Osteogenesis imperfecta (OI) is a heritable connective-tissue disorder characterized by skeletal fragility (amongst other manifestations) despite relatively preserved bone mineral density (BMD), suggesting that alterations in bone quality play a central role. Intrinsic matrix defects, including disrupted collagen assembly, altered enzymatic cross-linking, changes in matrix hydration, and disturbed mineral chemistry, are consistently observed and contribute to impaired mechanical competence. Although Raman spectroscopy is well suited to probe these compositional features, its application in OI has been limited to date, and prior studies have seldomly accounted for tissue age, a critical determinant of local bone composition. Whether cortical bone exhibits tissue-age–dependent spectroscopic abnormalities similar to those reported in trabecular bone remains unknown.To address this gap, in the present study we used Raman microspectroscopy to analyze the cortical compartment of iliac bone biopsies from 16 children with mild OI (aged 2–15 years). Bone-forming endosteal and osteonal surfaces were analyzed across three specifically defined tissue ages to characterize mineral and matrix composition.Compared with age-matched healthy controls, OI cortical tissue exhibited elevated mineral/matrix ratio, nanoporosity, and pyridinoline cross-link content, coupled with decreased crystallinity mineral crystallites.These findings reveal distinct cortical matrix abnormalities in children with mild OI mutations and complement previously published data obtained in the cancellous compartment. The altered compositional profile and accelerated maturation kinetics likely contribute to compromised tissue-level mechanical competence and increased fracture susceptibility in children diagnosed with mild OI.
Beta-tricalcium phosphate (βTCP) is widely used as a bone graft substitute, but it lacks intrinsic osteogenic cells. Human induced pluripotent stem cells (iPSCs) are a promising cell source for bone regeneration; however, the suitability of clinically available, uncoated βTCP as a scaffold for iPSC osteogenic differentiation remains unclear. We compared interconnected porous and unidirectional porous βTCP combined with either negative-pressure or atmospheric-pressure seeding. Metabolic activity was assessed using a CCK-8 assay, and the selected condition was further evaluated by RT-qPCR, scanning electron microscopy, and immunofluorescence staining during osteogenic induction. In vivo osteogenic progression was examined after subcutaneous transplantation into immunodeficient rodents. Negative-pressure seeding was associated with lower metabolic activity, whereas atmospheric-pressure seeding onto unidirectional porous βTCP yielded the highest values among the tested conditions. Under this condition, undifferentiated markers decreased after osteogenic induction, while osteoblast- and osteocyte-related genes showed time-dependent changes consistent with osteogenic lineage progression. Scanning electron microscopy demonstrated cell attachment and three-dimensional extension within the oriented pores, and immunofluorescence staining showed increasing type I collagen deposition during culture. After transplantation, human cell-derived RNA remained detectable, and several osteogenic markers increased over time. These findings indicate that clinically available, uncoated unidirectional porous βTCP can support the survival and osteogenic differentiation of human iPSCs in the absence of additional scaffold coating. This system may provide a simple platform for further studies of iPSC-based bone regenerative strategies.
We report a 30-year-old male with early-onset primary hyperparathyroidism (PHPT) and incidental papillary thyroid carcinoma. Biochemical tests showed hypercalcemia, hypophosphatemia, elevated PTH and normal renal function. Planar 99ᵐTc-MIBI scintigraphy projected a parathyroid lesion to the left thyroid inferior pole, while surgery revealed an ectopic solitary parathyroid adenoma in the left upper mediastinum; serum calcium, phosphate and PTH normalized two months postoperatively. Whole-exome sequencing detected a novel heterozygous PTH1R variant c.982G > A (p.Gly328Ser), classified as a variant of uncertain significance by ACMG/AMP criteria. The identical variant was identified in the proband's father, whose annual routine calcium and phosphorus tests remained persistently normal, so he declined additional parathyroid-related biochemical testing. Unlike previously reported PTH1R mutations linked to skeletal/dental defects, this patient presented isolated PHPT without skeletal or dental abnormalities. Neither classic loss-of-function nor canonical gain-of-function mechanisms fully explain this unique phenotype, and no in vitro functional data are available to validate variant pathogenicity. This case expands the phenotypic spectrum of PTH1R-related disorders and offers a new genetic clue for early-onset PHPT. Further functional experiments and long-term family follow-up are needed to verify the clinical relevance of this variant.
