Inflammatory bone loss is a frequent complication of chronic inflammatory and immune-associated disorders. In this review, we synthesize the osteoimmune mechanisms through which persistent inflammation disrupts coupled bone remodeling, with emphasis on RANKL-dependent osteoclastogenesis, suppressed osteoblast-supportive signaling, cytokine networks, immune-cell plasticity, and lesion microenvironment. We distinguish canonical inflammatory bone-loss settings, such as rheumatoid arthritis, periodontitis, and inflammatory osteolysis, from supportive models, including diabetic, ovariectomy-associated, osteoarthritis-related, and steroid-associated bone pathology. We further discuss local versus systemic bone loss and the emerging concept that osteoclasts arising in inflammatory environments may differ from those in physiological remodeling. Natural small molecules are reviewed as multifunctional candidates, but their therapeutic potential is evaluated cautiously in light of model heterogeneity, limited clinical data, pharmacokinetic constraints, and uncertain lesion-specific exposure. Finally, delivery platforms are considered as disease-context-dependent tools for improving local retention, formulation stability, and potentially lesion-specific exposure to natural small molecules.

To optimize osteoporosis therapy with the parathyroid hormone fragment teriparatide (PTH1-34), we sought to determine whether strontium (Sr) could potentiate the bone anabolic action of intermittent PTH1-34 in ovariectomized rats. Female rats were either Sham-operated or ovariectomized (Ovx) at 6 months of age. Eight weeks after surgery, Ovx rats received either vehicle solutions, 625 mg/kg/day Sr (5 days per week), 8 µg/kg/day PTH1-34 (5 days per week), or the combined treatments for 8 weeks. PTH1-34 reversed Ovx-induced deterioration of trabecular microarchitecture, apparent volumetric bone mineral density (vBMD), and strength, whereas Sr alone increased tissue-level vBMD without significantly affecting trabecular bone mass. Co-treatment with Sr and PTH1-34 further increased trabecular thickness (+ 8.9% vs. PTH1-34 alone), apparent and tissue-level vBMD (+ 9.6% and 6.7% vs. PTH1-34 alone), bone material properties (maximum force, + 18.2% vs. PTH1-34 alone; working energy, + 17% vs. PTH1-34 alone), and trabecular bone strength compared with PTH1-34 alone. In cortical bone, PTH1-34 increased bone volume, cortical thickness, and apparent vBMD, while co-treatment further enhanced cortical thickness (+ 7.2% vs. PTH1-34 alone) and apparent vBMD (+ 7% vs. PTH1-34 alone), maintained the Sr-induced increase in tissue-level vBMD, and significantly improved bone strength. In primary osteoblast cultures, Sr and PTH1-34, administered either alone or in combination, increased Rankl and decreased Opg expression, consistent with the elevated urinary levels of the bone resorption marker deoxypyridinoline in vivo. Sr or PTH1-34 alone stimulated Igf1 and Alpl expression, whereas co-stimulation further enhanced these osteogenic markers. In conclusion, combining Sr with PTH1-34 integrates the osteoanabolic effects of PTH1-34 on bone mass with the mineral-level effects of Sr on bone material properties, leading to synergistic stimulation of bone formation and superior improvements in bone quality and strength.

