JBMR Plus

Background Vitamin D may influence bone healing and recovery after spine surgery, but its clinical effects remain uncertain. Objective To evaluate clinical, functional, and bone-related outcomes associated with vitamin D status and supplementation in patients undergoing spine surgery. Methods This systematic review and meta-analysis was registered in PROSPERO (CRD420261467482) and reported according to PRISMA 2020. PubMed/MEDLINE, Scopus, Web of Science, Embase, and the Cochrane Library were searched from inception through 1 June 2026. Random-effects meta-analyses used mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes. Direct supplementation analyses were prioritized, while analyses combining supplementation, baseline vitamin D status, or co-interventions were considered exploratory. Risk of bias was assessed using design-specific Joanna Briggs Institute tools. Results Thirteen studies were included. Four supplementation studies involving 177 participants showed no significant reduction in postoperative pain (MD -0.82, 95% CI -2.50 to 0.86; I2 = 84.3%). Three studies involving 277 participants showed lower Oswestry Disability Index scores in an exploratory analysis (MD -6.40, 95% CI -10.41 to -2.39; I2 = 96.8%). Three supplementation studies involving 128 participants showed no significant improvement in fusion rate (RR 1.17, 95% CI 0.78 to 1.74; I2 = 31.5%). An exploratory four-study fusion analysis was also not statistically significant (RR 1.24, 95% CI 0.98 to 1.57; I2 = 45.5%). Conclusion Current evidence does not establish that vitamin D supplementation independently improves postoperative pain or fusion rates after spine surgery. Possible benefits for disability and other bone-related outcomes remain uncertain because of small study numbers, heterogeneity, co-interventions, and residual confounding. Larger randomized trials stratified by baseline vitamin D status are needed.

Background Lean mass is positively associated with bone mineral density (BMD), and this relationship may vary according to age and sex. Sedentary behavior has also been associated with BMD, although findings differ across populations and skeletal sites. However, it remains unclear whether sedentary time modifies the relationship between regional lean mass and BMD and whether such modification varies across sex and age. These relationships were explored using nationally representative U.S. data. Methods Adults aged 18-59 years from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) were analyzed. Mean bilateral leg lean mass and mean bilateral leg BMD were derived from dual-energy X-ray absorptiometry measurements, and sedentary time was obtained from self-report. Survey-weighted regression models incorporated NHANES examination weights, strata, and primary sampling units. The primary model examined the four-way interaction among leg lean mass, sedentary time, sex, and continuous age, with adjustment for race/ethnicity and height. Quadratic lean-mass terms were examined in sensitivity analyses. Results The primary complete-case analysis included 2,543 adults (1,191 men and 1,352 women). Women showed a more apparent decline in both leg lean mass and leg BMD at ages 50-59 years, whereas sedentary time did not increase in parallel with these age-related changes. Leg lean mass was positively associated with leg BMD in both sexes, with modest nonlinearity, particularly among women. In the primary survey-weighted model, the four-way interaction among leg lean mass, sedentary time, sex, and age was positive (beta = 0.000111 per year, 95% CI 0.000039-0.000183; P = 0.0051), indicating increasing sex divergence in sedentary-time modification of the lean mass-BMD association with age. At younger ages, conditional interaction estimates were similar between sexes; at older ages, estimates became increasingly positive in women while remaining negative but imprecise in men. Quadratic sensitivity analyses attenuated the four-way interaction estimate by approximately 9-12% and reduced its statistical precision, while broadly preserving its direction and magnitude. Conclusions In this exploratory cross-sectional analysis, sedentary-time modification of the association between DXA-derived leg lean mass and leg BMD varied according to sex and age. The sex difference was small at younger ages and became progressively more apparent with increasing age. These findings suggest that behavioral and demographic context may contribute to variation in the muscle-bone relationship itself, although confirmation in independent and longitudinal datasets is needed.