Cerebral palsy (CP) is associated with poor bone architecture. It is unclear if abnormal bone architecture is localized to the area affected by spasticity and whether these deficiencies are dependent on physical activity. This study aimed to examine differences in tibial bone architecture between the spastic and non-spastic limbs in children with unilateral spastic CP and the association between physical activity habits with spastic limb bone architecture. Twenty-four ambulatory children with CP (13 females, 11 males; 7.8 ± 1.7 years) completed bilateral high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal tibia metaphysis. The frequency of participation (FPS), bone specific physical activity questionnaire (BPAQ), and dynamic participation survey (DPS) were used to assess physical activity habits. Differences between limb architecture were assessed with paired t-tests. Linear regressions were performed on FPS/BPAQ/DPS scores with each HR-pQCT outcome separately. HR-pQCT data without significant motion artifacts were available for eighteen participants. The spastic limb had less total area (p = 0.013, 95%CI 4.87–35.13mm2), trabecular area (p = 0.035, 95%CI 1.22–29.96mm2), cortical area (p = 0.008, 95%CI 1.35–7.63mm2), cortical perimeter (p = 0.012, 95%CI 0.52–3.60 mm), cortical thickness (p = 0.046, 95%CI 0.001–0.112 mm), stiffness (p = 0.012, 95%CI 2065-13,429 N/mm), and failure load (p = 0.008, 95%CI 128-747 N) than the non-spastic limb. Only BPAQ was associated with limb length (p = 0.011, R = -0.584). The distal tibia metaphysis of the spastic limb had similar bone density but was smaller and weaker compared to the non-spastic limb. Differences in bone geometry likely accounted for between-limb differences in estimated bone strength.
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) can obscure fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets/osteomalacia. We report two FD/MAS patients with recurrent fractures, hypophosphatemia, elevated FGF23, and serial imaging showing overlooked rachitic changes years before diagnosis. Burosumab corrected hypophosphatemia after dose adjustment and was associated with mobility gains in Case 1 and increased growth velocity with physeal normalization in Case 2. Age-appropriate phosphate assessment and FGF23 testing are warranted when orthopaedic findings suggest impaired mineralization.
SUNFLOWER is a 10-year longitudinal observational cohort study of patients with X-linked hypophosphatemia (XLH) in Japan and South Korea. This report describes the 3-year cut-off of SUNFLOWER, including data from 1 year of burosumab administration (burosumab-treated group) and 1 year after providing informed consent (non-burosumab-treated group). The real-world effectiveness of burosumab and the associations between bone metabolism markers and quality of life (QoL)/patient-reported outcomes (PROs) and rickets severity scores (RSS)/height over 1 year in burosumab-treated patients with XLH were assessed. As burosumab had not been launched in South Korea at the time of cut-off, data from South Korea were not available. The main outcome measures were changes in serum parameters, and correlations between alkaline phosphatase (ALP) levels and RSS and height (children), and between ALP (children) or bone-specific ALP (BALP; adults) levels and QoL/PROs and motor functions. In total, 146 patients were enrolled, including 69 (47.3%) children and 77 (52.7%) adults. After 1 year of treatment, burosumab-treated patients (43 [62.3%] children, 29 [37.7%] adults) had improved serum phosphate levels, 1,25-dihydroxyvitamin D, and ALP/BALP compared with pre-treatment levels. In children, RSS changes significantly correlated with ALP changes (correlation coefficient: 0.806, p < 0.001), but height changes did not show significant correlation. There were no significant correlations between changes in ALP/BALP and QoL/PRO assessments or motor function. In conclusion, decreased ALP correlated with an improvement in rickets severity score in Japanese children with XLH, suggesting that ALP may be a useful marker for monitoring both the severity and improvement of rickets/osteomalacia. Clinical trial registration NCT03745521 and UMIN000031605.
