Neuroblastoma amplified sequence gene (NBAS) variants are associated with short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) syndrome. We previously identified compound heterozygous variants in NBAS to cause atypical Osteogenesis Imperfecta (OI), with these patients presenting with short stature, developmental delay, and recurrent long-bone fractures. However, skeletal disease progression due to these variants and the disease mechanisms underlying NBAS-associated OI remain poorly understood. Here, we provide a clinical update on previously identified patients and investigate the role of NBAS during skeletal development using zebrafish knockout and patient-specific missense variant zebrafish models. Homozygous knockout larvae exhibited delayed operculum development, reduced bone ossification, and defects in Meckel's cartilage morphology and its underlying cellular structure. Homozygous missense larvae displayed milder cartilage defects without any major defects to early skeletal structures. Seemingly opposing phenotypes were observed in compound heterozygous zebrafish carrying the knockout and missense alleles in trans, with no obvious phenotypes seen in the Meckel's cartilage and accelerated operculum development observed. Together, our results demonstrate that different nbas variants differentially affect skeletal development, suggesting complex spectrums of phenotypic and pathogenic mechanisms in NBAS-associated atypical OI.

Atypical femoral fracture (AFF) is a rare fracture associated with long-term bisphosphonate treatment that occurs in the subtrochanteric and midshaft femur. AFF is not fully explained by bone mineral density motivating identification of biomarkers of AFF risk that reflect bone quality. Cortical bone water has been linked to mechanical properties of bone. Ultra-short echo time magnetic resonance imaging (UTE MRI) can quantify water compartments in bone, including matrix-associated bound water (BW) and porosity-related pore water (PW). Here, we investigated the influence of BW and PW on fracture formation in the AFF region using MRI-based extended finite element modeling and applied fuzzy approximation to capture nonlinear effects between BW and PW on mechanical outcomes. Simulation results showed that individually, mean BW and PW were not correlated with FE-predicted whole femur fracture load or stiffness. Mean porosity index, which is the ratio of PW to total water, was negatively associated with strain at the crack site (R = -0.54, p = 0.026). Stiffness values from BW and PW-based FE simulations were significantly correlated (R = 0.92, p < 0.01), whereas no correlation was observed for fracture load. Fuzzy sensitivity analysis showed that PW and BW are interrelated variables, and their relative influence on stiffness and strain at crack location depends on their levels within the AFF region. These results provide new insights into mechanisms of AFF using MRI including the compartment-specific roles of bone water.

Romosozumab is an antisclerostin antibody that increases bone formation and decreases bone resorption. This study aimed to identify predictors of the response to romosozumab in women with postmenopausal osteoporosis previously treated with denosumab. The study had an observational pre-post design and included 167 women with primary osteoporosis. Romosozumab 210 mg was administered subcutaneously every 4 weeks for 12 months in 87 patients who had been treated with denosumab (DMAb group) and 80 who had not (naïve group). The safety, incidence of new fractures, and changes in bone mineral density (BMD) and bone turnover markers were recorded. At 12 months, a response was defined as a ≥ 3.0% increase in BMD and a non-response as a ≥ 3.0% decrease in BMD. Non-serious adverse events occurred in six patients (3.6%) in each group. New fractures occurred in three patients (4.0%) in the DMAb group and one (1.6%) in the naïve group. At 12 months, the changes in BMD at the lumbar spine and total hip were + 12.6% and + 4.7%, respectively, in the naïve group and + 3.9% and + 0.5% in the DMAb group. Bone turnover markers increased gradually after discontinuation of denosumab. A higher P1NP at baseline was associated with a response to romosozumab and a higher TRACP-5b at 3 months and longer duration of treatment with denosumab were associated with no BMD response at the total hip (TH). Longer denosumab use (≥18 months) followed by romosozumab may be associated with reduced TH BMD response and requires validation in larger prospective studies.