Implant-associated bone infection involves a complex interplay between pathogenic stimuli and host cell responses, yet analysis in preclinical models has typically relied on qualitative or semi-quantitative measures. We aimed to establish a quantified evaluation framework to define host-pathogen relationships in a preclinical implant infection model. Staphylococcus aureus-coated stainless-steel implants were inserted trans-cortically in mouse tibiae and bone changes recorded longitudinally by in vivo micro-CT. An automated segmentation task list was developed to independently isolate and quantify cortical, periosteal-reactive, and trabecular bone compartments. RGB trichrome histomorphometry was used to quantify bone matrix integrity, osteocyte lacunar geometry, and osteoclastic activity. Droplet digital PCR was used to determine absolute bacterial and host genome copy number. Infected implants produced marked reductions in trabecular bone volume fraction, number, and bone mineral density (BMD), together with decreased cortical bone volume fraction and increased cortical porosity, accompanied by significant elevations in periosteal bone volume fraction. Histologically, infected bone exhibited increased eroded surface indicative of osteoclastic resorption, extensive degraded bone matrix and pathological remodelling of osteocyte lacunae towards circularity, consistent with an osteocytic osteolysis response. Infection-induced changes to cortical bone structure correlated mostly with host cell rather than bacterial load; however, cortical BMD negatively correlated with the bacterial:host genome ratio. This multifaceted, quantified framework reveals distinct pathobiological effects of implant-associated infection on trabecular, cortical, and periosteal bone compartments, bone matrix and osteocyte and osteoclast populations, consistent with reports in human patients, suggesting that major pathological changes are driven by the host bone cell response to infection.

Purpose: Psychosocial factors are underexplored in relation to osteoporosis. This study examined whether depressive symptoms are associated with incident osteoporosis in middle aged and older adults, and whether this association is modified by age or sex. Methods: Prospective cohort study of 8,577 adults aged [&ge;]50 years from the English Longitudinal Study of Ageing. The sample were free of osteoporosis at baseline (2002-2003) and were followed up for incident osteoporosis until wave 11 (2023-2024). Depressive symptoms were measured at baseline (2002-03) using the 8-item Center for Epidemiologic Studies-Depression Scale (CES-D). Cox proportional hazards regressions were used to estimate associations, adjusting for age, sex and wealth. Results: Over 20 years of follow-up, 948 (11.1%) participants reported incident osteoporosis. Each one-point increase in baseline CES-D was associated with a higher hazard of incident osteoporosis adjusted for age, sex, and wealth (hazard ratio (HR) 1.07, 95% CI 1.04-1.11, p<0.001). The association was modified by age (interaction p=0.008) and concentrated in participants aged 50-64 years at baseline (HR 1.10, 95% CI 1.06-1.14), with no significant association in older age strata. Osteoporosis incidence was higher in women, but this was not modified by depressive symptoms. Findings were robust to sequential adjustment (informed by a directed acyclic graph) for education, wealth, inflammatory conditions and health behaviours (HR 1.04, 95% CI 1.01-1.08) Conclusion: Depressive symptoms are associated with incident osteoporosis over two decades of follow-up, particularly among adults aged 50-64. Mid-life may represent a target for psychosocial intervention to support bone health.

Abstract Fractures in older adults cause high morbidity and mortality. This study aims to identify fracture incidence and risk factors, and to develop the Fracture Risk Model-Abu Dhabi (FRM-AD). Method This retrospective cohort study of 1757 males and females aged 40+ from Abu Dhabi, United Arab Emirates, who participated in a screening program from 2016 to 2020, followed until 2024 for 4.7 years, SD =1.8. It utilized Electronic Medical Records (EMRs) data and telephone interviews. The outcome assessed was the occurrence of fractures. Results There were 58 out of the 1149 females (5.0%) and 26 out of the 608 males (4.3%) who had at least one incident fracture. Hip and vertebral fractures accounted for 12.1% and 11.5%, respectively. There was an annual incidence of 10.5 fractures per 1,000 person-years, 10.7 cases among females and 9.9 among males, rising after age 80 to 39.1 among females and 25.3 among males. Fracture Predictors identified using Poisson regression analysis were older age, smoking, history of previous fracture(s), interaction of history of fracture in a parent with a family history of osteoporosis, positive history of hip fracture in a parent after the age of 40, lack of dyslipidemia diagnosis and the interaction of diabetes mellitus diagnosis and family history of osteoporosis. A higher Body Mass Index (BMI) increased the risk of fractures in this cohort, especially in obese males. Logistic regression of variables at the end of follow-up showed that lower latest vitamin D levels were associated with increased fracture risk. FRM-AD, derived using Poisson regression, performed well in predicting fractures, with Receiver Operating Characteristic (ROC) curves of 0.736 (0.677-0.794) and 0.742 (0.684-0.800) without and with BMD, respectively. The FRAX AUC to predict MOF and hip fracture ranged between 0.624 and 0.683. Conclusion In this Emirati cohort, the locally derived FRM-AD showed moderate discrimination for incident fracture and outperformed FRAX-AD, suggesting that a locally derived model may improve fracture risk stratification. Several risk factors and predictors were identified that can be targeted for prevention.