Autophagy is a cellular recycling pathway in which cytoplasmic components are delivered to lysosomes for degradation. Changes in autophagy levels have been implicated in various skeletal pathologies including osteoporosis. Elimination of autophagy at different stages of the osteoblast lineage reduces bone formation and bone mass. However, whether autophagy plays a role specifically during development, growth, or maintenance of bone remains unclear. To start addressing this question, we eliminated autophagy in the entire osteoblast lineage prenatally or at weaning and subjected the mice to skeletal phenotyping at 4.5 and 10 months of age. We found that regardless of when autophagy was eliminated from the osteoblast lineage, autophagy deficiency reduced bone mineral density (BMD), cortical thickness, and cancellous bone volume in the femur and spine. Serial BMD analysis revealed that autophagy-deficient mice had consistently lower BMDs from 3 to 9 months of age, and the BMD difference between genotypes became progressively greater in the spine. The reduction in vertebral cancellous bone volume of autophagy-deficient mice was associated with reduced bone formation. To assess autophagy-induced changes at the cellular and molecular level, we performed single-cell RNA-sequencing (scRNA-seq) analysis of periosteal mesenchymal cells and compared autophagy deficiency-induced changes in periosteal and endosteal cell preparations. This analysis revealed that autophagy deficiency disrupts proteostasis, causes mitochondrial dysfunction, induces senescence, and increases stress response pathways like TNF and TGF-β. Overall, we conclude that autophagy is important for skeletal growth and maintenance of bone, and we identify potential cellular populations and cellular processes via which autophagy support bone formation.
Bone regeneration requires coordinated interactions between multiple cell types responding to biochemical and biomechanical cues from the extracellular matrix (ECM). Gingival fibroblasts (GFs) and periodontal ligament fibroblasts (PDLFs) contribute to the regeneration of lost alveolar bone, as they can differentiate into osteoblast-like cells and regulate osteoclastogenesis. However, it remains unclear whether these two fibroblast populations contribute similarly to bone regeneration and how ECM properties modulate their osteogenic differentiation and subsequent osteoclast-inducing capacity. Here, we compared the osteogenic potential of GFs and PDLFs from 12 donors, cultured in 2D monolayers or 3D fibrin hydrogels under normal or osteogenic conditions, and assessed how fibroblast-conditioned media regulates osteoclast formation from peripheral blood mononuclear cells (PBMCs). Both fibroblast populations underwent osteogenic differentiation, as evidenced by increased alkaline phosphatase (ALP) activity, calcium deposition, and robust mineral nodule formation in 3D fibrin hydrogels. Osteogenic stimulation reduced macrophage colony-stimulating factor (M-CSF) secretion and increased osteoprotegerin (OPG) release. Functionally, conditioned media from non-osteogenic cultures promoted formation of multinucleated TRAcP-positive osteoclasts and upregulated osteoclast-associated genes, including TRACP, RANK, Cathepsin K, and the fusion marker DC-STAMP. In contrast, osteogenic differentiation attenuated the osteoclast-inducing capacity of both fibroblast populations. Across all parameters, GFs and PDLFs displayed largely comparable osteogenic and osteoclast-modulating phenotypes, irrespective of culture dimensionality. These findings indicate that osteogenic differentiation functions as a regulatory switch that diminishes the osteoclast-inductive potential of oral fibroblasts and support the interchangeable use of GFs and PDLFs in periodontal regenerative strategies.
Bruck syndrome type 2 (BRKS2) is a rare disorder marked by congenital joint contractures and bone fragility, caused by variants in PLOD2, which encodes lysyl hydroxylase 2 essential for collagen stability. We report the first genetically confirmed BRKS2 cases from Indonesia and Ukraine, both showing fractures, skeletal deformities, and contractures. The Indonesian patient had compound heterozygous variants, while the Ukrainian patient had a homozygous missense variant, expanding the phenotypic and geographic spectrum of the disorder.
