The management of osteoporosis in real-world clinical practice is highly heterogeneous, reflecting the complexity and variability inherent in therapeutic decision-making. Although artificial intelligence (AI)-based tools have been developed to support diagnosis, limited research has investigated their potential to elucidate the rationale underlying treatment choices. This study applied explainable machine learning to replicate and interpret pharmacological treatment decisions made by two board-certified osteoporosis specialists. We retrospectively analyzed 1481 patients who underwent dual-energy X-ray absorptiometry (DXA) and lateral spine radiography between 2020 and 2023 at Hokkaido University Hospital and two affiliated institutions. Two specialists independently assigned patients to one of five non-overlapping treatment categories. External validation was performed in 372 outpatients from three independent hospitals in 2024. The LightGBM model demonstrated the highest predictive performance. To interpret this model, we analyzed feature importance and applied SHapley Additive exPlanations (SHAP) to identify the most influential clinical factors driving treatment decisions. The LightGBM model achieved an accuracy of 0.90 and an F1-score of 0.90 in external validation. SHAP analysis revealed that femoral neck bone mineral density (BMD) and severity of vertebral fractures (especially grade 3) were the most influential factors in treatment selection. These patterns mirrored the expert reasoning, highlighting the prioritization of objective imaging data in therapeutic decisions. This study demonstrated that explainable AI can clarify the clinical reasoning behind osteoporosis treatment decisions. Bone mineral density and vertebral fracture severity are key determinants, supporting a transparent and reproducible framework for future decision support tools that assist clinicians in making consistent therapeutic decisions.

Previous in vitro studies have demonstrated direct effects of Rooibos (Aspalathus linearis) on bone cell populations, notably osteoblasts and osteoclasts, but in vivo evidence of Rooibos effects on bone remain scant. Here, we compared the effects of a green (minimally oxidized) Rooibos extract (GRT) on the femora of male Wistar rats, against the background of a medium-fat/high-sugar (MF/HS) and a high-fat/high-fructose (HF/Fr) diet. Male Wistar rats were maintained for 17 weeks on one of three diets: control (CON), MF/HS (OB1) or HF/Fr (OB2) (n = 24 each). From weeks 11-17, n = 12 animals in each group received oral GRT supplementation (60 mg/kg body weight daily). Femoral bone mineral content and density (BMC, BMD) were analysed by densitometry; cortical and cancellous bone microarchitecture was assessed using micro-computed tomography (μCT); and osteoblast (N.Ob), osteoclast (N.Oc), adipocyte (N.Ad) and chondrocyte numbers (N.Ch) were quantified histomorphometrically. GRT supplementation did not affect femur weight, BMC or BMD, but improved trabecular measurements were observed in the CON-GRT group, compared to all other groups. GRT increased N.Ob/mm and decreased N.Oc/mm in the CON and OB2 dietary groups. Notably, GRT reversed the OB2 diet-associated increase in N.Oc/mm in both cortical and cancellous bone. Although GRT had no effect on serum malondialdehyde (MDA) levels as a measure of systemic oxidative stress status, serum MDA levels were nevertheless positively correlated with cortical and cancellous N.Oc/mm and negatively correlated with cortical N.Ob/mm. Overall, GRT supplementation had pro-osteogenic and anti-osteoclastogenic effects in vivo, indicating that green Rooibos should be further explored as a bone-supporting nutraceutical.

Osteomyelitis (OM) is a severe bone-destructive disease characterized by infection and inflammation. Transcriptomic analysis of datasets GSE18043 and GSE30119 identified CTLA4 as a key regulator associated with immune modulation and osteogenic differentiation. Subsequent bioinformatic and immune infiltration analyses revealed that CTLA4 expression correlated with increased anti-inflammatory macrophage infiltration and activation of the Wnt/β-catenin signaling pathway of osteoblasts. Functionally, CTLA4-Ig promoted osteogenic differentiation, enhanced matrix mineralization, and upregulated osteogenic markers in MC3T3-E1 cells, while concurrently inhibiting osteoclast formation and bone resorption activity. In a Staphylococcus aureus-induced rat OM model, histological and immunohistochemical analyses further confirmed enhanced osteoblast activity and reduced osteoclast presence in the CTLA4-Ig treated group. CTLA4-Ig administration preserved bone structural integrity by modulating the inflammatory microenvironment, characterized by reduced expression of pro-inflammatory cytokines, increased levels of anti-inflammatory cytokines, enhanced osteogenic regeneration, and a reduction in bacterial burden. Collectively, these findings established CTLA4-Ig as a dual-action modulator that promoted bone regeneration while inhibiting bone destruction, offering a promising therapeutic strategy for OM.