Osteoporosis is a systemic skeletal disorder fundamentally characterized by an imbalance between bone formation and bone resorption, ultimately leading to reduced bone mass, microarchitectural deterioration, and increased fracture susceptibility. As bone is a highly mechanoresponsive tissue, mechanical stimulation is indispensable for the maintenance of skeletal homeostasis, and insufficient loading is a recognized driver of bone loss. In recent years, Piezo1, integrins, and YAP/TAZ have emerged as key nodes in bone cell mechanotransduction. Piezo1 functions primarily as a mechanosensitive ion channel that converts membrane deformation into calcium-dependent intracellular signaling, integrins mediate extracellular matrix adhesion and focal adhesion-based force transduction, and YAP/TAZ act as nuclear effectors that translate mechanical inputs into transcriptional programs. Increasing evidence indicates that these pathways do not function independently but are organized into a complex and dynamic signaling network that governs osteocyte mechanosensation, osteoblast differentiation, mesenchymal stem cell fate determination, and osteoclast-related remodeling responses. Dysregulation of this mechanotransduction axis has been implicated in aging-related bone loss, estrogen deficiency-induced osteoporosis, and unloading-associated skeletal deterioration. Moreover, these pathways are increasingly being recognized as potential therapeutic targets for osteoporosis, with translational strategies ranging from pharmacological modulation to biomaterial-guided and mechanically assisted interventions. This review summarizes the roles of Piezo1, integrins, and YAP/TAZ in osteoporotic mechanotransduction, emphasizes their crosstalk in the membrane-to-nucleus signaling continuum, and discusses future research priorities, particularly cell specificity, spatiotemporal heterogeneity, and translational applications in precision skeletal medicine. In the revised version, we further distinguish experimentally validated links from proposed models, define the hierarchy of Piezo1-, integrin-, and YAP/TAZ-dependent signaling across osteocytes, osteoblast-lineage cells, BMSCs, and osteoclast/macrophage-lineage cells, and emphasize context-dependent controversies that are essential for therapeutic translation.

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 SU[1349] 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 SU[1349] exhibited cortical bone loss. Histomorphometrical in vivo and functional in vitro studies confirmed that SU[1349] suppressed osteoclastogenesis, but both enhanced and reduced osteoblast number and activity. Mechanistically, despite SU[1349] 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.

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% CI -0.10 to 0.07). Serum phosphate was lower with teriparatide (WMD -0.28, 95% CI -0.45 to -0.12). Urinary calcium excretion findings were variable, although longer-term studies suggested reductions. Growth and bone mineral density remained within normal ranges. Renal outcomes were heterogeneous. Overall teriparatide maintains serum calcium and may improve phosphate balance in children with hypoparathyroidism. However, given limited and heterogeneous evidence, conventional therapy should remain first-line, with teriparatide considered in selected patients.

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% dietary adenine to induce CKD. Eight weeks after induction of CKD, a subset of young and aging adenine-CKD mice were given romosozumab (10 mg/kg, 1x/week for 4 weeks); the study also included age-matched healthy controls. At the study endpoint, all adenine-CKD mice had high blood urea nitrogen and parathyroid hormone compared to controls. Romosozumab-treated groups of both ages had higher trabecular bone volume due to increased trabecular thickness, indicating an anabolic effect of therapy. Romosozumab-treated young mice had higher midshaft femur cortical bone area and cortical thickness, but there were no differences in cortical porosity compared to untreated adenine. Aging mice had no differences in cortical thickness, but cortical pore number was lower with romosozumab treatment. Four-point-bending mechanical tests showed 20% higher ultimate force with romosozumab treatment in both ages, statistically different from untreated adenine in the young cohort. These data demonstrate positive cortical bone effects from four weeks of romosozumab treatment in both young and aging mice with established CKD.

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%. No significant differences were observed between groups regarding age, weight, height, BMI, fracture history, bone mineral density, or antiresorptive therapy exposure and duration. HR-pQCT showed no significant microarchitectural differences, although a trend toward higher cortical thickness was noted in AFF patients. AFF are a rare complication in adults with classical OI and appear to be multifactorial in origin. Our findings suggest that AFF are not exclusively related to antiresorptive therapy but may be influenced by disease-specific factors, particularly the underlying collagen defect, femoral deformities and altered biomechanics. Individualized management strategies are essential, and further studies are needed to clarify underlying mechanisms and best treatment options.

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%) showed persistent hypophosphatasemia. Two (0.2%) were compound heterozygotes, and 29 (3.4%) carried monoallelic variants without DNE. Clinical symptoms and secondary causes of hypophosphatasemia were similar between monoallelic without DNE and variant-negative patients, whereas serum ALP, urinary phosphoethanolamine (PEA), and plasma inorganic pyrophosphate (PPi) differed significantly. A model using thresholds of ALP < 35 IU/L, urinary PEA > 91 µmol/gCr, and plasma PPi > 1.96 µmol/L demonstrated high diagnostic performance for identifying patients with monoallelic variants without DNE. This study elucidated the complex clinical spectrum of patients with low ALP. Although clinical manifestations were comparable between monoallelic individuals without DNE and variant-negative individuals, distinct biochemical profiles were observed. Integrating genetic nosology into current diagnostic criteria may refine clinical decision-making.

