Bone remodeling is regulated by circadian rhythm, yet the molecular mechanisms linking circadian clock components to osteoclast function remain largely undefined. We previously showed that osteoclast-specific deletion of Per1, a core circadian regulator, increased osteoclastogenesis and reduced bone mass in male mice, whereas deletion of Per2 had little effect. Here, we investigated Per1;Per2 conditional double-knockout (dKO) mice and unexpectedly found the opposite phenotype. In contrast to Per1 deficiency, dKO suppressed osteoclastogenesis and increased bone mass specifically in male mice, revealing previously unrecognized functional interactions between PER1 and PER2 in osteoclasts. Transcriptomic analyses showed that dKO osteoclasts preferentially downregulated innate immunity genes, including both positive and negative regulators of osteoclastogenesis. Chromatin immunoprecipitation and reporter assays further identified innate immunity genes as downstream targets of PER-dependent circadian regulation. These findings indicate that PER1 and PER2 regulate osteoclastogenesis through coordinated control of a network of immune genes with opposing effects on osteoclast differentiation, rather than acting as simple promoters or inhibitors of bone resorption. More broadly, this study establishes innate immunity as a mechanistic interface between the circadian clock and osteoclast function, providing a framework for understanding how circadian disruption influences bone remodeling and inflammatory bone diseases.
The synovial joints are essential for skeletal function and dexterity and do so by virtue of their components and structure. The capsule protects and insulates the joint from the surrounding environment, articular cartilage provides mechanical resilience and endurance, the ligaments stabilize motion, and the synovial cavity and fluid sustain frictionless sliding. These and other fundamental aspects of synovial joint biology are well known and recognized. However, how the joints form during embryogenesis and acquire their components and functional attributes remains unclear. Happily, the last few years of research have provided new insights into limb joint development. In particular, new light has been shed on: morphogenetic mechanisms establishing the mesenchymal interzone which is the cradle of joint tissue progenitors; spatio-temporal processes endowing the joint progenitors with distinct developmental and tissue forming potentials; osmoregulatory and hydraulic forces set by Na/K-ATPase ion pumps that bring about joint cavitation and fluid accrual; cellular and signaling mechanisms establishing articular cartilage's zonal organization; and potentials of embryonically-derived progenitors residing in adult joints to engage in repair. This review describes and comments on those new studies, frames them within the broader field of joint research, and identifies lingering questions. Clinically, the treatment of joint disease remains ineffective and new directions and strategies are needed to move forward. Studies on synovial joint development are poised to provide such new directions and bring about future regenerative tools based on principles and mechanisms of developmental biology. This review is meant to highlight the potentials of such basic-to- translational-to-clinical strategies and provides an overall framework for research goals ahead.
Patients receiving dialysis face a 5-fold higher risk of skeletal fractures compared to the general population, along with increased mortality and a longer hospital stay after a fracture. However, fracture risk varies among patients, and reliable methods to assess risk are limited. Using linked healthcare databases, we conducted a population-based cohort study of adults aged 40-90 years receiving maintenance dialysis with an available parathyroid hormone (PTH) value in Ontario, Canada (2010-2017). Patients were followed for 3 years or until death, first major fracture, or provincial emigration. Using Fine and Gray subdistribution hazards models accounting for the competing risk of death, we developed a fracture prediction tool (Dial-Frac) that included demographic, comorbidity, and laboratory information. Models were compared using measures of discrimination, calibration, and model fit and were internally validated using 10-fold cross-validation. The cohort included 11,599 patients receiving dialysis. Mean age was 66 years; 39% were female, and 12% had a previous fracture. Over 3 years, 839 patients (7.2%) experienced a fracture (44% of which occurred in the first year); hip fracture was most common (299/839). The final prediction model included age, sex, previous fracture, previous kidney transplant, proton pump inhibitor use, and PTH and serum albumin concentrations. The time dependent area under the receiver operating curve for fracture at 1 and 3 years were 0.79 and 0.71, respectively, indicating good discrimination. We developed Dial-Frac, an easy-to-implement equation that predicts fracture risk in patients receiving maintenance dialysis. It predicts risk at 1 and 3 years without requiring bone density measurements or additional tests, helping to identify high-risk patients for further screening, preventive interventions and clinical trial participation. Next steps include external validation.