Sclerostin neutralizing antibody is an approved anabolic drug used to increase bone mass. Numerous preclinical studies examined bone mass and microstructural changes in mice receiving sclerostin neutralizing antibodies or mice lacking sclerostin, such as Sost knock out mice. Surprisingly no preclinical studies examined the effect of sclerostin deficiency with aging, despite the treatment being used primarily in older individuals. Thus, our primary aim was to examine the effect of long-term Sost deficiency on bone microstructure, including osteocyte lacunar and bone vascular porosity properties across ages. Our results show that Sost deletion led to sustained bone formation across the mouse's lifespan, whereas wild-type control mice experienced bone maturation followed by age-related declines in bone volume. Lacunar parameters were also affected due to Sost deletion, with altered lacunar density and volume in young mice, but these differences were not present in old mice. Our secondary aim was to examine the effect of short-term sclerostin deficiency on bone microporosity in woven and cortical bone after an osteotomy in adult female C57BL6J mice. Short term sclerostin antibody treatment did not alter vascular or lacunar porosity within lamellar or newly formed woven bone, suggesting that timing and duration are critical for therapeutic efficacy. In summary, Sost KO mice exhibit sustained cortical thickening and pronounced bone vascular porosity, particularly as the mice aged. As sclerostin neutralizing antibody becomes more widely used in an aging population, for extended periods of time, this work helps us understand the effects of long-term inhibition.
Local anesthetics such as lidocaine have anti-inflammatory effects. However, the anti-inflammatory mechanism remains vague, but phagocytosis, migration, exocytosis, cellular metabolism and cellular pH levels seem to be affected. During COVID-19 pandemic was found that pro-inflammatory serum levels of IL-1, IL-6, TNF-α were reduced when lidocaine was given to these patients. These pro-inflammatory markers are also elevated in periodontitis and osteoporosis. IL-1 is known as an osteoclast activating factor. To investigate if lidocaine can inhibit osteoclast activity lidocaine was added to osteoclast precursors (PBMCs) alone or in co-cultures with GF cells. Lidocaine was added in a concentration of 3 mM for 6 h and 6 mM for 24 h. After 3 weeks of culture osteoclast formation, gene expression of RANKL, and inflammatory cytokines and resorption activity were measured. Exposure for 24 h to 6 mM lidocaine showed large vacuoles in both cell types. After three weeks of culture osteoclasts were formed but their number was significantly lower in the with 6 mM lidocaine treated co-cultures. Also, gene expression of RANKL, MCP-1, IL-1 and TNF-α was lower. When a 3 mM lidocaine concentration was added for 6 h the vacuoles were only visible in the GF cells and not in the PBMCs and after 3 weeks the number of osteoclasts formed was not reduced. When osteoclasts cultured on bone their resorptive activity was significantly lower. The lower lidocaine concentration and shorter incubation time showed that cell number was not affected but resorption activity of the osteoclasts was decreased. This indicates that lidocaine can inhibit osteoclast activity.
Background:Concomitant use of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and bone resorption inhibitors (BRIs) may increase the risk of medication-related osteonecrosis of the jaw (MRONJ). The relative contribution of VEGFR-TKI, BRI type, and patient-related risk factors remains unclear. Methods:We retrospectively reviewed patients treated with BRIs, with or without concomitant VEGFR-TKIs. The primary endpoint was MRONJ-free survival, defined as time from BRI initiation to MRONJ diagnosis. Secondary endpoints included MRONJ incidence and skeletal-related events (SREs). Results:Overall, 233 patients received BRI/VEGFR-TKI combination (study group) and 986 received BRI alone (control group). Median MRONJ-free survival was shorter in the study group than in controls (79 vs 202 months). However, after adjustment for smoking status, age, sex, and BRI type, concomitant VEGFR-TKI use was not independently associated with MRONJ-free survival (HR 1.3, 95% CI 0.8-2.1; p = 0.2), whereas denosumab use and active smoking remained independent predictors. VEGFR-TKI therapy was associated with earlier MRONJ occurrence among BP-treated patients (adjusted HR 3.22, 95% CI 1.08-9.56; p = 0.03), but not among denosumab-treated patients. MRONJ-incidence did not differ between BRI/VEGFR-TKI and BRI groups (14.6% vs 12.0%; p = 0.3), but BRI-exposure was shorter in the combination group. SRE occurrence was 69.5%, similar between BP- and denosumab-treated patients; however, denosumab-treated patients had longer exposure, resulting in a lower SRE rate (0.13 vs 0.39 events/month). Conclusion:MRONJ risk depends on BRI type and individual patient profile. VEGFR-TKIs may accelerate MRONJ onset in BP-treated patients, whereas denosumab showed higher MRONJ risk independently of VEGFR-TKI use. Treatment choices should balance MRONJ risk against skeletal disease burden.
