic mouse models of osteoporosis expressing human RANKL (receptor activator of nuclear factor-κB ligand). Our results showed that TgRANKL mice of both sexes developed dramatically increased BMAT expansion compared to wild-type (WT) littermates, that was analogous to the levels of RANKL expression and the severity of the bone loss phenotype. BMAT was formed at close proximity to areas undergoing active bone remodelling and bone resorption, whereas bone resorption preceded BMAT development. Expression analysis in bone fractions demonstrated that BMAT constitutes a major source for RANKL production. Ex vivo analysis of isolated bone marrow stromal cells from TgRANKL mice showed an increased adipogenic differentiation capacity compared to WT, while osteoclast supernatants further exaggerated adipogenesis, supporting a critical role of the osteoclast-derived secretome in the differentiation of bone marrow adipocytes. Furthermore, the effectiveness of an antiosteoporosis treatment in BMAT development was investigated upon treatment of TgRANKL models with the bisphosphonate alendronate. Notably, alendronate effectively improved bone mass and attenuated BMAT expansion, indicating a possible involvement of osteoclasts and bone resorption in BMAT development. On the contrary, inhibition of BMAT with PPARγ antagonists (GW9662 or BADGE) effectively ameliorated BMAT expansion but failed to reverse the osteoporotic phenotype of TgRANKL mice. Overall, our data demonstrate that TgRANKL mice constitute unique genetic mouse models for investigating the pathogenic mechanisms that regulate the development and expansion of BMAT in osteolytic diseases.

Objective: Imaging biomarkers of bone, muscle, and fat by magnetic resonance imaging (MRI) may depict osteopenia, sarcopenia, and adiposity as the three different conditions of osteosarcopenic adiposity (OSA). Methods: Subjects from a prospective, population-based case-control study underwent a health assessment and 3 Tesla whole-body MRI scan. Imaging biomarkers of bone (bone marrow fat-fraction (BMFF)), skeletal muscle (skeletal muscle FF (SMFF)), and fat (total adipose tissue (TAT)) were determined. Participants were allocated to one phenotype according to the OSA complex. Results: Among 363 participants forming the study cohort, 81 (22.3%, 48.1% males, 62.4 ± 6.9 years) were allocated into the OSA subgroup. Participants with an OSA phenotype were significantly older compared to all remaining subjects and showed the highest grades of SMFF (all p < 0.005). Together with subjects from the osteopenic sarcopenia group, OSA subjects exhibited the highest amounts of BMFF and together with the three other adiposity-containing subgroups also exhibited the highest BMIs. The highest prevalence of an impaired glucose tolerance as well as significantly higher blood pressure, blood dyslipidemia, and hepatic steatosis was found in the OSA subgroup (all p < 0.005). Conclusions: MR biomarkers of bone, skeletal muscle and fat are feasible for body composition phenotyping and may allow for targeted risk stratification in suspected OSA syndrome.

Oxytocin (OXT) is a neurohypophysial nonapeptide that exerts its effects mainly through the oxytocin receptor (OXTR). Several studies have pointed out the role of OXT in the modulation of stem cell (SC) fate and properties. SCs are undifferentiated cells characterized by a remarkable ability to self-renew and differentiate into various cell types of the body. In this review, we focused on the role of OXT in SC differentiation. Specifically, we summarize and discuss the scientific research examining the effects of OXT on mesodermal SC-derived lineages, including cardiac, myogenic, adipogenic, osteogenic, and chondrogenic differentiation. The available studies related to the effects of OXT on SC differentiation provide little insights about the molecular mechanism mediated by the OXT-OXTR pathway. Further research is needed to fully elucidate these pathways to effectively modulate SC differentiation and develop potential therapeutic applications in regenerative medicine.

Metabolic bone diseases (MBDs) are a diverse group of diseases, affecting the mass or structure of bones and leading to reduced bone quality. Parameters representing different aspects of bone health can be obtained from various magnetic resonance imaging (MRI) methods such as proton MR spectroscopy, as well as chemical shift encoding-based water-fat imaging, that have been frequently applied to study bone marrow in particular. Furthermore, T2* mapping and high-resolution trabecular bone imaging have been implemented to study bone microstructure. In addition, quantitative susceptibility mapping and ultrashort echo time imaging are used for trabecular and cortical bone assessment. This review offers an overview of technical aspects, as well as major clinical applications and derived main findings, for MRI-based assessment of bone quality in MBDs. It focuses on osteoporosis as the most common MBD.