Although bone loss progresses rapidly in older adults, its biological drivers are poorly understood, and effective biomarkers are not available. We used large-scale discovery proteomics to identify serum proteins associated with bone loss, and to develop predictive signatures, in older men (mean age 84 yr). Rates of distal radial and tibial bone loss were assessed with high-resolution peripheral quantitative computed tomography (HR-pQCT) over ~6 yr, and ~ 7 K serum proteins were measured with aptamer-based assays (SomaLogic). Using stringent statistical criteria, 22 proteins were found to be associated with incident bone loss. Higher levels of FSH were most consistently and robustly linked to greater loss. Several other biological pathways were associated with change in bone, including inflammation and endocrine influences. Protein associations with radial and tibial loss were broadly similar, but with distinct patterns. A 22-protein signature was strongly related to bone loss and was considerably more predictive of change than other bone remodeling markers. These data are among the first to examine the serum proteins associated with longitudinal bone loss, and they implicate several underlying biological processes that might be related. The distinct protein patterns associated with loss at radial and tibial sites suggest the nature of those events may be site specific. Serum protein signatures may provide value in predicting those with more rapid bone loss.
Genome-wide association studies (GWAS) have identified numerous RA associated genetic variants, most of which localize to non-coding regulatory regions (eg, enhancers), but their functional annotation remains a barrier to translating GWAS findings into mechanistic insights. This study hypothesized that these enhancer SNPs reside in the accessible chromatin domains of RA's target tissue (synovium) and modulate target gene expression by altering transcription factor (TF) binding affinity. Thus, leveraging prospectively collected RA synovial tissues, it aimed to identify key regulatory TFs and their roles in RA pathogenesis. The study integrated assay for transposase-accessible chromatin sequencing (ATAC-seq) data from synovial tissues of 7 RA patients with GWAS-derived RA-associated enhancer SNPs to prioritize TFs that bind these enhancers, with functional validation performed using primary fibroblast-like synoviocytes (FLSs) from RA synovial tissues and MH7A cell lines. Results showed that 1006 GWAS SNPs localized to enhancer regions and were significantly enriched in the open chromatin domains of RA synovium. Transcription factor enrichment analysis identified RUNX3 as the top candidate TF, which regulates FLS migration and invasion. Mechanistically, the G allele of rs1930785 binds RUNX3 in an allele-specific manner, upregulating the expression of its target gene TRAF1, which in turn exerts a protective effect on FLS homeostasis. The study confirms RUNX3 as a key TF regulating the activity of RA-associated enhancers, highlights the value of patient-derived synovial tissue data and the dual validation system, and lays a foundation for mechanistic research and targeted therapy for RA. Rheumatoid arthritis is a chronic inflammatory joint disease associated with numerous genetic variations whose functions remain poorly understood. Using joint tissue from patients, we investigated how these genetic differences affect cellular activity in affected joints. We identified a key regulatory protein called RUNX3, and found that the G allele of genetic variant rs1930785 enhances its binding to DNA and increases expression of the TRAF1 gene, helping to maintain normal joint cell function. These findings improve our understanding of RA genetics and may support the development of future targeted therapies.