Early life experiences of physical activity have been shown in humans, rodents, and chickens to have long-lasting effects on bone density, structure, and fracture susceptibility. Nevertheless, commercial egg-laying chickens reared with opportunities for exercise still exhibit high fracture incidence. Thus, this study compared two genetic strains of female egg-laying chickens raised in four housing systems differing in structural complexity and the amount and type of exercise possible. At 6, 11, and 16 weeks of age, long bones of the wings and legs were analyzed for length, diameter, breaking strength via 3-point bending, and DEXA-based bone mineral content. Cortical bone density and microstructure was assessed with micro-computed tomography images in tibiae at 16 weeks of age. We found that both rearing environment (i.e. loading history) and genetic strain influenced bone structural and mechanical properties. Compared to conventionally cage-housed chickens, aviary-housed birds consistently exhibited stronger, longer, and wider bones normalized to body weight, as well as tibial microstructural changes associated with increased bone strength. Surprisingly, most improvements compared to caged birds were observed in the moderate-complexity aviary group. The white-feathered genetic strain tended to have longer, stronger bones than the brown (normalized to body weight). Overall, restricted activity was detrimental to bone strength and structure, and bone structure and strength differed between genetic strains of chickens. These data allow for a broader, cross-species understanding of the relationship between bone form and function, and also inform egg farmers when selecting optimal housing environments to improve the welfare and bone health of their flocks.

Patients with Alzheimer's disease (AD) often exhibit abnormal bone loss alongside cognitive impairment. However, the mechanisms linking these two conditions remain insufficiently understood. We first employed amyloid precursor protein/presenilin 1 (APP/PS1) mice as the experimental model and demonstrated that they exhibit significant bone loss concurrent with cognitive impairment. Subsequently, we analyzed public datasets for AD and osteoporosis (OP) and identified CXC chemokine ligand 16 (CXCL16) as a shared hub gene between the two diseases. Transcriptomic sequencing further showed increased CXCL16 expression in the femoral tissue of APP/PS1 mice. Immunoblot analysis of brain and bone tissues, together with serum enzyme-linked immunosorbent assay (ELISA), verified the systemic elevation of CXCL16. These findings suggest that CXCL16 may link cognitive impairment with bone loss in APP/PS1 mice. In vitro experiments showed that CXCL16 did not directly affect the differentiation of bone marrow mesenchymal stem cells or bone marrow-derived macrophages. Instead, CXCL16 acted through neutrophils by promoting their migration and potentiating PMA-stimulated neutrophil extracellular trap (NET) formation. Conditioned medium from NET-producing neutrophils inhibited osteogenic differentiation and promoted osteoclastogenesis. In APP/PS1 mice, antagonism of CXCR6, the cognate receptor for CXCL16, with ML339 improved trabecular bone microarchitecture and osteogenic activity and alleviated cognitive impairment. Degradation of NETs with deoxyribonuclease I (DNase I) produced similar effects. Collectively, these results implicate CXCL16-associated enhancement of NET formation in AD-related skeletal deterioration and highlight the CXCL16-NETs pathway as a possible intervention target for maintaining bone homeostasis.

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 toward 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.

Staphylococcus aureus osteomyelitis drives progressive bone destruction through dysregulated osteoblast-osteoclast crosstalk, yet the role of exosome-mediated circular RNA (circRNA) communication in this process remains poorly understood. This study aimed to determine whether exosomal circRNAs derived from S. aureus-infected osteoblasts orchestrate osteoclast-mediated bone resorption. Exosomes were isolated from hFOB1.19 osteoblasts with or without S. aureus infection, characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting, and their circRNA profiles were screened by RNA sequencing. A murine femoral osteomyelitis model was established via intramedullary S. aureus inoculation followed by tail-vein exosome injection, with bone microarchitecture and osteoclastogenesis assessed by micro-CT, histology, TRAP/ALP staining, qPCR, and Western blotting. The circ_0001843/miR-369-5p/TAFA5 axis was validated by dual-luciferase reporter assays. S. aureus infection markedly upregulated exosomal circ_0001843. In vivo, exosomes from infected osteoblasts aggravated bone destruction, evidenced by decreased BV/TV, increased trabecular separation, enhanced osteoclast activity, and suppressed osteogenic markers. In vitro, circ_0001843 knockdown attenuated RANKL-induced osteoclast differentiation while promoting osteoblast proliferation and mineralization; these protective effects were reversed by exosomes from infected osteoblasts or miR-369-5p inhibition. Mechanistically, circ_0001843 sponged miR-369-5p to derepress TAFA5, thereby disrupting bone remodeling homeostasis. These findings identify exosomal circ_0001843 as a novel mediator of infection-induced bone loss via the miR-369-5p/TAFA5 axis, highlighting a potential therapeutic target for osteomyelitis-associated bone destruction.