Histone deacetylase 3 (Hdac3) is an epigenetic regulator of gene expression and interacts with skeletal transcription factors such as Runx2. We previously reported that conditional deletion of Hdac3 in Osterix-Cre recombinase-expressing osteoprogenitor cells (Hdac3 CKOOsx) caused osteopenia and increased marrow adiposity, both hallmarks of skeletal aging. We also showed that Runx2+ cells within osteogenic cultures of Hdac3-depleted bone marrow stromal cells (BMSCs) contain lipid droplets (LDs). Cellular senescence, a nonproliferative metabolically active state, is associated with increased marrow adiposity, bone loss, and aging. In this study, we sought to determine if Hdac3 depleted Runx2+ pre-osteoblasts from young mice exhibit chromatin changes associated with early cellular senescence and how these events correlate with the appearance of LDs. We first confirmed that BMSCs from Hdac3 CKOOsx mice have more Runx2 + LD+ cells compared with controls under osteogenic conditions. We then measured senescence-associated distention of satellite (SADS) DNA and telomere-associated foci (TAFs) in Hdac3 CKOOsx and control BMSCs. In situ, Runx2+ cells contained more SADS per nuclei in Hdac3 CKOOsx femora than in controls. Runx2+ BMSCs from Hdac3 CKOOsx mice also contained more SADS and TAFs per nuclei than Runx2+ cells from age-matched control mice in vitro. SADs and TAFs were present at similar levels in Runx2 + LD+ cells and Runx2 + LD- cells from Hdac3 CKOOsx mice. Hdac inhibitors also increased the number of SADS in Runx2 + LD+ and Runx2 + LD- WT BMSCs. Senolytics reduced viable cell numbers in Hdac3 CKOOsx BMSC cultures. These data demonstrate that the depletion of Hdac3 in osteochondral progenitor cells triggers LD formation and early events in cellular senescence in Runx2+ BMSCs through mutually exclusive mechanisms.

Osteoporosis and fragility fractures are crucial musculoskeletal complications in long-term survivors of gastric cancer. However, the relationship between changes in body composition after gastrectomy and bone loss has not been investigated. Therefore, this study aimed to explore whether computed tomography (CT)-derived body composition parameters are associated with bone loss after gastrectomy in patients with gastric cancer.

We retrospectively reviewed medical records and abdomen CT scans of patients who underwent gastrectomy at Yonsei University Severance Hospital between 2009 and 2018. Patients with non-metastatic gastric adenocarcinoma and preoperative and postoperative non-contrast CT scans were analyzed. Section area of skeletal muscle (SMA), visceral fat (VFA), and subcutaneous fat (SFA) were assessed using semi-automatic segmentation software. Changes in trabecular bone attenuation of L1 mid-vertebra level (L1 Hounsfield units [HU]) were measured.

Fifty-seven patients (mean age, 65.5±10.6; 70.2% males) were analyzed, and the median duration was 31 months. Fortyseven patients (82.5%) lost weight after gastrectomy. Baseline SMA and VFA did not differ between the bone loss and preserved groups; however, baseline SFA was significantly higher in the bone preserved group than in the bone loss group (P=0.020). In a multivariable linear regression model adjusted for confounding factors, one standard deviation higher VFA at baseline was associated with greater annualized L1 HU loss (%) (P=0.034). However, higher preoperative SFA was associated with protection against bone loss after gastrectomy (P=0.025).

Higher preoperative SFA exhibited a protective effect against bone loss after gastrectomy in patients with non-metastatic gastric cancer, whereas VFA exhibited a negative effect.