We aimed to evaluate treatment patterns, complications, and associated risk factors in a large cohort of patients with permanent hypoparathyroidism (HypoPT). This retrospective cross-sectional study included 958 adults with permanent HypoPT. Clinical and laboratory features were compared by etiology: postsurgical (86.4%) and nonsurgical (13.6%). The surgical group was further stratified by benign versus malignant thyroid histopathology. Risk factors for HypoPT-related complications were assessed using regression analyses. Patients received calcium, calcitriol, thiazide diuretics, cholecalciferol, teriparatide, or palopegteriparatide. Nephrolithiasis/nephrocalcinosis, basal ganglia calcifications (BGC), cataract, and hypercalciuria were detected in 13.5, 15.2, 20.8, and 44.4%, respectively, intravenous (IV) calcium was required in 8.4% within two years. Compared with postsurgical group, nonsurgical patients had lower calcium and parathyroid hormone (PTH), higher phosphate levels, greater calcium and calcitriol requirements, higher rates of BGC and IV calcium requirement, and higher T-scores (p < 0.05); nephrolithiasis/nephrocalcinosis and cataract were also more frequent (p = 0.086 and 0.072). Compared with malignant histopathology, benign group was associated with a higher BGC prevalence and higher phosphate levels (p = 0.022 and < 0.001). Hypercalciuria was independently associated with nephrolithiasis/nephrocalcinosis; older age, nonsurgical etiology, longer disease duration, hyperphosphatemia, and undetectable PTH with BGC; nonsurgical etiology with cataract; younger age, treatment suboptimal-adherence, and absence of hypercalciuria with IV calcium requirement (p < 0.05). Additionally, in univariable analyses, high-dose calcitriol was associated with nephrolithiasis/nephrocalcinosis and high-dose calcium with BGC (p < 0.05). In conclusion, HypoPT-related complications were associated with hyperphosphatemia, hypercalciuria, undetectable PTH, and high-dose conventional treatment, underscoring the need for better treatments and future studies to determine whether PTH-replacement therapy reduces complication risks.

X-linked hypophosphatemia (XLH) is a rare genetic rachitic/osteomalacic and dental disorder caused by pathogenic variants in PHEX gene resulting in fibroblast growth factor 23 (FGF23) excess leading to hypophosphatemia by renal phosphate wasting and decreased 1,25-dihydroxyvitamin D production. The aim of the study was to provide insight into natural history and phenotype in untreated adults with XLH (no phosphate supplements and active vitamin D metabolites or burosumab). Clinical, biochemical, skeletal features, co-morbidities, and patient-reported outcomes (PROs) were examined in 52 patients (51.5 ± 12.2 years; 18 men and 34 women). Mean height Z-score and mean leg length Z-score were lower than normal (P < 0.0001) and were lower (P < 0.01) in men (-3.8 ± 1.2 and -4.2 ± 1.2, respectively) than in women (-2.9 ± 0.8 and -3.4 ± 0.9, respectively). BMI was in the range of overweight in 30 patients (57.7%) and in the range of obesity in 15 patients (28.8%). Most of patients had severe skeletal deformities and dental-periodontal abnormalities. Pseudofractures were documented in 17 patients (33%). Mean concentration of intact FGF23, osteocalcin, PINP, CTX, and BALP was higher in men compared to women (P < 0.05-P < 0.001). PROs ranged from moderate to severe scores, with no difference (P = NS) between sexes. The phenotype in adult individuals with XLH was characterized by severe and disproportionate short stature, overweight/obesity, severe skeletal deformities with difficulty walking, osteoarticular pain, poor dental health, and reduced quality of life. Stature and biochemical markers of bone turnover were more compromised in men than in women.