Low bone mineral density (BMD) is common in older adults and is associated with increased mortality risk. Although higher protein intake is recommended for skeletal health, it remains unclear whether total protein intake or protein source is more relevant for mortality risk. We examined associations of dietary protein quantity and source with mortality risk among adults with low BMD. Data from 4148 adults aged ≥ 40 years with osteopenia or osteoporosis who participated in six National Health and Nutrition Examination Survey cycles from 2007 to 2008 through 2017–2018 were analyzed. Survey-weighted estimates indicated a mean age of 58.1 years, a female proportion of 65.0
Artificial intelligence (AI) has rapidly transformed the potential for opportunistic assessment of bone mineral density (BMD) and bone microarchitecture from routinely acquired imaging. This narrative review synthesizes recent advances across radiography, computed tomography (CT), and magnetic resonance imaging (MRI), focusing on AI-driven methods for automatic extraction of bone quality markers. In radiography, convolutional and transformer-based architectures achieve near-DXA precision by integrating regional texture and clinical features. In CT, deep learning pipelines combining segmentation and end-to-end regression now enable scalable volumetric BMD and trabecular texture analysis, with correlations of approximately 0.8–0.9 versus reference techniques and near-perfect agreement with dedicated quantitative CT. MRI-based methods, leveraging fat–water signal ratios and textural radiomics, increasingly provide surrogate markers of bone integrity. Barriers to clinical translation include interoperability with existing systems, lack of reimbursement frameworks, and limited explainability of black-box models. Emerging foundation models (e.g., SAM, BiomedCLIP) and synthetic imaging networks promise cross-modality generalization. Future work must focus on regulatory validation, model drift surveillance, and equitable deployment to ensure AI-based opportunistic osteoporosis screening improves outcomes across diverse populations.
Raised levels of serum interleukin 6 (IL-6) have been found in some studies of Paget’s disease of bone (PDB), and this cytokine has been suggested to act as a mediator of increased osteoclast activity in the disease. Here weevaluated serum IL-6 in two cohorts of patients with PDB and controls and related serum IL-6 levels in PDB patients to clinical features of the disease. Serum IL-6 was measured by ELISA in 553 individuals with PDB from the PIP study (n = 165), the PRISM study (n = 388) and 533 population-based controls. In the PDB cases, we studied associations between IL-6 and disease extent, pain, previous bisphosphonate therapy, and biochemical markers of bone turnover. Serum IL-6 was correlated with age (r = 0.256, p < 0.001) and serum creatinine (rho = 0.148, p < 0.001) but values did not differ in males and females. Following adjustment for age and serum creatinine, there was no significant difference in IL-6 between PIP cases and controls (p = 0.268) or PRISM cases and controls (p = 0.399) nor was there a significant correlation between serum IL-6 and number of affected bones in PDB or bodily pain. Serum IL-6 was correlated with total alkaline phosphatase (rho = 0.174, p < 0.001), and PINP (rho = 0.095, p < 0.05) but not with the bone resorption marker CTX. In summary, we found no difference between circulating IL-6 values in PDB and controls but serum IL-6 was related to alkaline phosphatase and PINP. These observations do not support a role for raised circulating IL-6 values as an important driver of osteoclast activity in PDB.