Background: For years, bone mineral density (BMD) has played a key role in assessing bone health, but the trabecular bone score (TBS) is emerging as an equivalent measure. However, BMD alone may not fully measure bone quality or predict osteoporosis risk. To evaluate the usefulness of TBS and BMD in estimating the risk of bone fracture in young women with FHA, this study examined the association between metabolic parameters and bone quality, which was measured using TBS and BMD. Methods: We analyzed the association of metabolic factors with tests assessing bone quality-TBS and BMD. Patients were checked for BMI, measured body fat, and determined serum glucose levels and insulin levels in a 75g glucose load test. Spearman correlation analysis was used. Results: Significant positive correlations were found between BMD and age (p < 0.001) and body fat (p < 0.001), as well as between TBS values and BMI (p < 0.001) and TBS and percent body fat (p < 0.001). Of the variables analyzed in the multivariate analysis, the only independent predictor of higher bone mineral density in the lumbar spine was found to be higher values of the trabecular bone index in the same segment (p < 0.001). Conclusions: The use of TBS provides a simple tool for estimating the risk of bone damage. Ultimately, early screening, diagnosis and treatment of patients with FHA may help prevent osteoporosis and fragility fractures in the long term.

The brain-bone axis has emerged as a captivating field of research, unveiling the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This comprehensive review delves into the current state of knowledge surrounding the brain-bone axis, exploring the complex mechanisms, key players, and potential clinical implications of this fascinating area of study. The review discusses the neural regulation of bone metabolism, highlighting the roles of the sympathetic nervous system, hypothalamic neuropeptides, and neurotransmitters in modulating bone remodeling. In addition, it examines the influence of bone-derived factors, such as osteocalcin and fibroblast growth factor 23, on brain function and behavior. The therapeutic potential of targeting the brain-bone axis in the context of skeletal and neurological disorders is also explored. By unraveling the complex interplay between the CNS and skeletal metabolism, this review aims to provide a comprehensive resource for researchers, clinicians, and students interested in the brain-bone axis and its implications for human health and disease.

Norisoboldine (NOR) is a major isoquinoline alkaloid component in the traditional Chinese herbal plant Lindera aggregata (Sims) Kosterm, with previously reported anti-osteoclast differentiation and antiarthritis properties. However, the roles of NOR on osteoblasts, bone marrow mesenchymal stem cells (BMSCs), and osteoporosis in vivo have never been well established.

This study investigates the ability of NOR to improve bone formation in vitro and in vivo. Osteoblasts and BMSCs are used to study the effect of NOR on osteogenic and adipogenic differentiation. It finds that NOR promotes osteogenic differentiation of osteoblasts and BMSCs, while inhibiting adipogenic differentiation of BMSCs by reducing the relative expression of peroxisome proliferator-activated receptor γ (Ppar-γ) and adiponectin, C1Q and collagen domain containing (Adipoq). Mechanistic studies show that NOR increases osteoblast differentiation through the mechanistic target of rapamycin kinase (mTOR)/ribosomal protein S6 kinase; polypeptide 1 (S6K1) pathway, and treatment with an mTOR inhibitor rapamycin blocked the NOR-induced increase in mineral accumulation. Finally, the study evaluates the therapeutic potential of NOR in a mouse model of ovariectomy (OVX)-induced bone loss. NOR prevents bone loss in both trabecular and cortical bone by increasing osteoblast number and phospho-S6K1 (p-S6K1) expression in osteoblasts.

NOR effects in enhancing osteoblast-induced bone formation via S6K1 pathway, suggesting the potential of NOR in osteoporosis treatment by increasing bone formation.

Magnetic resonance Z-spectral imaging (ZSI) has emerged as a new approach to measure fat fraction (FF). However, its feasibility for fat spectral imaging remains to be elucidated. In this study, a single-slice ZSI sequence dedicated to fat spectral imaging was designed, and its capability for fatty acid characterization was investigated on peanut oil samples, a multiple-vial fat-water phantom with varied oil volumes, and vertebral body marrow in healthy volunteers and osteoporosis patients at 3 T. The peanut oil spectrum was also recorded with a 400-MHz NMR spectrometer. A Gaussian-Lorentzian sum model was used to resolve water and six fat signals of the pure oil sample or four fat signals of the fat-water phantom or vertebral bone marrow from Z spectra. Fat peak amplitudes were normalized to the total peak amplitude of water and all fat signals. Normalized fat peak amplitudes and FF were quantified and compared among vials of the fat-water phantom or between healthy volunteers and osteoporosis patients. An unpaired student's t-test and Pearson's correlation were conducted, with p less than 0.05 considered statistically significant. The results showed that the peanut oil spectra measured with the ZSI technique were in line with respective NMR spectra, with amplitudes of the six fat signal peaks significantly correlated between the two methods (y = x + 0.001, r = 0.996, p < 0.001 under a repetition time of 1.6 s; and y = 1.026x - 0.003, r = 0.996, p < 0.001 under a repetition time of 3.1 s). Moreover, ZSI-measured FF exhibited a significant correlation with prepared oil volumes (y = 0.876x + 1.290, r = 0.996, p < 0.001). The osteoporosis patients showed significantly higher normalized fat peak amplitudes and FF in the L4 vertebral body marrow than the healthy volunteers (all p < 0.01). In summary, the designed ZSI sequence is feasible for fatty acid characterization, and has the potential to facilitate the diagnosis and evaluation of diseases associated with fat alterations at 3 T.