Background:IGF2 is an imprinted growth factor essential for fetal development. A single nucleotide variation at a conserved ZBED6 binding site within Igf2 intron 3 induces post-natal IGF2 expression and resulted in increased lean mass in multiple species. While the role of IGF2 in muscle growth is established, its impact on the adult skeleton remains incompletely defined. Methods:We studied 13-week-old male and female Igf2 G/A knock-in mice carrying the pig-derived G ➔ A substitution that prevents ZBED6 binding. We quantified Igf2 expression in bone and visceral tissues, measured body and organ size, assessed femoral geometry and microarchitecture by micro-CT, examined growth plate morphology, evaluated bone turnover markers (P1NP, CTX1), and tested whole-bone mechanical properties. Results:Igf2 G/A mice exhibited increased size, body weight, length, and kidney mass, while liver mass trended higher. Igf2 mRNA levels were elevated in kidney, liver, and bone tissues. Femurs demonstrated greater length and larger periosteal perimeter, with increased cortical area in both sexes but no changes in cortical thickness or bone mineral density. Trabecular parameters remained unchanged in males but improved in females, characterized by higher BV/TV, increased trabecular thickness and number, and reduced spacing. Growth plate metrics were predominantly unaffected, except for a modest increase in mean thickness observed in Igf2 G/A females. Serum P1NP and CTX1 levels showed no genotype-dependent differences. Mechanical testing revealed reduced elastic modulus in both sexes of the Igf2 G/A compared to wildtype and lower ultimate stress in females, while other mechanical properties remained unchanged. Circulating IGF1 and IGFBP3 levels as well as bone expression of Igf1/Igf1r/Igfbp3 were unchanged, suggesting small if any impact of the greater GH-IGF axis on the phenotype. Conclusions:Post-natal IGF2 expression alters the adult murine skeleton by augmenting longitudinal growth and cortical accrual and inducing female-specific trabecular gains, with selective decrements in material properties. These data establish IGF2 as a regulator of postnatal bone architecture and mechanics and extend the functional scope of the conserved ZBED6-IGF2 regulatory axis to the skeleton.
Osteogenesis imperfecta (OI) is a rare genetic disorder most often caused by mutation in genes that encode collagen type I. The collagen pathway is a complex process involving collagen folding, secretion and fibril assembly. The underlying mutation of OI causes a cascade effect resulting alterations at all levels of the collagen pathway. The objective of this study is to use knowledge synthesis to quantify the collagen-I folding kinetics, secretion kinetics, crosslinks, fibril diameter and melting temperature. A systematic search in Medline, Ovid and Web of Science, identified 1001 studies reporting on selected outcomes in OI patients. After screening, we included 51 qualitative studies, 8 quantitative and 43 studies for meta-analysis. Meta-analysis of studies with quantitative data was performed using normalized mean difference as a study-level effect size and a random-effects model with the Hunter and Smith with sample size correction. The collagen-I folding half-life dataset included 8 patients across 3 studies and had an effect size of 0.88 (confidence interval (CI) 0.31, 1.46). The collagen secretion half-life dataset included 8 patients across 7 studies and had an effect size of 0.23 (CI: -0.13, 0.59). The collagen crosslink dataset included 44 patients across 2 studies and had an effect size of 0.37 (CI: 0.09, 0.65). The fibril diameter dataset included 168 patients across 11 studies and had an effect size -0.13 (CI: -0.24, 0.02). The melting temperature dataset is expressed as absolute mean difference, it included 85 patients across 26 studies and had an effect size of -2.29 (CI: -3.32, -1.35). These findings show the collagen pathway is altered in OI, beyond the initial mutation. Our study provides new insights into collagen-I pathophysiology in OI, generating new hypotheses regarding the collagen pathway and mediating disease presentation in different tissues and overall severity.