Fracture healing is a complex, multi-phase process involving mesenchymal progenitor cell (MPC) recruitment, chondrogenesis, osteogenesis and bone remodelling. The cyclin-dependent kinase inhibitor p21 is known to regulate cell cycle progression and has been implicated in tissue regeneration. Here, we investigated the role of p21 in endochondral fracture repair using a transverse tibial fracture model in physiologically normal mice. Prx1CreERT2-GFP;R26RTdtomato mice on C57BL/6 and p21 backgrounds enabled lineage tracing of MPCs. Longitudinal in vivo micro-CT, histological analysis, tissue cytometry and mechanical testing were used to assess callus formation, cellular composition, and mechanical integrity. Our results demonstrate that p21 mice exhibit enhanced bone regeneration, with significantly higher bone mineral density (BMD) and bone volume fraction (BV/TV) in the fracture callus at 2 and 4 weeks post-fracture (wpf). Histology revealed increased Prx1 cell recruitment, along with greater expression of chondrogenic (Sox9) and osteogenic (BSP) markers in p21 mice at 2wpf. Biomechanical testing showed that despite similar strength, p21 calluses had reduced toughness, suggesting altered matrix remodelling. Collectively, our findings highlight p21 as a negative regulator of bone regeneration, likely through modulation of MPC recruitment and differentiation. Together, these data suggest therapeutic targeting of p21 may enhance fracture healing and counteract osteoporosis in terms of bone remodelling and repair.

The vascularization of bone still holds several unknowns, crucial to future developments in reconstructive surgery: both for bone transplantation and decellularized allograft. This study introduces a novel method to analyze pressure-dependent vascular territories in the human mandible, with direct implications for the optimization of decellularization by perfusion protocols. Traditional anatomical approaches have struggled to delineate perfusion territories due to the complexity of multiple arterial inputs and the dynamic nature of blood flow. Our methodology integrates pressure-controlled perfusion with 3D imaging to map vascular distribution within the mandibular bone under varying perfusion pressures. We conducted controlled perfusions on human cadaveric mandibles, progressively increasing pressure while monitoring the expansion of perfused territories using contrast-enhanced cone beam computed tomography. A custom segmentation pipeline allowed for the reconstruction of pressure maps detailing the minimal pressure required to perfuse different regions of the mandible. Our results demonstrate a low-pressure anastomosis of the maxillary artery to the facial artery through the mental artery, suggesting the equivalence of intraosseous territories, followed by a radial perfusion pattern from the inferior alveolar artery, with increasing resistance at the cortical bone. Perfusion saturation was achieved at approximately 100-125 hPa, in accordance with physiological arterial pressures. Furthermore, cortical bone exhibited higher perfusion thresholds than cancellous bone, emphasizing differential vascular resistance across bone structures. These findings suggest that pressure-driven perfusion analysis can provide crucial insights into bone vascularization. By optimizing pressure parameters, it may be possible to achieve more effective decellularization by perfusion in massive bone allografts, improving graft integration and long-term viability. This study also underscores the need for pressure-controlled anatomical studies, as perfusion territories vary significantly with applied pressure, challenging traditional static angiosoma models. Future research should explore the applicability of these findings in living tissues and refine decellularization techniques based on controlled perfusion dynamics.

Vertebral fractures (VFs) are among the most common osteoporotic fractures, yet they are frequently underdiagnosed and left untreated. The use of an artificial intelligence (AI) tool may support improved detection rates. This study aimed to evaluate the diagnostic performance of the AI-based software (IB Lab FLAMINGO) in identifying VFs on thoracic and abdominal CT scans, using radiologist assessment as the reference standard.