Teriparatide (PTH 1-34) is an anabolic agent used to treat osteoporosis, yet clinical response varies widely among patients. To investigate genetic and sex-specific determinants of skeletal response, we administered intermittent PTH to male and female mice from eight genetically diverse inbred strains. Mice were treated for four weeks, and bone phenotypes were assessed via DXA, microCT, and mechanical testing. Response to PTH was highly strain- and sex-dependent, with some strains responding at the femur but not the spine, and vice versa. Heritability estimates for PTH-induced changes in areal bone mineral density (aBMD), cortical bone area at the femoral mid-diaphysis, femur strength, and trabecular bone volume fraction (BV/TV) ranged from moderate to high, with BV/TV showing the strongest genetic influence. Cortical bone response mechanisms differed by sex: males exhibited periosteal expansion, while females showed endosteal remodeling. These findings mirror clinical observations where non-response to PTH can be anatomic site specific. Further, our study suggests that genetic background and sex significantly influence bone response to PTH. Our data support the future use of genetically diverse mouse models to elucidate the genetic architecture of skeletal response to PTH.

Age-related bone loss results from an imbalance between bone resorption and formation, which is heavily influenced by senescence of osteoblasts. Oxidative stress and the associated production of reactive oxygen species (ROS) are key contributors to bone aging and impaired bone formation. Our previous study demonstrated that protein arginine deiminase 2 (PADI2) is downregulated by ROS, leading to cellular senescence and impaired osteoblast differentiation. In this study, lncRNA H19 was identified as a critical factor co-regulated by ROS and Padi2 deficiency through mRNA-sequencing analysis. Using a stratified transcriptomic analysis in which genes commonly regulated by ROS and Padi2 deficiency were further classified according to their response to H19 knockdown, we investigated the biological processes associated with H19 in this context. This analysis suggested that H19 is a candidate regulator of osteoblast differentiation under oxidative stress and Padi2 deficiency. H19 knockdown significantly inhibited osteogenic differentiation of MC3T3-E1 cells but did not induce the senescence-associated responses observed following H2O2 treatment or Padi2 knockdown. Moreover, H19 overexpression promoted bone repair in a mouse calvarial defect model. Together, these findings provide new insights into the molecular mechanisms underlying bone aging and identify H19 as a potential therapeutic target for promoting osteogenesis.

The immune response is essential in shaping bone healing outcomes and is of particular interest in mandible fractures, as opposed to other fractures, because of the presence of teeth that are colonised by a multitude of microbes that can cause infection or complicate healing. This study investigated the peripheral blood cell transcriptome during mandibular fracture healing phases with particular focus on immune-related indicators. Blood samples from mandibular fracture patients who had normal healing were collected at the time of injury, then 2 weeks and 6 weeks following the injury, corresponding to the inflammation, repair, and remodelling phases of bone healing, respectively. RNA sequencing was performed for blood cells and analysed using the Ingenuity Pathway Analysis (IPA) software. Data validation was conducted using ELISA for soluble serum factors and blood cell counting using Sysmex. The results indicated distinctive systemic changes between the three healing phases. A significant increase in activity and counts of blood neutrophils and monocytes was noted during the inflammatory and repair phases compared to the remodelling phase. In contrast, a prominent activity and increased quantity of blood lymphocytes were detected in the remodelling phase. Furthermore, increased serum levels and activated signalling of interleukin 10 (IL10) were detected, mainly during the inflammation and repair phases. Interestingly, blood cells were found to express high levels of osteogenesis-related markers during the repair phase, with significantly increased serum levels of Insulin-like growth factor 2 (IGF2). In conclusion, systemic blood cell transcriptomic profiling showed a shift from predominantly innate toward adaptive immune response during mandible healing, with serum IL10 and IGF2 levels indicating the resolution of inflammation and the start of osteogenic repair. Therefore, peripheral blood cells and serum factors could be a promising source of non-invasive biomarkers for monitoring healing trajectories of mandible injuries.