Purpose:During the menopausal transition, female individuals experience declines in bone health. Menopausal female individuals also lose lean mass due to aging; however, few exercise trials have included peri- and early post-menopausal participants. The main objective of this study was to explore changes in prespecified secondary muscle and bone outcomes of the Strength Training for Osteoporosis Prevention during Early Menopause (STOP-EM) feasibility trial. Methods:STOP-EM was a randomised waitlisted controlled feasibility trial completed in Calgary, Canada. Participants were randomised to either a 9-month, twice-weekly, supervised progressive heavy strength (80-85% one-repetition maximum (1RM)) and impact (drop landings) training program (n = 20) or the waitlisted controlled group (n = 20). Inclusion criteria included being between 45 and 60 years old and peri- or early post-menopausal. Outcome assessors were blinded to group allocation, while participants were not blinded. Outcomes included lean mass, muscle strength, leg power output, and areal bone mineral density (aBMD). Results:At baseline, mean age was 52.9 (SD: 4.1), 47.5% were peri-menopausal, and 7.5% were on menopausal hormone therapy. All 20 intervention participants and 18 waitlisted controlled participants returned at follow-up. 1RM improved by 12.6% to 30.5% for chest press, shoulder press, deadlift, and back squat lifts. The intervention group experienced increases in total body lean mass (between-group difference for change (95% CI) = 0.90 kg (0.08 to 1.72)), absolute leg power output (97 W (2 to 193)), and lumbar spine aBMD (0.020 g/cm2 (0.001 to 0.034)) compared to the waitlisted controlled group. Conclusions:Nine months of heavy strength and impact training increased lean mass, muscle strength, leg power output, and lumbar spine aBMD. These promising results warrant a definitive trial to assess the program's efficacy.
Early-life stress (ELS) constitutes an enormous socio-economic burden and is an acknowledged risk factor for the development of several affective and somatic conditions, including bone disorders. However, its effects on bone fracture healing have not been studied yet. Here, we implemented a novel two-hit model in male and female C57BL/6N mice, where we used maternal separation (MS) to induce ELS and combined it with a standardized right femur osteotomy stabilized by an external fixator. Behavior was analyzed using the Open Field/Novel Object test, Social Preference/Avoidance test and Saccharin Preference test. Fracture healing was evaluated by biomechanical testing, μCT, histology, and cytokine assays. Maternal separation let to an altered inflammatory response 3 h after fracture, indicated by a significant reduction in several pro- and anti-inflammatory cytokines. This effect was more pronounced in male mice. However, later fracture phases (10 days and 21 days after osteotomy) showed no significant differences between stressed and control mice. Our results indicate that ELS might alter inflammatory responses towards bone fracture in a sex-specific manner without disturbing fracture healing.
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare benign bone disorder caused by postzygotic mutations in GNAS, characterized by skeletal lesions leading to pain, deformities, and fractures. Although antiresorptive agents such as denosumab and zoledronate are used, evidence remains limited, and denosumab carries a well-known rebound risk. Given the heterogeneous disease activity in FD/MAS, standardized treatment approaches are frequently insufficient, raising the need for individualized treatment strategies. We therefore evaluated the effects and safety of individualized denosumab-zoledronate therapy with clinically guided treatment adjustments. A single-center FD/MAS cohort (n = 42) managed between 2014 and 2025 was retrospectively analyzed. Clinical, radiographic, histopathological, and baseline biochemical characteristics were assessed in the overall cohort, whereas longitudinal analyses of treatment response, laboratory markers, pain scores, and adverse events were restricted to an antiresorptive-treated subgroup of 11 patients. Compared with untreated patients, the treated subgroup showed higher skeletal lesion burden and elevated osteocalcin levels. During therapy, elevated bone turnover markers decreased, particularly ALP (-44.3%, p = 0.016). Most treated patients showed stable biochemical trajectories and reported pain reduction under therapy. One young MAS patient experienced severe rebound hypercalcemia (4.43 mmol/L) with renal failure after delayed denosumab administration. In conclusion, individualized antiresorptive therapy with denosumab and zoledronate was associated with symptomatic improvement and largely stable clinical courses in most treated FD/MAS patients. However, denosumab treatment may carry a clinically relevant rebound risk, particularly in young MAS patients with extensive skeletal burden and high bone turnover. Further studies are needed to establish specific, safe and effective treatment strategies.