Hip fractures (HF) are among the most serious consequences of osteoporosis. Many individuals who subsequently sustain a HF may already fulfill recognized criteria for fracture risk assessment, bone mineral density (BMD) evaluation, or anti-osteoporosis treatment before the event occurs, yet remain unidentified and untreated. We aimed to quantify these missed opportunities for osteoporosis management prior to fragility HF occurrence. We performed a cross-sectional analysis of 1,103 patients aged ≥ 50 years hospitalized for fragility HF and evaluated within a Fracture Liaison Service. Pre-fracture fracture risk was retrospectively estimated using FRAX® based on clinical risk factors only, excluding the index HF. Eligibility for anti-osteoporosis treatment and BMD assessment was evaluated according to international recommendations and national reimbursement criteria. Only 82 patients (7.4
Type 2 diabetic patients generally have higher BMD but greater fracture risk. Exploring their bone microarchitecture might help to explain their bone fragility. We conducted a cross-sectional matched analysis within three prospective cohorts including 477 men and women. Each patient with T2DM was matched for age, sex and BMI with two controls, yielding 159 cases and 318 controls. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to characterize cortical and trabecular bone microarchitecture. In predefined subgroup analyses within T2DM, we compared bone parameters according to glucose-lowering treatment, including metformin-containing regimens versus non-metformin oral regimens and metformin versus insulin-treated patients. In men, femoral neck aBMD was higher in T2DM (0.83 ± 0.13 vs. 0.79 ± 0.14 g/cm2; p < 0.05). Bone size was 5
Enamel, the outermost mineralized tissue of the tooth, is produced by specialized dental epithelial cells called ameloblasts. Unlike human enamel, which lacks regenerative capacity, the mouse incisor grows throughout life, driven by adult stem cells residing in the labial cervical loop (LaCl). To maintain tissue homeostasis, dental epithelial stem cells produce transit-amplifying cells (TACs) that commit to preameloblasts (PABs), migrate distally, and differentiate into enamel-forming ameloblasts. The full dental epithelial differentiation trajectory coexists within a single mouse incisor, making it an accessible model for studying adult tissue repair and regeneration. We have shown that the genome organizer SATB1 is enriched in PABs and is required for their differentiation into ameloblasts. Here, we investigated the injury response of PABs following mouse incisor tip trimming. Injured wild-type (wt) incisors exhibited an expanded PAB zone with intensive proliferation, reduced SATB1 in the ameloblast lineage, associated with a spatial delay in the deposition of the dentin/enamel matrix compared to uninjured controls. Trimming of Satb1 cKO mouse incisor failed to elicit this response, highlighting SATB1’s role in PAB’s response to injury. Compared with wt controls, injured wt incisors and both Satb1 cKO groups showed increased Ki67 immunoreactivity in LaCl mesenchymal and epithelial compartments, along with reduced Col1a1 expression in PAB microenvironment. In vitro, SATB1-transduced ameloblast lineage cells (ALCs) cultured on increasing concentrations of type I collagen exhibited reduced Ki67 but elevated Amelx/Ambn expression. There findings indicate that SATB1 is required for epithelial TACs to exit the cell cycle and transition toward PABs. Incisor tip injury delays PAB differentiation by stimulating LaCL mesenchymal proliferation and altering ECM remodeling within the PAB niche.
The effects of gliflozins on bones of CKD patients on dialysis are unknown. Recently, SGLT2 expression in bone tissue of patients with CKD has been reported. We hypothesized that dapagliflozin may act in bone cells and modulate the Klotho-FGF23 axis. This study analyzed the effects of dapagliflozin on serum bone biomarkers and related outcomes. In this predefined post-hoc analysis of a previous RCT, patients on dialysis received (1:1) dapagliflozin 10 mg daily or standard care for 24 weeks. The primary endpoint was the change from baseline in serum Klotho and FGF23 levels, compared by ranked analysis of covariance, adjusted by baseline. Exploratory analyses evaluated calcium, phosphate, PTH, bone-ALP, TRAP-5b, DKK1, sclerostin, and bone proteins. Bone fractures, osteopenia, and osteoporosis were outcomes of interest. Seventy-nine patients were included in this analysis (Control N=40 and Dapagliflozin N=39). At baseline, no significant differences in biomarkers were observed. The prevalence of osteopenia and osteoporosis was 73
This study used a network meta-analysis to evaluate the effects of different resistance training intensities and frequencies on bone mineral density (BMD) in middle-aged and older adults, aiming to identify the optimal exercise strategy for each skeletal site. PubMed, Embase, Cochrane, Web of Science, Google Scholar, and Scopus databases were searched for randomized controlled trials (RCTs) meeting the inclusion criteria. The Cochrane RoB 2 tool was used for literature quality assessment, and Stata 17.0 was used for network meta-analysis. The standardized mean difference (SMD) and 95
Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors secreting fibroblast growth factor 23 (FGF23). In children, TIO may be mistaken for more common causes of rickets and osteomalacia, including monogenic forms, leading to long diagnostic delays. This review aimed to identify evidence on the diagnostic journey and burden of TIO in pediatric patients. A literature review was conducted to identify publications reporting disease characteristics, investigations, treatments, and clinical outcomes in pediatric patients diagnosed with TIO. In total, 41 studies were included in the review, reporting on 46 pediatric patients. Mean age at presentation was 11.2 years (standard deviation [SD]: 4.6). The majority of individuals (60.9