Prostate cancer (PC) bone metastases (PCBM) are a debilitating disease morbidity that primarily affects the axial skeleton. PCBM are predominantly osteosclerotic with mixed osteosclerotic/osteolytic features, including irregular bone deposition, loss of collagen alignment and increased porosity that mimic features of woven bone formed during development and repair. We hypothesize that progression of PCBM is driven by interactions between tumor cells and the bone microenvironment and is associated with changes in the stromal compartment. We performed tandem mass tag mass spectrometry proteomics on lumbar vertebral specimens from 32 cadaveric PCBM specimens and 3 age-matched controls. Unsupervised clustering segregated specimens into three clusters associated with benign, mixed, and osteosclerotic lesion states, characterized by distinct immune-, tumor-, and osteogenic-associated protein signatures. Histological analysis showed tumor infiltration was accompanied by marrow fibrosis and increased collagen III deposition. We identified a marker signature associated with osteosclerotic remodeling and mapped this signature to independent metastatic PC transcriptomic datasets. The proteomics-derived markers reproduced similar molecular groupings at RNA level, and robustly segregated bone PCBMs from soft tissue metastases PC in RNA data. Together, these findings define molecularly distinct states of tumor-driven changes in PCBM that extend beyond histological classification and may inform biomarker development and therapeutic stratification.

Bone strain and remodeling are important factors for bone health. Improved characterization of relationships between these factors in response to acute loading will improve our understanding of bone maintenance, adaptation to load, and pathophysiology. The purpose of this study was to evaluate colocalization between finite-element-estimated bone strain and [18F]sodium fluoride positron emission tomography imaging-estimated subchondral bone remodeling in the tibial diaphysis in response to acute exercise. We hypothesized that the exercise-induced change in standardized uptake values would be greatest in regions of higher strain. 26 participants underwent bilateral positron emission tomography/magnetic resonance scans before and after a bout of stair ascent and descent exercise. Finite element analysis was performed to calculate principal strain distributions in the tibial diaphysis. [18F]sodium fluoride standardized uptake values were calculated from pre- and post-exercise positron emission tomography data and mapped to the tibial surface. Mean pre-exercise and exercise-induced change in standardized uptake values were calculated and compared between regions defined by strain percentile. Both normalized mean pre-exercise and exercise-induced change in standardized uptake values increased with maximum principal strain in a pattern suggesting an exponential relationship. Pre-exercise and exercise-induced change in standardized uptake value were notably much greater in the region of highest maximum principal strains (estimated marginal means = 76.9 and 71.0 percentile, respectively) when compared to all other regions of the tibial diaphysis ([&le;] 61.1 and [&le;] 57.0 percentile, respectively, p < 0.001). This study is the first to directly show a relationship between bone mechanical loads and acute [18F]sodium fluoride uptake in humans in vivo. Our results highlight the influence of tensile strain magnitude on bone metabolic activity in response to acute loading. Furthermore, we demonstrate the utility of a combined finite element analysis and positron emission tomography approach to interrogate relationships between bone loading and bone metabolic response to acute exercise.

Many hormones and substances acting through G-protein coupled receptors and protein kinase A (PKA) activation inhibit the salt-inducible kinases (SIKs) by phosphorylation. SIKs tonically phosphorylate CREB-regulated transcriptional coactivators (CRTC1, 2 and 3), sequestering them in the cytoplasm and, thus, preventing their translocation into the nucleus. Once in the nucleus, CRTCs bind CREB family member transcription factors and enhance their activity. We and others have shown that parathyroid hormone (PTH) activation of PKA and resultant SIK2/3 inhibition allows CRTC2/3 nuclear translocation. One of the major actions of CRTC2/3 in the osteoblast lineage is the regulation of transcription of Rankl, as well as other PTH-controlled genes. However, little is known about the role of these co-activators in the osteoblast lineage in vivo. Here, we have investigated whether there are basal effects in vivo on bone examined at 2 different ages of conditional deletion of these two co-activators in the osteoblast lineage using Col2.3-Cre. We found significant increases in body weight, length, bone mineral density, bone volume/total volume, trabecular thickness and number with decreased trabecular separation in young (2 months old) male mice, all of which dissipated by 6 months of age. Female mice showed minimal changes in the bone phenotype at either age. Nevertheless, there were gene expression changes in bones of both sexes at both ages, and in particular decreases in Rankl, Runx2 and Sost, and accompanying changes in Wnt pathway genes. These effects may explain the changes in the bone phenotype in the young male mice, but it is notable that there is a sexual dimorphism in the action of CRTC2 and CRTC3. Overall, the work supports the data from research in vitro and forms a basis for investigation of the role of these co-activators in PTH action in vivo.