Open access has widened access to scientific knowledge while shifting much of the cost of publication from readers and libraries to authors and their funders. At the same time, China has rapidly expanded its research output and journal infrastructure, reshaping the geography of scientific publishing. This Commentary examines how these developments intersect in bone science, using Bone Research as a case study. The journal's rise reflects genuine scientific achievement as well as the strategic combination of full open access, international publishing infrastructure, a large research community, authoritative reviews, and strong representation of rapidly expanding interdisciplinary topics. Its high Journal Impact Factor should be understood as a measure of citation performance, not as evidence that every article is more rigorous or clinically consequential than work published elsewhere. These changes matter for osteoporosis research and care because publication costs and citation-oriented editorial priorities may influence which investigators, research questions, and forms of clinical evidence become visible. China did not create these rules; it adapted to them at exceptional scale and speed. A more equitable system should preserve reader access, improve transparency about article processing charges and manuscript transfers, reduce reliance on journal-level metrics, protect editorial independence from publication revenue, and support researchers with limited publication funding.

Osteonecrosis, or avascular necrosis, of the femoral head (ONFH) results from an avascular insult of traumatic or non-traumatic origin and can lead to significant morbidity, including pain, arthritis and the need for joint replacement at a young age. Non-surgical management of ONFH focuses on preservation of femoral head shape to reduce the need for arthroplasty or delay the age at which it is performed. Thirty patients diagnosed with ONFH on bone scan were prospectively studied to determine the safety of alternating denosumab and zoledronic acid over a 66-week treatment period. Patients underwent 6-weekly scheduled biochemical monitoring and assessment of bone mineral density at baseline and after twelve months. Mild hypercalcaemia (range 2.65-2.85 mmol/L) was noted in 5 patients (16%) during the treatment period. One of these patients was subsequently diagnosed with familial hypocalciuric hypercalcaemia. Asymptomatic hypocalcaemia (range 1.79-2.00 mmol/L) was detected on routine biochemical testing in a total of 15 patients (48%). All episodes responded to an increase in oral calcium supplementation. Bone mineral density (BMD) increased in all patients following treatment, with maximum total body height-adjusted Z-score +2.4 and lumbar spine +3.3. There were no episodes of medication-related osteonecrosis of the jaw, atypical femoral fracture or hypophosphataemia. Our study demonstrates that, with regular monitoring and management of serum calcium, alternating doses of denosumab and zoledronic acid can be administered safely for ONFH in children.

Micro-computed tomography (μCT) is widely used to assess trabecular bone microarchitecture, with trabecular separation (Tb.Sp) among the core parameters recommended for reporting. Tb.Sp is typically expressed as a single volume-weighted mean derived from maximal sphere fitting, although the underlying distribution of local separation values is rarely examined. Here, we show that Tb.Sp distributions in metaphyseal trabecular bone are frequently non-Gaussian and bimodal or multimodal. Using μCT datasets from three established models of osteoporosis, spinal cord injury (SCI), ovariectomy (OVX), and ageing (AGE), we demonstrate that this behaviour is most evident in metaphyseal trabecular bone and is less apparent in epiphyseal trabecular bone or trabecular thickness distributions. We further show that multimodal metaphyseal Tb.Sp distributions contain lower- and higher-diameter components with different predominant spatial localisations. Lower-diameter values were predominantly associated with marrow spaces within the residual trabecular network, whereas higher-diameter values were predominantly associated with larger contiguous marrow cavities. Based on this observation, we introduce a simple extension to standard morphometric analysis in which Tb.Sp is decomposed into lower-diameter trabecular separation (Tb.SpL) and higher-diameter trabecular separation (Tb.SpH). Tb.Sp decomposition revealed model-specific patterns of trabecular deterioration. SCI showed increases in both components, dominated by a marked redistribution toward Tb.SpH, consistent with expansion of larger marrow cavities, whereas OVX showed increased Tb.SpL without a significant Tb.SpH difference. AGE showed progressive increases in Tb.SpL and greater representation of Tb.SpH in older animals. Together, these findings demonstrate that mean Tb.Sp can mask structurally distinct forms of metaphyseal marrow-space organisation, and support reporting distributional descriptors, and where appropriate, Tb.SpL and Tb.SpH, alongside conventional Tb.Sp.