Hypoparathyroidism in children is conventionally treated with calcium and active vitamin D, however, this approach does not restore parathyroid hormone (PTH) action and may leave hyperphosphatemia unresolved while increasing the risk of hypercalciuria. Teriparatide (PTH 1–34) offers a physiologic replacement, although evidence regarding its role in children remains limited. We systematically reviewed biochemical and skeletal effects of teriparatide in children with hypoparathyroidism. MEDLINE and Embase were searched from inception to January 2026, including studies of patients ≤ 21 years treated with teriparatide for ≥ 4 weeks. Outcomes included calcium and phosphate homeostasis, skeletal outcomes, growth, renal complications, and use of concomitant therapy. Data extraction followed Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines by 2 independent reviewers. Meta-analysis using weighted mean differences (WMDs) was performed when feasible. Other outcomes were summarized descriptively. Eighteen studies met the eligibility criteria, and a total of 94 pediatric patients were included. Serum calcium was maintained within target range with teriparatide, with no significant difference compared with conventional therapy (WMD –0.02, 95
IKKα, a key component of canonical and non-canonical NFκB signalling, is implicated in prostate cancer and bone metabolism. Here, we validated the anti-proliferative effects of selected molecules from a series of first-in-class IKKα inhibitors against a panel of human prostate cancer models and then showed that the potent anti-tumour and highly IKKα-selective SU1349 reduced the ability of human PC3 cells to migrate and invade in vitro, induce osteolysis ex vivo, and cause trabecular bone loss in mice. Paradoxically, mice treated with SU1349 exhibited cortical bone loss. Histomorphometrical in vivo and functional in vitro studies confirmed that SU1349 suppressed osteoclastogenesis, but both enhanced and reduced osteoblast number and activity. Mechanistically, despite SU1349 being an inhibitor with a significant selectivity for IKKα over IKKβ, it inhibited both canonical and non-canonical NFκB signalling in PC3 cells, osteoclasts, and osteoblasts, and reduced the levels of several PC3-secreted, NFκB-regulated factors. This study suggests that IKKα inhibitors could be of therapeutic value in the treatment of prostate cancer-induced osteolysis. However, osteoblast inhibition may limit their usefulness as osteoprotective agents.
Fracture healing is a complex biological process influenced by systemic conditions and medications. Given the high prevalence of cardiovascular disease in fracture surgery patients and the use of beta-blockers, evidence linking beta-adrenergic signaling to bone metabolism has raised interest in their effects on postoperative healing. This narrative review synthesizes experimental, translational, and clinical evidence regarding the impact of beta-blocker therapy on fracture healing. A structured literature-based approach was used to evaluate studies addressing β-adrenergic signaling in cardiovascular regulation, bone cell function, angiogenesis, and postoperative fracture outcomes. Both preclinical models and observational human studies were critically analyzed to identify mechanistic pathways and clinical associations. Experimental studies indicate that β-adrenergic signaling inhibits osteoblast activity and callus formation, enhances osteoclast activity, and impairs angiogenesis during bone repair. Beta-blockade, particularly with non-selective and lipophilic agents, may counteract these effects, thereby promoting bone formation and microvascular function in animal models. However, clinical evidence remains heterogeneous. Some observational studies report potential benefits, including reduced postoperative mortality or lower fracture risk, whereas other studies show no significant association with healing outcomes or suggest a possible increase in non-union risk. Confounding factors such as comorbid cardiovascular disease, polypharmacy, and differences in drug selectivity limit causal interpretation. Beta-blocker therapy may influence fracture healing through neurovascular and cellular pathways, but current clinical evidence is insufficient to confirm a definitive beneficial or harmful effect. Further prospective, mechanistic, and stratified clinical studies are required to clarify their role in optimizing both cardiovascular and skeletal outcomes in patients undergoing fracture surgery.
Osteoporosis results from impaired bone remodeling and deterioration of bone microarchitecture, ultimately increasing fracture risk. Although early-life nutritional stress has been implicated in long-term health outcomes, its impact on skeletal remodeling mechanisms remains unclear. We investigated whether gestational protein restriction induces persistent alterations in the skeletal immune microenvironment that contribute to age-related bone fragility. Pregnant C57BL/6J mice were fed either a normal-protein or low-protein (LP) diet during gestation. Male offspring were evaluated at 12 and 18 months of age. Microcomputed tomography revealed significant reductions in trabecular bone volume fraction, bone mineral density, and trabecular number in 18-month-old LP offspring, along with reduced cortical thickness at both ages. Three-point bending tests demonstrated reduced maximal load in LP-18 M femora, indicating compromised mechanical strength. Ultrastructural analyses revealed increased cortical porosity and disrupted collagen fiber organization in aged LP bone. RNA sequencing identified differentially expressed genes enriched in pathways related to macrophage recruitment, complement signaling, and osteoclast differentiation. RT-qPCR confirmed increased expression of C5ar1, Ccl3, Ccr2, Lilrb4a, and Trem2. Immunohistochemical analysis demonstrated increased CD68+ cells in aged LP animals, indicating expansion of the skeletal myeloid compartment. These findings demonstrate that gestational protein restriction induces long-term reprogramming of the skeletal immune microenvironment, associated with enhanced osteoclast-related signaling and impaired bone mechanical competence during aging.