Obesity, type 2 diabetes mellitus (T2DM) and osteoporosis are serious diseases with an ever-increasing incidence that quite often coexist, especially in the elderly. Individuals with obesity and T2DM have impaired bone quality and an elevated risk of fragility fractures, despite higher and/or unchanged bone mineral density (BMD). The effect of obesity on fracture risk is site-specific, with reduced risk for several fractures (e.g., hip, pelvis, and wrist) and increased risk for others (e.g., humerus, ankle, upper leg, elbow, vertebrae, and rib). Patients with T2DM have a greater risk of hip, upper leg, foot, humerus, and total fractures. A chronic pro-inflammatory state, increased risk of falls, secondary complications, and pharmacotherapy can contribute to the pathophysiology of aforementioned fractures. Bisphosphonates and denosumab significantly reduced the risk of vertebral fractures in patients with both obesity and T2DM. Teriparatide significantly lowered non-vertebral fracture risk in T2DM subjects. It is important to recognize elevated fracture risk and osteoporosis in obese and T2DM patients, as they are currently considered low risk and tend to be underdiagnosed and undertreated. The implementation of better diagnostic tools, including trabecular bone score, lumbar spine BMD/body mass index (BMI) ratio, and microRNAs to predict bone fragility, could improve fracture prevention in this patient group.

Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (knockout [KO]), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low-calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.

MR imaging-based proton density fat fraction (PDFF) and T2* imaging has shown to be useful for the evaluation of degenerative changes in the spine. Therefore, the aim of this study was to investigate the influence of myelotoxic chemotherapy on the PDFF and T2* of the thoracolumbar spine in comparison to changes in bone mineral density (BMD).

In this study, 19 patients were included who had received myelotoxic chemotherapy (MC) and had received a MR imaging scan of the thoracolumbar vertebrates before and after the MC. Every patient was matched for age, sex, and time between the MRI scans to two controls without MC. All patients underwent 3-T MR imaging including the thoracolumbar spine comprising chemical shift encoding-based water-fat imaging to extract PDFF and T2* maps. Moreover, trabecular BMD values were determined before and after chemotherapy. Longitudinal changes in PDFF and T2* were evaluated and compared to changes in BMD.

Absolute mean differences of PDFF values between scans before and after MC were at 8.7% (p = 0.01) and at -0.5% (p = 0.57) in the control group, resulting in significantly higher changes in PDFF in patients with MC (p = 0.008). BMD and T2* values neither showed significant changes in patients with nor in those without myelotoxic chemotherapy (p = 0.15 and p = 0.47). There was an inverse, yet non-significant correlation between changes in PDFF and BMD found in patients with myelotoxic chemotherapy (r = -0.41, p = 0.12).

Therefore, PDFF could be a useful non-invasive biomarker in order to detect changes in the bone marrow in patients receiving myelotoxic therapy.

Using PDFF as a non-invasive biomarker for early bone marrow changes in oncologic patients undergoing myelotoxic treatment may help enable more targeted countermeasures at commencing states of bone marrow degradation and reduce risks of possible fragility fractures.

Quantifying changes in bone marrow fat fraction, as well as T2* caused by myelotoxic pharmaceuticals using proton density fat fraction, is feasible. Proton density fat fraction could potentially be established as a non-invasive biomarker for early bone marrow changes in oncologic patients undergoing myelotoxic treatment.

The objective of this review is to summarize the literature on the prevalence and diagnosis of obesity and its metabolic profile, including bone metabolism, focusing on the main inflammatory and turnover bone mediators that better characterize metabolically healthy obesity phenotype, and to summarize the therapeutic interventions for obesity with their effects on bone health.