Bone metastasis, a frequent complication of advanced cancers, requires early, precise detection to enable timely interventions and improve patient outcomes. Computed tomography (CT), valued for non-invasive, high-resolution imaging, is essential for identifying bone metastatic lesions. However, these small, morphologically diverse, low-contrast lesions, combined with complex tumor microenvironments and computational limitations, challenge deep learning models' accuracy and real-time applicability. We propose BM-DETR, a Transformer-based model integrating spatial-contextual enhancement module (SCEM) to enhance low-contrast lesion features through channel attention and spatial mixing, AttentionUpsample for superior multi-scale feature fusion via dual-branch upsampling, and dilated transformer attention block (DTAB) to improve contextual modeling, addressing transformer limitations in local detail capture while optimizing efficiency. Evaluated on OsteoScan dataset, BM-DETR achieves mAP50 of 0.9376, and on BMSeg dataset, mAP50 of 0.9139, surpassing state-of-the-art methods. Balancing high accuracy with computational efficiency, BM-DETR's potential for edge deployment supports early screening and intelligent diagnosis of bone metastases. This work provides a robust foundation for automated lesion detection, advancing clinical translation of diagnostic systems.

This study aim to investigate the effects of inosine on rheumatoid arthritis (RA) disease and explore the potential mechanism. Collagen-Induced Arthritis (CIA) rats were used to investigate the effects of inosine on bone destruction and inflammation. Micro-CT scan was used to detect the bone injury. H&E and Safranin O staining were used to evaluate the synovial inflammation and cartilage damage. RANKL-induced osteoclasts differentiation assay was used to investigate the effects of inosine on osteclastogenesis. CCK-8 and transwell experiments were performed to investigate the RA synovioblast (RASFs) proliferation and invasion. We observed that inosine intraperitoneal injection led to significant reduction in arthritis score of CIA rats. Micro-CT scan showed the decreased degree of bone destruction and increased bone mass in inosine treated CIA-rats. H&E and Safranin O staining showed that inosine significantly inhibited the inflammation and cartilage erosion in CIA-rats. The IL-6 and IL-8 levels in synovial tissues were lower in inosine treated CIA-rats than that in vehicle group. Furthermore, TRAP staining showed that the osteoclasts numbers were decreased in inosine treated CIA-rats. In vitro, inosine led to the decrease of osteoclasts numbers, F-actin ring and the expression of osteoclasts-specific markers. Furthermore, we found that inosine inhibited osteoclastogenesis via down-regulating OPN. OPN supplementation could counteract the inhibiting effect of inosine on osteoclastogenesis. Additionally, we observed that inosine significantly inhibited proliferation, invasion and inflammatory cytokines secretion of RASFs. In conclusion, inosine alleviated bone destruction and inflammation in CIA-rats by inhibiting osteoclastogenesis and RASFs activation. Hence, inosine supplementation may be a potential strategy for RA therapy.

The incidence of hip fractures is higher in women. Thus, preventive interventions (e.g., exercise) are important. According to research, the strength of the proximal femur, which affects hip fractures, is more important in the cortical bone than in the cancellous bone. This study aimed to evaluate the presence and quality of evidence of exercise on the cortical bone of the proximal femur in women.