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which a recurrent ACVR1 (R206H) mutation drives progressive heterotopic ossification (HO). Although hypersensitive bone morphogenetic protein (BMP) signaling is well established, the mechanisms by which this mutation stabilizes a pro-osteogenic cell state remain unclear. Here, we integrated super-resolution stochastic optical reconstruction microscopy (STORM), transposase-accessible chromatin with sequencing (ATAC-Seq), and RNA sequencing (RNA-Seq) to determine how Acvr1R206H remodels chromatin to influence lineage commitment. Mutant mouse embryonic fibroblasts exhibited globally decondensed chromatin and enhanced accessibility at developmental and osteogenic loci, accompanied by transcriptional programs enriched for ossification, extracellular matrix organization, and cell adhesion. Upon BMP stimulation, Acvr1R206H/+ cells exhibited exaggerated chromatin remodeling, revealing markedly heightened ligand sensitivity. Notably, pharmacological inhibition of Rho/ROCK or BMP-SMAD signaling restored chromatin condensation, demonstrating that these chromatin alterations are dynamic and reversible. Together, these findings show that Acvr1R206H establishes a pro-osteogenic chromatin landscape through convergent Rho/ROCK-dependent mechanotransduction and BMP-dependent pathways, revealing potential therapeutic opportunities to prevent pathological bone formation in FOP. Fibrodysplasia ossificans progressiva is a rare genetic disease, where soft tissues such as muscles and tendons gradually turn into bone, severely restricting movement. The disease is caused by a mutation in the ACVR1 gene that misdirects cells to inappropriately form bone. In this study, we found that the mutation changes how DNA is organized inside cells, making bone-forming genes more accessible and easier to activate. Importantly, these changes were reversible: blocking the abnormal signaling restored DNA organization closer to that of healthy cells. Our findings suggest that disrupted control of gene activity is a central feature of the disease and may represent a promising therapeutic target.
Metabolites mediate inter-organ communication and this metabolic crosstalk often goes awry in systemic diseases, including chronic kidney disease-mineral bone disorder (CKD-MBD), where CKD disrupts skeletal homeostasis, with significant bone loss and increased fracture risk observed in patients. While metabolites from the injured kidney have been identified to disrupt bone function, whether metabolites from the bone influence kidney function over the course of CKD progression is less-understood. Given that bone-derived factors such as FGF23 and sclerostin influence CKD-MBD disease progression, we hypothesized that identifying skeletal metabolic fluxes disrupted in CKD may reveal other bone-derived metabolites that mediate nephropathy. We employed a combination of in vivo and ex vivo 13C-metabolic flux analysis (13C-MFA) to characterize how the adenine-induced kidney injury murine model of CKD-MBD rewires specific skeletal metabolic fluxes. Through 13C-MFA of bone tissue in vivo, and ex vivo cultures of calvariae and femora, we identified that this murine model of CKD-MBD accelerates osteocytic citrate production. 13C-isotopic tracing in OCY454 osteocytes suggests that this increased citrate flux is in part driven by PTH stimulation of glucose- and glutamine-to-citrate conversion in osteocytes. When citrate production is exacerbated by the loss of function mutation in SLC13A5 (Slc13a5R337*/R337*), a specialized plasma membrane citrate importer, we did not observe a significant worsening of bone loss in mutant mice due to chronic adenine-induced kidney injury. Intriguingly, kidney function appears to be protected, reducing secondary hyperparathyroidism and the severity of nephrolithiasis due to the adenine diet. Our observation on the role of citrate metabolism in CKD both confirms the relevance of citrate in managing patient kidney outcomes and suggests that organismal citrate metabolism may be modulated in the management of CKD-MBD. Altogether, this study reveals a potential new axis of metabolic regulation in the inter-organ communication between the skeleton and the kidneys.
Updated U.S. and international hypertension guidelines reflect new studies and analyses that support changes in hypertension management. The 2025 U.S. guideline for prevention, detection, evaluation, and management of high blood pressure (BP) recommends lower BP targets, greater use of out-of-office BP for diagnosis and medication titration, and a different approach to severe hypertension presenting without acute or evolving cardiovascular disease symptoms or signs. New treatments for resistant hypertension are recommended. Trial evidence supports benefit from tighter BP control to prevent mild cognitive impairment and dementia, further emphasizing the importance of lower BP goals.