Osteoporosis and fracture risk not only increase with age and menopause but also with metabolic diseases, such as diabetes mellitus. Thus, patients with high BMI may have a higher bone fragility and fracture risk. However, some obese individuals with healthy metabolic profiles seem to be less at risk of bone fracture. Obesity has become an alarming disease with growing prevalence and multiple metabolic comorbidities, resulting in a significant burden on healthcare and increased mortality. The imbalance between increased food ingestion and decreased energy expenditure leads to pathological adipose tissue distribution and function, with increased secretion of proinflammatory markers and harmful consequences for body tissues, including bone tissue. However, some obese individuals seem to have a healthy metabolic profile and may not develop cardiometabolic disease during their lives. This healthy metabolic profile also benefits bone turnover and is associated with lower fracture risk.

Poor eating habits and a sedentary lifestyle can impair health. Regular physical activity improves the quality of life and is essential for bone health. Therefore, the present study aimed to evaluate the effects of the cafeteria diet on bone quality of sedentary and exercised rats.

Sixty young male Wistar rats were divided into six groups (n=10) according to diet composition and activity level, being: SD+CON, standard diet and control; SD+SED, standard diet and sedentary; SD+EX, standard diet and exercised; CD+CON, cafeteria diet and control; CD+SED, cafeteria diet and sedentary; CD+EX, cafeteria diet and exercised. The exercise protocol consisted of 10 ladder-climbing sessions/day, 5 days/week, and the sedentary rats were maintained in individual cages with limited mobility. Body mass and food intake were evaluated weekly. After 10 weeks, the animals were euthanized, and white adipose tissue was collected. The bone structure was evaluated by densitometry, mechanical tests, histomorphometric, and micro-computed tomography analyses.

The cafeteria diet increased adipose tissue (p<0.001), decreased bone mineral density (p=0.004), and impaired biomechanical properties (p<0.05) and histomorphometry parameters (p=0.044). The sedentarism decreased bone mineral density (p<0.001) and biomechanical properties (p<0.05), and the exercise did not improve bone properties.

In this experimental model, it was concluded that the cafeteria diet and a sedentary lifestyle negatively affect bone, and ladder-climbing exercise could not prevent the effects of the unhealthy diet.

Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (KO), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.

Obesity induced by a high-fat (HF) diet increases bone resorption and/or decreases bone formation, resulting in reduced bone mass and strength in various animal models. Studies showed that Ca intake is a modifiable factor for osteoporosis and obesity. This study investigated whether Ca deficiency affects bone structure and adiposity in ovariectomized (OVX) rats fed a HF diet. We hypothesized that Ca deficiency further decreases bone mass and increases fat mass in HF-fed OVX rats. Forty-seven OVX at 6-month-old were randomly assigned to four groups in a 2 × 2 factorial design: normal-fat (NF, 10% fat as energy) or HF (45% fat as energy) diet with either low Ca (LC, 1 g/4057 kcal) or normal Ca (NC, 6 g/4057 kcal). In addition, 12 sham-operated rats at 6 months old were fed a NFNC diet as a control for the OVX procedure. Rats were fed the respective diet for 4 months. Dietary Ca content did not affect body weight, fat mass, lean mass, food intake, energy intake, and serum cytokines. Compared to NC, LC resulted in lower tibial bone volume/total volume (BV/TV, p < 0.01), connectivity density (p < 0.01), trabecular number (Tb.N, p = 0.01), bone mineral density (BMD, p < 0.01), and femur weight (p < 0.01), femur content of Ca (p < 0.01), Cu (p = 0.03), Zn (p < 0.01), and greater trabecular separation (Tb.Sp, p < 0.01) at proximal tibia indicating bone structure deterioration. Compared to rats on the NF diet, animals fed the HF had lower BV/TV (p = 0.03) and Tb.N (p < 0.01) with greater body weight (p < 0.01), fat mass (p < 0.01), Tb.Sp (p = 0.01), the content of Ca, Cu, and Zn in the femur, and serum leptin (p < 0.01). There were no significant interactions between Ca and fat for body composition and bone structural parameters. Compared to Sham, OVX resulted in greater body weight and fat mass. The trabecular bone structure of the tibia, but not the cortical bone, was significantly impaired by the OVX procedure. These data indicate that inadequate Ca intake and a high-fat diet have independent negative effects on bone structure and that Ca deficiency does not affect adiposity in OVX rats.