Vitamin D deficiency is associated with poor outcome in several cancers in humans, and administration of vitamin D or analogs has been shown to decrease tumor progression and metastasis in animal mammary cancer models. We previously demonstrated significant acceleration of carcinogenesis in vitamin D-deficient mouse mammary tumor virus-polyoma middle T (MMTV-PyMT) mammary cancer model as well as of its spontaneous metastasis to lungs. While vitamin D also plays a role in skeletal metastasis, detailed mechanisms of its promotion of bone invasion and metastatic events are not completely elucidated. In the present study we used tibially-injected MMTV-PyMT mammary tumor cells to analyse how dietary-induced vitamin D deficiency in non-immunodeficient FVB mice accelerates bone invasion. Mechanistically, we observed vitamin D deficiency to increase pro-inflammation cytokines and nestin expression in internal bone surface and marrow, and to increase epithelial-to-mesenchymal transition (EMT) through Zeb1 transcription factor. In vitro, treatment of MMTV-PyMT tumor cells with CXCL12 was observed to stimulate Zeb1 expression, and this effect was efficiently countered by 1,25(OH)2D treatment. Analysis of cytokines in MMTV-PyMT mammary tumor cells in vitro showed significant reduction in several pro-inflammatory cytokines with 1,25(OH)2D treatment (GM-CSF, ICAM-1, IL-1ra, IP-10, JE, MCP-5, MIP-1, MIP-1{beta}, MIP-2, RANTES and CXCL12), a crucial observation in view of the current evidence that inflammation is one of the hallmarks of cancer. Furthermore, vitamin D repleteness is associated with very high expression of Socs1 (suppressor of cytokine signalling 1), an inhibitor of JAK/STAT pathway which prevents excessive inflammatory responses and has a tumor-suppressive role. These findings provide a strong link between vitamin D deficiency and acceleration of inflammation-driven bone invasion, and nestin and EMT. The evidence suggests that vitamin D-repleteness in breast cancer patients could enhance the efficacy of co-administered therapies in preventing invasion of skeletal sites.

Objective To characterize regional subchondral bone metabolism before and after acute mechanical loading in individuals with unilateral knee pain using dynamic [18F]sodium fluoride ([18F]NaF) positron emission tomography (PET)/magnetic resonance imaging (MRI), and to investigate relationships with cartilage composition and pain severity. Design Twenty-two individuals with unilateral knee pain and 22 age- and sex-matched healthy controls underwent bilateral dynamic [18F]NaF PET/MRI before and after a standardized stair-climbing protocol in this prospective feasibility study. Automated MRI-based segmentations were used to quantify regional PET standardized uptake values (SUVmean, SUVmax) and pharmacokinetic parameters (K1: bone perfusion, Ki: bone mineralization, extraction fraction) across subchondral bone regions. Quantitative cartilage T2 mapping was performed using qDESS MRI. Painful knees were compared with contralateral asymptomatic knees and healthy control knees using regional effect sizes and regression analyses. Exploratory analyses evaluated associations between PET metrics, cartilage T2, and pain severity. Results Painful knees demonstrated consistently higher baseline subchondral bone metabolic activity than healthy controls, with the largest differences in the medial tibial and medial femoral subchondral bone (Cohen's d=0.51-0.90). Following mechanical loading, exercise-induced increases in bone metabolism were more widespread and demonstrated predominantly moderate-to-large effect sizes (d=0.62-1.15), particularly within the medial and lateral femoral and medial tibial subchondral bone. In contrast, comparisons between painful and contralateral knees showed only localized metabolic differences with predominantly negligible-to-small effect sizes (d=0.16-0.55). Sensitivity analyses adjusting for age and BMI produced similar regional patterns. Exploratory analyses demonstrated generally weak associations between PET-derived metabolic measures, cartilage T2, and pain severity, with only isolated moderate regional correlations. Conclusions Dynamic [18F]NaF PET/MRI demonstrates increased baseline subchondral bone metabolic activity and an exaggerated metabolic response to mechanical loading in symptomatic knees compared with healthy controls. The modest differences between painful and contralateral knees suggest that the asymptomatic limb may not represent a truly unaffected reference. Dynamic [18F]NaF PET provides complementary information beyond cartilage MRI and patient-reported pain and shows promise for investigating subchondral bone metabolism in knee pain, early joint degeneration, and treatment response.