Hypoparathyroidism is a rare disease characterized by hypocalcemia and deficient parathyroid hormone secretion. Cohort studies suggest a higher risk of cardiovascular disease. However, imaging-based assessment of coronary artery disease is limited. We aimed to characterize cardiovascular risk factors and coronary artery disease in 50 patients with chronic post-surgical hypoparathyroidism and 50 age- and sex-matched individuals from the general population, using coronary computed tomography angiography. The mean age of patients was 60 (range 31-84) years, 86% were female, and the median duration of hypoparathyroidism was 12 (range 5-49) years. Compared with controls, patients had a lower estimated glomerular filtration rate (78 vs. 83 mL/min, p = 0.04) and were more frequently treated with antihypertensive medication (56% vs. 36%, p = 0.05). Use of lipid-lowering therapy was more frequent (34% vs. 18%, p = 0.07). Prevalence of diabetes, smoking status, and arterial stiffness assessed by carotid-femoral wave velocity did not differ between groups. Angiography revealed coronary atherosclerotic plaques in 68% of patients, compared with 42% in controls (p < 0.01). This association remained significant after adjustment for sex, age, and presence of any cardiovascular risk factor, corresponding to a 24-percentage point higher prevalence of coronary atherosclerosis. Severe coronary artery disease (coronary artery calcium score ≥400) was present in 18% of patients versus 2% of controls (p = 0.02). Hypoparathyroidism was associated with increased odds of coronary calcification (coronary artery calcium score >0; OR 3.19, 95% CI 1.40-7.24, p < 0.01), independent of renal function. Compared with controls, patients had aortic valve calcification more often (29% vs. 8%, p<0.01) and calcifications of the ascending and descending aorta (34% vs. 8%, p<0.01). In conclusion, chronic post-surgical hypoparathyroidism is associated with an increased burden of atherosclerosis, which may explain the increased cardiovascular risk. Enhanced cardiovascular risk stratification and preventive strategies are warranted.
Unopposed denosumab (Dmab) discontinuation is followed by overshoot in bone turnover markers (BTM), rapid bone mineral density (BMD) loss, and elevated risk of multiple vertebral fractures. To preserve BMD gains and mitigate fracture risk it is currently recommended to administer bisphosphonates following Dmab discontinuation. We prospectively evaluate the efficacy of alendronate (ALN) in preventing BTM overshoot and BMD loss in women with postmenopausal osteoporosis (PMO) discontinuing Dmab. This is a 12-month prospective, observational study among patients treated with Dmab 60 mg every 6 months and achieved osteopenia at the lumbar spine (LS) and femoral neck (FN). Six months after the last Dmab injection participants received oral ALN 70 mg weekly for 6 months followed by 6 months without therapy (Group 1) or for 12 months (Group 2). The primary endpoint was the percent change in LS-BMD from baseline to month 12. Eighty women (39 Group 1, 41 Group 2) who had received 2-22 Dmab injections (mean 9.8) completed the study. Median age was 67 years; 27.5% had prevalent fractures and 59% had prior anti-osteoporotic therapy. At month 12, LS-BMD declined significantly in the overall cohort [-5.9% (8.2%), p < 0.001], with no difference between groups (Group 1: -6.8% vs Group 2: -5.0%, p = 0.50). FN-BMD decreased (-3.5%, p < 0.001), and similarly in both groups. Serum procollagen type 1 N-terminal propeptide (P1NP), C-terminal telopeptide of type 1 collagen (CTX), and tartrate-resistant acid phosphatase isoform 5b increased significantly; P1NP and CTX were significantly higher in Group 1 at month 12. One patient sustained multiple vertebral fractures (1.25%). In conclusion, alendronate did not consistently attenuate BMD loss and BTM rebound after denosumab discontinuation in women with PMO, with 6 months being as effective as 12 months of treatment. Importantly, both regimens were associated with low incidence of multiple vertebral fractures.