Skeletal fracture has recently emerged as a complication of obesity. Given the normal or better than normal bone mineral density (BMD), the skeletal fragility of these patients appears to be a problem of bone quality rather than quantity. Type 2 diabetes mellitus (T2DM), the incidence of which increases with increasing body mass index, is also associated with an increased risk for fractures despite a normal or high BMD. With the additional bone pathology from diabetes itself, patients with both obesity and T2DM could have a worse skeletal profile. Clinically, however, there are no available methods for identifying those who are at higher risk for fractures or preventing fractures in this subgroup of patients. Weight loss, which is the cornerstone in the management of obesity (with or without T2DM), is also associated with an increased risk of bone loss. This review of the literature will focus on the skeletal manifestations associated with obesity, its interrelationship with the bone defects associated with T2DM, and the available approach to the bone health of patients suffering from obesity.

This pilot study aimed to explore the feasibility of scanning the human distal radius bone marrow in vivo to detect osteoporosis-related changes using magnetic resonance and evaluate whether the radius may serve as an accessible probing site for osteoporosis. This may lead in the future to the use of affordable means such as low-field MRI scanners for the monitoring of disease progression.

A clinical trial was performed using a 3T MR scanner, including 26 women assigned into three study groups: healthy-premenopausal (n = 7; mean age 48.6 ± 3.5 years), healthy-postmenopausal (n = 10; mean age 54.5 ± 5.6 years), and osteoporotic-postmenopausal (n = 9; mean age 61.3 ± 5.6 years). Marrow fat composition was evaluated using T2 maps, a two-compartment model of T1, and a Dixon pulse sequence.

The osteoporotic group exhibited higher fat content than the other two groups and lower T2 values than the healthy-premenopausal group.

Osteoporosis-related changes in the composition of the distal radius bone marrow may be detected in vivo using MRI protocols. The scanning protocols chosen here can later be repeated using low-field MRI scanners, thus offering the potential for early detection and treatment monitoring, using an accessible, affordable means that may be applied in small clinics. This trial is registered with MOH_2018-05-23_002247, NCT03742362.

Bone fragility is an emerging complication of diabetes. People with diabetes are at a significantly higher risk of fractures compared to the general population. Bone fragility occurs in diabetes as a result of complex and poorly understood mechanisms occurring at the cellular level contributed by vascular, inflammatory and mechanical derangements. Bone mineral density (BMD) as assessed by DEXA is low in type 1 diabetes. Type 2 diabetes has a high risk of fracture despite a normal to raised BMD. DEXA thus underestimates the fracture risk in diabetes. Data are scare regarding the efficacy of the available therapies in this low bone turnover state.

While osteoporosis is reliably diagnosed using dual energy X-ray absorptiometry (DXA), screening rates are alarmingly low, contributing to preventable fractures. Raman spectroscopy (RS) can detect biochemical changes that occur in bones transcutaneously and can arguably be more accessible than DXA as a fracture risk assessment. A reasonable approach to translate RS is to interrogate phalangeal bones of human hands, where the soft tissues covering the bone are less likely to hamper transcutaneous measurements. To that end, we set out to first determine whether Raman spectra obtained from phalangeal bones correlate with distal radius fracture strength, which can predict subsequent osteoporotic fractures at the spine and hip. We performed RS upon diaphyseal and epiphyseal regions of exposed proximal phalanges from 12 cadaver forearms classified as healthy (n = 3), osteopenic (n = 4), or osteoporotic (n = 5) based on wrist T-scores measured by DXA. We observed a significant decrease in phosphate to matrix ratio and a significant increase in carbonate substitution in the osteoporotic phalanges relative to healthy and osteopenic phalanges. Multivariate regression models produced wrist T-score estimates with significant correlation to the DXA-measured values (r = 0.79). Furthermore, by accounting for phalangeal RS parameters, body mass index, and age, a multivariate regression significantly predicted distal radius strength measured in a simulated-fall biomechanical test (r = 0.81). These findings demonstrate the feasibility of interrogating the phalanges using RS for bone quality assessment of distant clinical sites of fragility fractures, such as the wrist. Future work will address transcutaneous measurement challenges as another requirement for scale-up and translation.