The pace of fracture repair declines with age, increasing the risk of delayed union and nonunion. Delayed union and nonunion are associated with significant morbidity and even mortality with few effective non-surgical interventions. Here, we identify cathelicidin antimicrobial peptide (CAMP) as an age-dependent regulator of bone repair. Single-cell RNA sequencing and immunohistochemistry demonstrated higher CAMP expression during fracture healing in young compared with aged mice. Global or myeloid lineage-depletion of Camp delayed fracture repair in young mice, whereas Camp depletion in aged mice increased callus bone formation. Heterochronic bone marrow transplantation using the conditional genetic knockout further implicated hematopoietic-lineage derived cells in these effects and demonstrated that myeloid-specific Camp expression is important in the rejuvenation of the pace of fracture healing. CAMP promotes osteogenic differentiation through P2X7 receptor (P2X7R)-dependent signaling, influencing the downstream regulation of NLRP3 expression. NLRP3 expression is also correlated with osteogenesis following Camp modulation in both young and old mice, supporting CAMP-P2X7R-NLRP3 signaling as a regulator of osteogenesis. Together, these findings identify CAMP as a hematopoietic-derived regulator of bone repair whose function is age-dependent, promoting fracture healing in young animals while constraining it in aged animals.

Purpose: The primary objective of the Stanford Knee Osteoarthritis PET/MRI Evaluation (SKOPE) study is to develop and evaluate a multimodal, dynamic [18F]NaF PET-MRI framework for characterizing whole-joint physiology and its relationship to osteoarthritis (OA) risk, pain, and disease progression. Specifically, we aim to integrate dynamic PET with quantitative and anatomical MRI, to characterize structural, compositional, and metabolic features across the knee and surrounding musculoskeletal system, evaluate acute tissue responses to exercise, and identify imaging biomarkers associated with OA risk, pain, and disease progression. Methods: The SKOPE study includes multimodal PET-MRI of the knee and surrounding musculoskeletal tissues, with imaging of the knee, tibia, ankle, thigh, hip, pelvis, and lumbosacral spine. Dynamic [18F]NaF PET is combined with conventional anatomical MRI and quantitative MRI techniques, including quantitative double-echo steady-state (qDESS) T2 mapping of cartilage, Dixon fat-fraction imaging, ultrashort echo time (UTE) T2* mapping of short-T2 tissues, UTE imaging of tibial bone, and zero echo time (ZTE) imaging for bone morphology and pseudo-CT generation. Additional MRI sequences characterize muscle composition, bone and joint anatomy, intervertebral discs, and regional vascular anatomy. Selected scans are acquired before and after a standardized exercise protocol to assess the acute physiological response of the joint. Automated segmentation is used to generate subject-specific masks of muscles, bones, vertebrae, and intervertebral discs. A subset of the MRI protocol is repeated at 1- and 2-year follow-up to assess longitudinal changes. Expected Impact: By combining dynamic bone metabolic imaging with quantitative measures of cartilage, menisci, muscle, bone, fat, vascular structures, and the spine and hip, the SKOPE protocol provides a whole-joint and multijoint framework for studying the structural, metabolic, and physiological processes associated with OA and pain. Exercise and longitudinal imaging further enable assessment of acute tissue responses and changes over time, supporting the development of quantitative imaging biomarkers for OA risk, pain, and disease progression.