The extracellular matrix provides a crucial tissue-specific signaling hub and structural scaffold that transduces biomechanical force load into cellular responses. While this is especially important in the musculoskeletal joint, the spatial organization of extracellular matrix (ECM) assemblies has been poorly investigated. Dense supra-structures, inaccessible epitopes and complex antigen retrieval negatively affect the 3D-visualization of ECM-scaffolds in connective tissues. We have developed multiplex ECM immuno-staining techniques that now permit mapping of the entire musculoskeletal ECM with embedded cells during skeletal growth and repair. Specifically, we show that osteoblasts deposit a bony ECM on the cartilaginous template in the hypertrophic growth plate, creating a unique ECM composite that likely confers both stiffness and flexibility to neonatal bone. We demonstrate that tendon collagen I fibrils anchor along a thin, continuous tidemark at the lateral cartilaginous surface, mechanically coupling cartilage and tendon matrices at contact sites. Finally, we reveal muscle-derived laminin γ1(+) vascular basement membrane infiltration of the cartilaginous fracture callus ECM, likely facilitating nutrient delivery and structural stabilization during skeletal repair. These advances provide insight into the complexity of the ECM and its interplay with embedded cell clusters at previously unattainable spatial resolution and biological context during skeletal growth and repair.
This expert position statement reframes arthroplasty and spinal fusion complications under the unified endpoint of implant fixation failure, defined as loss of mechanical integrity of the bone–implant unit over time. It synthesizes mechanistic and clinical evidence and provides evidence-informed recommendations for peri-operative bone health optimization. Osteoporosis is traditionally conceptualized as causing fragility fractures. However, compromised bone quality also affects the integrity of bone–implant constructs, influencing whether implants maintain fixation, interfaces remain stable, and fusion constructs consolidate. To synthesize mechanistic, translational, and clinical evidence on how osteoporosis and osteoporosis pharmacotherapies influence implant fixation failure across arthroplasty and spinal fusion, and to provide evidence-informed clinical recommendations for peri-operative bone health assessment and optimization within a unified construct-level framework. A position statement was developed following a structured literature search. Evidence was synthesized narratively by defining implant fixation failure as a construct-level outcome encompassing periprosthetic fracture, loosening, subsidence, pseudarthrosis, and junctional failure. Recommendations were categorized by strength (strong or conditional) and certainty of evidence (high, moderate, or low). Low bone mineral density (BMD) is associated with implant fixation failure across arthroplasty and spinal fusion. In arthroplasty, randomized trials demonstrate preservation of periprosthetic BMD with bisphosphonates, while registry analyses suggest improved implant survival. In spinal fusion, antiresorptive and anabolic therapies influence fixation-related parameters, with anabolic agents showing the most consistent evidence for enhanced fusion mass and earlier union. Much of the literature relies on radiographic or biomechanical endpoints rather than definitive outcomes. Viewing arthroplasty and spinal fusion complications through a shared construct-level perspective provides a coherent link between osteoporosis and reconstructive durability. Systematic peri-operative bone health optimization may improve construct longevity, although more definitive outcome-driven trials are needed. Closer integration between orthopedic surgeons and osteoporosis specialists will be central to advancing peri-operative bone health care.
AI-derived bone mineral density from routine radiographs showed strong agreement with DXA and comparable ability to predict incident fractures. This opportunistic approach may support osteoporosis screening and early identification of high-risk individuals without reliance on dedicated DXA examinations. Osteoporosis is a major cause of fragility fractures, yet limited access to DXA leads to underdiagnosis and delayed treatment. Recent advances in artificial intelligence enable extraction of bone structural information from routine radiographs, providing a potential tool for opportunistic osteoporosis screening. Whether AI-derived BMD can approximate DXA and predict real-world fracture risk remains unclear. Adults aged ≥ 20 years who underwent both lumbar DXA and radiographic examinations (lumbosacral or kidney–ureter–bladder) within six months between January 2014 and December 2024 were retrospectively analyzed. Lumbar BMD was estimated using DeepXray Spina and compared with DXA using Pearson correlation, intraclass correlation coefficient (ICC), and Bland–Altman analysis. Diagnostic performance for osteoporosis (T-score ≤ − 2.5) and fracture prediction was evaluated using receiver operating characteristic (ROC) analysis, Cohen’s κ, and logistic regression. Among 540 participants (73.9