Previous studies have revealed the protective effects of statins on bone but the association of statins use with osteoporosis-related measurement has shown controversial results. In this study, we found an age, dose andduration-dependent osteoprotective effect of statins in general older population.

Previous studies have revealed the protective effects of statins on bone but the association of statins use with osteoporotic fractures has shown controversial results.

In this study with Korean National Health Insurance Service-Senior cohort database, a total of 365,656 elderly without previous history of osteoporosis and who were started on statin since January 1 2004 were included and observed until December 31 2012. Hazard rations (HR) for major osteoporotic fractures were calculated using the weighted Cox proportional hazards model with inverse-probability of treatment weighting method.

During 6.27 years of follow-up period, 54,959 osteoporotic fractures occurred and the majority of fractures (69.5%) were vertebral fractures. Compared with non-users, statin use was associated with a decreased risk of all outcomes with adjusted HR (95% CI) of 0.77 (0.72-0.83; P < 0.001) for major osteoporotic fractures, 0.49 (0.38-0.62; P < 0.001) for hip fractures, and 0.70 (0.64-0.77; P < 0.001) for vertebral fractures. When outcomes were examined separately by sex, the results were broadly comparable in terms of patterns of risk reduction by statin use. The patients with statin initiated at age ≥ 80 years had the highest risk reduction for most outcomes relative to non-users. Higher cumulative dose of statin was negatively associated with the osteoporotic fracture risk; 0.97 (0.91-1.02) for 30-364 cumulative daily defined dose (cDDD), 0.45 (0.40-0.51) for 365-1,094 cDDD, and 0.22 (0.15-0.33) for ≥ 1,095 cDDD.

Our results showed that statin use was associated with significant reduction in the risk of osteoporotic fractures in general older population.

Adipose tissue is a dynamic component of the bone marrow, regulating skeletal remodelling and secreting paracrine and endocrine factors that can affect haematopoiesis, as well as potentially nourishing the bone marrow during periods of stress. Bone marrow adipose tissue is regulated by multiple factors, but particularly nutrient status. In this Review, we examine how bone marrow adipocytes originate, their function in normal and pathological states and how bone marrow adipose tissue modulates whole-body homoeostasis through actions on bone cells, haematopoietic stem cells and extra-medullary adipocytes during nutritional challenges. We focus on both rodent models and human studies to help understand the unique marrow adipocyte, its response to the external nutrient environment and its effects on the skeleton. We finish by addressing some critical questions that to date remain unanswered.

Introduction: In the rapidly aging U.S. population, age-induced bone loss (senile osteoporosis) represents a major public health concern that is associated with a significant increased risk for low trauma fragility fractures, which are debilitating to patients, cause significant morbidity and mortality, and are costly to treat and manage. While various treatments exist to slow bone loss in osteoporosis patients, these suffer from poor tolerability and label restrictions that limit their overall effectiveness. Over the past decade, skeletal stem/progenitor cells (SSPCs), which are the main precursor of osteoblasts and adipocytes in adult bone marrow (BM), have emerged as important players in osteoporosis. Methods: Age-induced skeletal pathology was quantified in elderly (24-month-old) vs. mature (3-month-old) mice by micro-CT and changes in SSPC abundance in the BM of these mice was quantified by fluorescence-activated cell sorting (FACS). SSPCs from elderly vs. mature mice were also analyzed by RNA-Seq to identify differentially expressed genes (DEGs), and gain and loss-of-function studies were performed in human BM-derived mesenchymal stromal cells (BM-MSCs) to assess A2M function. Results: Elderly mice were shown to exhibit significant age-induced skeletal pathology, which correlated with a significant increase in SSPC abundance in BM. RNA-seq analysis identified alpha-2-macroglobulin (A2M), a pan-protease inhibitor that also binds inflammatory cytokines, as one of the most downregulated transcripts in SSPCs isolated from the BM of elderly vs. mature mice, and silencing of A2M expression in human BM-MSCs induced their proliferation and skewed their lineage bifurcation toward adipogenesis at the expense of osteogenesis thereby recapitulating critical aspects of age-induced stem cell dysfunction. Conclusion: These findings identify A2M as a novel disease modifying protein in osteoporosis, downregulation of which in bone marrow promotes SSPC dysfunction and imbalances in skeletal homeostasis.