This retrospective study aimed to compare pelvic muscle parameters between female patients with and without femoral neck fractures and to evaluate the feasibility of an automated CT-based workflow for exploring associations between pelvic muscle quality measures and femoral neck fracture status. The study included 119 female patients with low-energy femoral neck fractures and 107 age-matched female controls. Non-contrast computed tomography images were analyzed using a cloud-integrated deep learning segmentation tool. Pelvic muscle volume and quality parameters, including intramuscular adipose tissue, myosteatosis, and functional lean muscle, were quantified for the iliopsoas and gluteal muscles. Age-adjusted multivariate analysis, receiver operating characteristic analysis, and logistic regression were performed. Age and cortical bone parameters did not differ significantly between groups. In contrast, pelvic muscle quality parameters showed significant between-group differences after adjustment for age. Iliopsoas myosteatosis demonstrated the highest individual discriminatory performance, with an area under the curve of 0.711. The combined four-muscle myosteatosis model achieved the highest apparent within-sample discrimination, with an area under the curve of 0.739, indicating moderate discriminatory performance. Iliopsoas MYO values above the ROC-derived cut-off were associated with higher odds of belonging to the fracture group (OR, 4.22). Automated measurements showed excellent reliability. These findings suggest that pelvic muscle quality measures may provide complementary information for fracture-related assessment on routine CT examinations. Automated CT-based muscle quality assessment may provide a reproducible approach for opportunistic body-composition analysis on routine CT examinations. The cloud-enabled workflow used in this study illustrates technical feasibility; however, its clinical utility for fracture-risk stratification requires prospective validation.
Chronic kidney disease (CKD) leads to significant bone loss and high risk of fractures. Fractures are even more prevalent in the aging population with CKD. Cortical bone is particularly impacted in CKD due to cortical thinning and the development of cortical porosity. The goal of this study was to assess the impact of romosozumab, a bone anabolic therapy, on cortical bone in young and aging mice with adenine-induced CKD. Male C57Bl6/J mice, aged 16- and 66-weeks, were given 0.2
Distal radius fractures and proximal humerus fractures are common fractures in postmenopausal women with osteoporosis. The question of whether bone microstructural deficits are reflected in specific changes in bone microstructure at peripheral skeletal sites has not yet been investigated. In this retrospective study, treatment-naïve postmenopausal women with distal radius fractures (DRF) or proximal humerus fractures (PHF) were included. Of more than 500 patients screened, 30 patients with DRF and 30 patients with PHF were included in the final analysis following propensity score matching. All participants underwent biochemical testing, dual-energy X-ray absorptiometry assessment, and bone microstructural evaluation by high-resolution peripheral quantitative computed tomography. After propensity score matching, both groups showed no significant differences in terms of age, weight, height, BMI, and lowest T-score (all p > 0.05). Mean age was 64.4 ± 10.7 years in the DRF group and 66.7 ± 9.0 years in the PHF group (p = 0.365). In both groups, the lowest mean T-score was − 2.9 (p = 0.539). Overall, both groups showed a reduction in total BMD and microarchitectural parameters compared to reference values at the distal radius and tibia. The PHF group exhibited significantly reduced bone geometry at the distal radius compared with the DRF group, including lower total area (p = 0.004), trabecular area (p = 0.021), and cortical area (p = 0.006), as well as reduced cortical thickness at both the distal radius (p = 0.031) and tibia (p = 0.024). PHF are characterized by reduced cortical thickness and unfavorable bone geometry, which is independent of areal bone mineral density.