Background: Giant cell tumor of bone (GCTB) is an intermediate osteolytic neoplasm characterized by a high rate of local recurrence. The tumor comprises two main cell populations: neoplastic stromal cells and osteoclast-like giant cells. Current adjuvant therapies primarily target osteoclast-like giant cells but have limited activity against the neoplastic stromal cells that drive tumor growth and recurrence. Here, we sought to identify actionable vulnerabilities in GCTB stromal cells by profiling druggable receptor tyrosine kinases (RTKs) and associated signaling pathways and evaluating their pharmacological inhibition in patient-derived in vitro models. Methods: RTK activation and downstream signaling were assessed using phospho-protein arrays and western blotting in therapy-naive and denosumab-treated GCTB patient samples and in patient-derived GCTB cell lines, representing clinically relevant models of the neoplastic component. Tyrosine kinase inhibitors (TKIs) targeting activated pathways were evaluated in patient-derived GCTB cell lines cultured under both two-dimensional (2D) and three-dimensional (3D) conditions. Effects on cell viability, proliferation, cell cycle distribution, and cell death were assessed using MTT and XTT assays, flow cytometry, live-cell imaging, and confocal microscopy. Results: Several activated RTKs, including EGFR, IGF-IR, InsR, PDGFR, and PDGFR{beta}, together with downstream signaling proteins MEK1/2 and ERK1/2, were identified as potential therapeutic targets. Among the inhibitors tested, trametinib, a MEK1/2 inhibitor, and axitinib, a multi-target inhibitor of VEGFR1-3, PDGFR{beta}, and c-Kit, demonstrated the strongest antiproliferative and cytotoxic effects, markedly reducing cell viability and proliferation while promoting cell death in vitro. Importantly, trametinib showed selective activity against GCTB stromal cells compared with healthy controls, suggesting a potential therapeutic window. Conclusions: This study identifies trametinib and axitinib as promising therapeutic candidates for targeting the neoplastic component of GCTB. Our findings provide a rationale for further preclinical and clinical evaluation of RTK-directed therapies to complement current treatments and specifically target the neoplastic GCTB stromal cells underlying tumor persistence and recurrence.

Critical sized defects (CSDs) are a serious challenge in orthopedics that require the development of more robust and effective treatments to improve quality of life for patients. Current CSD research is limited by the applicable and affordable animal models available. Mice would be the preferred species as they are cheaply housed and have many transgenic variations readily available; however, their small size makes CSD surgeries difficult and expensive. We propose the use of cerclage wires to achieve internal plate fixation. PEEK plates were secured to the right femur of 26 C57BL/6 mice using four cerclage wires to achieve modified double-loop fixation implemented through bicortical holes and defects were created. 10 received 3mm defects and 6 received 4mm defects that were left empty and were taken out to 20 weeks (Group E3, E4). Another 10 received 3mm defects that were filled with a morselized bone graft and were taken out to 8 weeks (Group G3). Blinded longitudinal x-ray grading by orthopedic surgeons was conducted on the empty defects for plate stability and wire fixation. All samples received microCT analysis at their endpoints. There were no significant differences in plate or wire stability between the empty groups and wire scores worsened negligibly over time. MicroCT analysis further supported wire integration as bone growth directly upon the wires was observed in all samples. The efficacy of this model in achieving non-union when left untreated was also confirmed via microCT. Further, only three mice in group G3 achieved union and two of these unions were not optimal. Our study is the first to successfully show that cerclage wire can be used in a murine CSD model to achieve affordability and clinical relevancy.

Background: Bone mechanical competence depends not only on bone mass but also on the spatial organization of mineral and organic matrix properties. Whereas quantitative backscattered electron imaging (qBEI) characterizes mineral heterogeneity using Bone Mineral Density Distributions (BMDDs), no equivalent framework currently exists for describing the biochemical heterogeneity of the bone matrix by Raman microspectroscopy. Methods: We developed a quantitative Raman analysis (qRA) workflow to generate Bone Material Properties Distributions (BMPDs). Raman spectra were acquired along full-thickness line scans crossing successive bone structural units in human trabecular and cortical bone. Pixel-wise Raman-derived biochemical parameters describing collagen organization, advanced glycation end-products, glycosaminoglycans, mineral-to-matrix ratios, carbonate substitution, and mineral crystallinity were converted into normalized frequency distributions and modeled using gaussian functions. BMPDs were generated from undecalcified pMMA-embedded iliac biopsies (n=38) and routinely processed decalcified paraffin-embedded osteomedullary biopsies (n=21). The analytical framework was validated against conventional two-dimensional Raman mapping, and reproducibility, interindividual variability, and demographic influences were evaluated. Results: BMPDs were consistently well described by gaussian functions (typically R2 > 0.95), allowing extraction of three descriptors for each biochemical parameters: Mean, Peak, and Width. One-dimensional line scans showed excellent agreement with conventional two-dimensional Raman mapping while reducing acquisition time approximately 100-fold. Technical variability remained substantially lower than biological variability for all parameters, and a single trabecular line scan provided reliable estimates of BMPD descriptors for nearly all Raman-derived indices. Cortical bone exhibited narrower BMPDs than trabecular bone, indicating lower biochemical heterogeneity. Comparable BMPDs were obtained from undecalcified and routinely decalcified specimens, demonstrating robustness to tissue processing. No significant associations with age or sex were observed after correction for multiple testing. Reference BMPDs further enabled visualization and standardized quantification of deviations in representative pathological bone biopsies. Conclusions: Quantitative Raman analysis introduces BMPDs as a novel framework for assessing the spatial heterogeneity of bone extracellular matrix composition. By extending Raman microspectroscopy beyond conventional mean measurements, BMPDs provide robust, reproducible descriptors of bone material organization and establish a methodological foundation for investigating alterations of bone quality in metabolic bone diseases.