Atypical periprosthetic femoral fracture (APFF) is a rare but increasingly recognized complication of hip arthroplasty. Although cemented stems are generally considered protective against fractures, APFFs have also been reported around these implants. However, their clinical and radiographic characteristics remain poorly understood. This multicenter retrospective study aimed to clarify the features of APFFs occurring around cemented stems. Twenty hips from 19 patients were identified, based on the revised criteria of the American Society for Bone and Mineral Research Task Force, without excluding periprosthetic fractures. Fracture location was classified by distance from the stem tip: beyond 25 mm proximally as subtrochanteric type, within 25 mm as stem tip-type, and beyond 25 mm distally as femoral shaft type. Stem tip-type fractures were most common (15 hips, 75 %), followed by femoral shaft type (four hips, 20 %) and subtrochanteric type (one hip, 5 %). All varus aligned stems (four hips) and 83 % of neutrally aligned stems (10 of 12 hips) were stem tip-type fractures. Beaking or flaring of the lateral cortex was present in 76 % (13 of 17 hips) with pre-fracture radiographs. Prodromal pain was reported in 40 % (eight hips) and bisphosphonate use was identified in 94 % (16 of 17 hips) with available medication data. Surgical treatment was performed in 85 % (17 hips), including internal fixation (10 hips) and revision arthroplasty (seven hips); 15 % (three hips) were managed conservatively. Cemented APFFs frequently occur around the stem tip and are often preceded by radiographic changes and symptoms. Early recognition may support timely diagnosis and intervention.

Aseptic craniofacial osteolysis around the implant-bone interface, induced by wear particles, leads to the loosening and failure of dental implants, temporomandibular joint prostheses and internal fixation during maxillofacial reconstruction. Osteoclasts, as terminally differentiated multinucleated giant cells and the exclusive bone resorptive cells, play an important role in this pathological process. The PINK1/Parkin pathway is involved in mitochondrial quality control; however, its effects on osteoclast-mediated physiological bone homeostasis and the therapeutic potential on craniofacial osteolysis remains unexplored. We generated the mutant mice in which Parkin was conditionally deleted in myeloid lineage cells (LysM-Cre/Park2; Park2). Unexpectedly, the Park2 mice displayed no overall skeletal phenotype. In tandem, upon osteoclastogenic induction, Park2 macrophages undergone RANKL-induced osteoclastogenesis normally with compensated increased PINK1 expression. Notably, Mdivi-1 remarkably simultaneously inhibited the PINK1 and Parkin expression, leading to significant attenuated osteoclastogenesis in a concentration-dependent manner. The aseptic titanium particle-induced calvaria erosion model was constructed to simulate craniofacial osteolysis. Importantly, Mdivi-1 effectively alleviated the bone resorption and trabecular structure destruction induced by titanium particles, and blocked the osteoclast accumulation in the lesions. Taken together, Mdivi-1 alleviated titanium particle-induced aseptic craniofacial osteolysis via inhibition of PINK1/Parkin-dependent mitophagy. In summary, while myeloid lineage conditionally deletion of Park2 does not interfere with osteoclast differentiation and physiological bone homeostasis in mice probably due to the compensation by PINK1 expression, Mdivi-1 as the inhibitor of PINK1/Parkin-dependent mitophagy may provide a novel therapeutic strategy towards aseptic craniofacial osteolysis.

Pregnancy- and lactation-associated osteoporosis (PLO) describes a fragility fracture presentation around pregnancy/lactation. Presentation often includes multiple vertebral fractures, but can also involve hip, sacral/pelvic, or other fractures. Substantial bone structural deficits and low bone formation rate have been documented. Most have no known secondary cause. Many have a history of childhood fracture and/or family history of osteoporosis. These characteristics, together with early onset and disease severity, lead to the hypothesis that genetic factors may contribute to PLO. We enrolled 110 women with PLO (mean #fractures = 6, vertebral fractures in 88 %) in an exome sequencing (ES) study. Analyses identified rare (<1 % allele frequency in gnomAD) predicted deleterious variants (RPDV) in 33/110 (30 %) women. All were heterozygous; two participants had multiple RPDV. No RPDV in COL1A1/COL1A2 were identified. 28/110 (25 %) had RPDV in genes related to WNT signaling, critical to bone formation: LRP5 (n = 19), LRP6 (n = 6), WNT1 (n = 2) or WNT1&LRP5 (n = 1). Seven had RPDV related to renal/calcium handling (SLC34A1, SLC34A3, SLC9A3R1), or other osteoporosis mechanisms (PLS3 (n = 3), HGD (n = 1)). Those with RPDV did not differ from those without in terms of BMD, fracture characteristics, and most clinical characteristics. Among 110 PLO women, exome sequencing analyses identified a potential genetic osteoporosis contribution in 30 %, suggesting that many genetic contributors to PLO have yet to be elucidated. The finding of variants related to WNT signaling in 25 % of the cohort is consistent with the predominantly low bone formation phenotype of PLO and may have implications for prognosis and treatment response.