Atypical femoral fractures (AFF) are rare fractures with characteristic radiographic features, most commonly associated with long-term bisphosphonate use. Their occurrence in patients with osteogenesis imperfecta (OI), a hereditary bone disease leading to bone fragility, is not well understood. In this study, 138 adults with genetically confirmed classical OI were screened for AFF. Five patients with AFF were identified and compared to an age- and treatment-matched adult OI cohort without AFF (n = 23). Demographical parameters, biochemical markers, bone mineral density (DXA), bone microarchitecture (HR-pQCT), and radiographs were analyzed. In addition, antiresorptive therapy and the duration of treatment were determined and compared. In the screened OI cohort, AFF prevalence was 3.6
Hypophosphatasia (HPP) is a rare metabolic disorder caused by loss-of-function ALPL variants and characterized by heterogeneous skeletal and extra-skeletal manifestations. Although recent diagnostic criteria include ALPL variants, the diagnosis can be made based solely on clinical features. In adult-onset HPP, however, symptoms are often mild or nonspecific, including musculoskeletal symptoms and fatigue, making it difficult to differentiate from other conditions. This retrospective, cross-sectional study aimed to integrate genetic and biochemical data to enhance the clinical interpretation of low alkaline phosphatase (ALP) in patients with bone disorders. Among 865 consecutive adults visiting a bone-specialized outpatient department, patients with persistent hypophosphatasemia underwent ALPL sequencing. Clinical and biochemical characteristics were compared among three groups: biallelic or monoallelic variants with dominant-negative effect (DNE), monoallelic variants without DNE, and variant-negative individuals. Fifty-six patients (6.5
Defects in Odontogenesis-Associated Phosphoprotein (ODAPH) cause autosomal recessive non-syndromic amelogenesis imperfecta (AI; OMIM #614832). We present a 14-year-old boy with delayed tooth eruption and generalized soft and yellow enamel. The proband’s parents and two siblings were unaffected. Whole exome analyses identified the AI-causing homozygous ODAPH truncation mutation (p.Arg77*) in the proband. Both unaffected parents and one sibling were heterozygous for this change. The other sibling had the reference sequence. To better understand the role of ODAPH in normal amelogenesis and resolve conflicting reports of ODAPH expression and function during postsecretory transition (PST), we performed comprehensive Focused-Ion Beam Scanning Electron Microscopy analyses of continuously growing mandibular incisors from one wild-type and two OdaphC41*/C41* mice. Montages of sagittal sections were constructed using 5000 × images covering the surface enamel, ameloblasts, stratum intermedium and papillary layer during late secretory, PST, and early maturation stages. OdaphC41*/C41* ameloblasts completed the secretory stage showing no evidence of pathology. Dramatic histological differences between wild-type and OdaphC41*/C41* ameloblasts were observed during postsecretory transition closely preceding the onset of cyst formation in OdaphC41*/C41* ameloblasts. PST ameloblasts show marked abnormalities, including loss of polarity (nucleus moves distally), disrupted cellular organization, indistinct cell boundaries and rapid reduction in cell height. During PST and early maturation, a dark line indicative of a basal lamina is apparent in the superficial enamel, but it fails to maintain attachment with the ameloblast distal membrane, and a cyst forms between the enamel surface and the overlying flattened ameloblasts, which eliminates the entire maturation stage of amelogenesis. Immunohistochemistry of a Day 12 mandibular incisor detected ODAPH protein in PST and the maturation stage ameloloblasts, and concentrated along the basement membrane. We conclude that ODAPH is required for a successful transition into the maturation stage of amelogenesis. Loss of ODAPH function results in hypomineralized amelogenesis imperfecta.
Bone metastasis is a major clinical challenge and is frequently associated with resistance to immunotherapy and progressive skeletal destruction. Although cytokines are recognized as key regulators of both immune responses and bone remodeling, their integrated roles in the bone metastatic niche remain incompletely understood. Here, we propose a conceptual framework in which cytokine-driven osteo–immune reprogramming shapes the bone microenvironment into a state that supports tumor persistence. Within this framework, cytokines can be categorized into three functional groups—immune-dominant mediators, osteo–immune regulators, and divergent factors—whose context-dependent activities collectively coordinate immune suppression and osteoclastic bone destruction. Rather than acting independently, these cytokines form interconnected networks that establish reinforcing interactions, thereby stabilizing an immunologically cold and therapy-resistant niche. This integrated perspective suggests that immune resistance in bone metastasis does not arise solely from tumor-intrinsic properties, but emerges from dynamic crosstalk in the osteo–immune axis. The spatiotemporal regulation of cytokine signaling likely defines stage-specific vulnerabilities, providing opportunities for therapeutic intervention. Targeting cytokine networks in combination with immune checkpoint inhibitors and bone-modifying agents may represent a rational strategy to disrupt pathogenic osteo–immune circuits. A deeper understanding of the reprogramming of the bone microenvironment by cytokines will be essential for enabling durable immunotherapeutic responses in patients with bone metastatic disease.