Background: Knee osteoarthritis (OA) is characterized by progressive joint degradation and altered gait biomechanics. Inter-limb load asymmetry during daily living tasks may accelerate joint deterioration, particularly when combined with physical fatigue. This study investigates the relationship between daily physical fatigue and inter-limb load asymmetry patterns during functional activities in individuals with unilateral knee OA. Objective: To evaluate the impact of fatigue on inter-limb load asymmetry and joint loading rates during daily living tasks in patients with unilateral knee osteoarthritis, and to identify biomechanical and clinical factors associated with load distribution patterns. Methods: One hundred eighteen participants with unilateral knee OA (mean age 62.6 (SD 7.4) years, BMI 29.9 (SD 4.2) kg/m2) completed biomechanical assessments during non-fatigued and fatigued conditions. Ground reaction force measurements were obtained during functional tasks including stair climbing, sit-to-stand transitions, and level walking. Load asymmetry was quantified as the inter-limb difference in peak vertical ground reaction forces. Statistical analysis was conducted using Python (v3.9), including paired t-tests, analysis of variance, and linear regression modeling. Results: Participants demonstrated significantly increased load asymmetry under fatigue conditions (mean difference 8.7% (SD 12.3) %, p < 0.001). Fatigue-induced asymmetry was task-dependent, with stair negotiation showing the greatest increase (11.2% (SD 14.1) %). Peak loading rates on the affected knee were inversely correlated with time-to-peak load during fatigued conditions (r = -0.68, p < 0.001). Disease severity (WOMAC score) and age significantly predicted asymmetry changes (R2 = 0.52, p < 0.001). Conclusions: Physical fatigue exacerbates inter-limb load asymmetry in unilateral knee OA, potentially accelerating joint degeneration. Task-specific interventions targeting fatigue management and load redistribution may improve long-term outcomes. Future longitudinal studies should examine the temporal relationship between acute biomechanical changes and progressive structural joint damage. Keywords: Knee osteoarthritis, load asymmetry, fatigue, biomechanics, ground reaction forces, functional tasks.

Abstract Calcific deposits in the arterial media have been associated with a number of metabolic and genetic disorders including diabetes, chronic kidney disease and generalized arterial calcification of infancy. While medial calcification and physiologic hard tissue mineralization in the skeleton are both regulated by several common determinants, emerging data suggest that there might be fundamental differences in the mechanisms underlying these two processes. Objective: We previously demonstrated that elastin haploinsufficiency delays medial calcification in MGP-deficient mice. Here, using mice in which a human ELN transgene rescues mouse elastin deficiency, we investigated whether the origin and abundance of arterial elastin differentially affect the initiation and progression of medial calcification. Approach and Results: We pursued a transgenic approach to alter the arterial elastin scaffold in MGP-deficient mice. Our analyses of a humanized MGP-deficient model with 40% reduction of medial elastin content showed a complete absence of the early-stage vascular calcification. Additionally, we showed that mouse and human elastin orthologues affect vascular calcification in a comparable manner. Conclusion: Arterial elastin abundance, rather than orthologue origin, modulates the initiation and progression of medial calcification in MGP-deficient mice. A further reduction in arterial elastin beyond that achieved by elastin haploinsufficiency profoundly delays mineral deposition and maturation, whereas restoration of elastin abundance through transgenic human ELN expression restores arterial calcification.