Background:Osteosarcoma (OTS) is a highly aggressive primary bone malignancy characterized by profound genomic instability and a complex, immunosuppressive tumor immune microenvironment (TIME). Despite the established standard of neoadjuvant chemotherapy and surgical resection, the 5-year overall survival rates for metastatic or relapsed disease have remained stagnant at approximately 40% for decades. The high degree of heterogeneity and the "immune cold" nature of OTS pose significant challenges to the efficacy of conventional and emerging therapies. This review aims to summarize recent advances in the genomic and immunological landscape of OTS to inform personalized precision medicine. Main body:Genomic profiling reveals that OTS is driven by large-scale structural variations rather than single oncogenic drivers, with chromothripsis occurring in over 70% of cases. Frequent alterations in tumor suppressor genes, such as TP53 (80%) and RB1 (40%), fuel clonal evolution and therapeutic resistance. Furthermore, epigenetic dysregulation, including aberrant DNA methylation and alternative mRNA splicing, further complicates the molecular landscape. The OTS TIME is predominantly "cold," characterized by low T-cell infiltration and an abundance of M2-polarized tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). While immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have shown limited clinical success, emerging precision strategies, such as antibody-drug conjugates (ADCs) targeting B7-H3 or LRRC15, CAR-T cell therapies, and targeting of the CD47-SIRPα axis, demonstrate promising potential in preclinical and early-phase clinical trials. Conclusion:The transition from universal treatment to precision therapy in OTS requires a multi-omics approach for patient stratification. Future strategies must focus on overcoming the physical and immunological barriers of the TIME, reprogramming immunosuppressive cells, and exploiting novel targets like B7-H3 and MTAP deletion to improve outcomes for patients with advanced disease.
People with osteogenesis imperfecta (OI) suffer frequent fracturing of bones. Dual-energy absorptiometry (DXA) is considered a surrogate measure of bone strength, and DXA scans are usually acquired yearly to guide treatment. However, DXA provides only limited insight into bone strength as it does not account for bone geometry or microarchitecture. This systematic review outlines current clinical practice regarding the DXA in children with OI, and evaluates evidence for conventional and alternative DXA-derived measures in OI. The search was conducted in Pubmed, Embase, and Web of Science databases at 12-Dec-2025 and records were screened by two reviewers. Studies presenting DXA measurement locations in children with OI or results on the relation between DXA-derived measures and OI type or fractures were eligible and presented in a descriptive manner. Risk of bias was assessed using the Newcastle-Ottawa Scale. In total, 91 studies were included. Data was extracted from 38 observational studies including 3696 patients. The results showed that DXA measurement locations are not standardized. Although studies were variable in methods and results, the association between DXA-derived areal bone mineral density (aBMD) and fractures was generally weak - particularly when fracture incidence was evaluated over short time intervals. However, location-specific measurements may offer some improvement. DXA-based measures reflecting trabecular structure or estimated bone volume did not outperform aBMD. Given the presented results of conventional DXA in OI, alternative methods of bone strength assessment in patients with OI are needed. Assessment targeting fracture-prone skeletal regions and incorporating geometric properties may enhance DXA's predictive value.
Purpose:Dental evaluation is recommended before bisphosphonates (BPs) initiation because of the rare but serious risk of medication-related osteonecrosis of the jaw. In this context, the objective of this study was to assess the prevalence of the indication for dental care (DC) prior to BPs initiation for osteoporosis (OP). Methods:Monocentric retrospective study between January 2019 and August 2022. Inclusion criteria: patients requiring OP treatment with dental evaluation (panoramic dental X-ray (PD) and dental teleconsultation). Exclusion criteria: PD without tele-dental evaluation, BPs for other indications than OP, OP not treated with BPs. Collected data: demographic characteristics, medical history, bone status, conclusions of tele-dental expertise. Results:130 patients were included, mean age of 74.3 years (±12.2), 102 were women. DC was required for 95/130 patients (DC group). In the DC group, 77/95 required surgical DC, 35/77 completed the surgical DC, and 30/35 initiated BPs. 18/95 patients required non-surgical DC, 6/18 completed the DC, and 5/6 initiated BPs. BPs were initiated in 35/95 (36,8%) patients in the DC group and 29/35 (82,9%) in the non-DC group. Conclusion:The prevalence of DC required before BPs initiation in OP patients is high and have a negative impact on the effective implementation of OP treatment. These results emphasize the need for healthcare policies aimed at improving access to DC and the necessity for clear guidelines regarding DC management in the context of BPs therapy.