Bone adapts to its loading environment throughout the lifespan, with rapid gains during adolescence. Accelerometers are commonly used to measure physical activity (PA) and examine its associations with bone outcomes; however, common approaches reduce high-resolution data to a few metrics (e.g., minutes per day (min/d) in various activity intensities). In this observational cohort study, we investigated whether using new accelerometry metrics to synthesize count-based accelerometry data would explain relationships between PA and estimated bone strength accrual. Four years of longitudinal data from over 300 children and adolescents in the Healthy Bones Study III were used to examine associations between the accelerometer-derived intensity gradient (IG) and daily impact score (DIS) with estimated bone strength (failure load, N; 8 % site of the distal tibia) as measured with high-resolution peripheral quantitative computed tomography. We also explored whether associations were independent of a traditional metric of min/d of vigorous physical activity (VPA). In linear mixed effects models, IG was not associated with bone strength independent of VPA (β = -515.2 (-1302.1, 270.4), p = 0.20; β= 25.5 (14.0, 37.0), p < 0.001), but DIS was positively associated with bone strength independent of VPA (β = 25.2 (7.0, 43.6), p = 0.007; β= 3.2 (-6.1, 1.4), p = 0.67). Our findings suggest that the DIS may be a more appropriate metric for evaluating accelerometry data in relation to adolescent bone strength accrual compared with traditional duration (minutes of PA per day) metrics.

This study aimed to evaluate the diagnostic value of special AT-rich sequence binding protein 2 (SATB2) in distinguishing between osteogenic tumors and non-osteogenic tumors, providing reliable scientific evidence for its use as an adjunct diagnostic tool in clinical practice.

To investigate the combined effect of the metabolic score for visceral fat (METS-VF) and arterial stiffness on fragility fractures, and to further examine whether arterial stiffness, measured by brachial-ankle pulse wave velocity (baPWV), mediates the association between METS-VF and fragility fractures.

Postmenopausal osteoporosis (PMOP) is a prevalent condition among postmenopausal women, closely linked to estrogen deficiency, aging, and oxidative stress. Cellular senescence, through mechanisms such as the senescence-associated secretory phenotype (SASP) and bone marrow stromal cells (BMSCs) differentiation imbalance, disrupts bone homeostasis in PMOP. Macrophages play a critical role in maintaining bone homeostasis. However, the extent of macrophage senescence in PMOP and the mechanisms by which it disrupts bone homeostasis have not yet been elucidated. Eldecalcitol (ED-71), a novel drug, has shown potential in osteoporosis treatment, though its effects on macrophage are not fully elucidated. In this study, using hydrogen peroxide (H₂O₂), we induced senescence in macrophages and assessed senescence-associated markers by SA-β-gal staining, Western blotting, and RT-qPCR. We then employed an indirect co-culture system to investigate the paracrine impact of these senescent macrophages on the osteogenic differentiation of BMSCs. The PMOP model was established using ovariectomy (OVX) in mice, followed by histological evaluation. Both 17β-Estradiol (E2) and ED-71 effectively reduced cellular senescence-related indicators such as p16, p53 and β-galactosidase in macrophages, suggesting E2 can alleviate macrophage senescence, and ED-71 may serve as an alternative. Co-culture systems revealed that senescent macrophages impaired BMSCs osteogenic differentiation, an effect reversed by ED-71. SIRT1 inhibition with EX-527 disrupted ED-71's anti-senescence action. Additionally, ED-71 improved bone mass and aging in OVX mice. In conclusion, ED-71 alleviates macrophage senescence via the SIRT1/PGC-1α signaling axis, thereby enhancing BMSC osteogenic potential and mitigating bone loss in OVX-induced osteoporosis.

The aim of this study was to describe the intensity of the pain in patients with genetic metabolic bone disease and to identify possible risk factors.