Objective: To examine associations between volume and intensity of leisure time physical activity (LTPA) and fracture risk during midlife and determine whether adherence to World Health Organisation (WHO) physical activity recommendations was associated with fracture risk. Methods: Cross-sectional analysis of UK Biobank participants aged 40 to 65 years using self-reported physical activity and fracture data. LTPA volume (LTPAV) was derived from walking, moderate and vigorous activity. Participants were categorised into LTPAV quintiles and by adherence to WHO physical activity recommendations. Multivariable logistic regression examined associations with self-reported fracture within the previous five years, with sex stratified analyses. Results: Among 322,749 participants, 53% were female with a mean age of 47 years. Fracture risk increased with higher LTPAV, although the association was non-linear and varied by age and sex. The strongest associations were in the highest quintile among men and women aged 40 to 49 years (OR 1.81, 95% CI 1.64 to 1.99 and OR 1.42, 95% CI 1.28 to 1.58 respectively). In mutually adjusted models, vigorous activity demonstrated the strongest independent association with fracture risk. Meeting WHO physical activity recommendations, without exceeding them, was not associated with increased fracture risk. Conclusions: Higher fracture risk was observed in individuals undertaking higher volumes of leisure-time physical activity, with the association largely driven by vigorous-intensity activity. The association was strongest in adults aged 40 to 49 years and in men. Physical activity consistent with current WHO recommendations was not associated with increased fracture risk, supporting continued promotion of physical activity during midlife.

Abstract Purpose: Haemochromatosis due to HFE-C282Y homozygosity can lead to excess iron absorption and is typically associated with liver malignancy, plus widespread arthritis. Recent evidence suggests that limb fractures are more common, but little is known about vertebral effects. This study investigated the association of vertebral compression fractures, assessed with intelligent dual-energy X-ray absorptiometry (iDXA), and HFE genotype in a large community cohort. Methods: UK Biobank data from 227 European genetic ancestry C282Y homozygotes (mean 64.6 years) and 234 age, sex, and BMI-matched controls without common HFE haemochromatosis variants were included. Lateral vertebral assessment scans (iDXA, GE-Lunar) were acquired at imaging reassessment (2014-2020) and reviewed, blind to genotype, for radiological evidence of vertebral fracture. Matched logistic regression models assessed associations between C282Y homozygosity and vertebral fractures. Results: 78 vertebral fractures (16.9%) were identified within 461 participants. Male C282Y homozygotes had increased odds of vertebral fracture (n=22/89, 24.7%) compared to participants without HFE alleles (n=9/90, 10.0%); Odds Ratio [OR]: 2.95, 95%CI: 1.28-6.85, p=0.01. The association persisted after excluding individuals with a diagnosis of haemochromatosis (OR: 3.37, 95% CI: 1.41-8.10, p=0.007). No excess fracture risk was observed in female C282Y homozygotes (n=23/138, 16.7%) vs those without HFE alleles (n=24/144, 16.7%); OR: 0.99, 95%CI: 0.53-1.87, p=1.00. Conclusion: In this community-based imaging study, male HFE C282Y homozygotes had a markedly higher likelihood of vertebral fractures than those without HFE variants. These findings support further evaluation of vertebral fracture assessment in C282Y homozygous men to ensure prompt treatment to prevent future fracture if appropriate.

Background: Vertebroplasty and balloon kyphoplasty are used for symptomatic vertebral hemangiomas, although comparative evidence is limited. We summarized pain relief, cement leakage, and recurrence after vertebral augmentation and assessed whether direct comparison of the two techniques was feasible. Methods: Five databases were searched from inception to January 2, 2026, with an update on July 5, 2026. Because only one small cohort directly compared vertebroplasty with kyphoplasty, outcomes were pooled as single-arm proportions or, for early pain change, as a mean difference using random-effects models. Prespecified subgroup, sensitivity, small-study effect, and influence analyses were performed. Results: Forty-four studies were included: 33 case series, 10 cohort studies, and one randomized trial. Kyphoplasty-specific evidence comprised one dedicated series and one comparative cohort. Any cement leakage occurred in 10.5% of patients (14 studies; 95% CI 5.7-18.4%), while trim-and-fill gave an exploratory adjusted estimate of 20.4%. Early pain reduction averaged 5.13 points on a 0-10 scale (8 studies; 95% CI 4.48-5.77; I2=89.4%). Complete or near-complete pain relief occurred in 79.4% of patients (10 studies), and recurrence, progression, or retreatment occurred in 3.9% (13 studies). Symptomatic cement leakage was uncommon at 0.4%. Conclusion: The available literature, which is mainly retrospective and vertebroplasty-based, supports substantial pain relief with infrequent symptomatic complications. Kyphoplasty data remain insufficient for a reliable technique comparison. Prospective studies with standardized clinical and imaging outcomes are needed.