Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive fibroblast growth factor 23 (FGF23) secretion. However, TIO lesions located in the neurocranium (NC) and intracranial (IC) structures remain poorly characterized. To characterize the clinical features of TIO lesions in NC and IC structures and to compare them with those located in the sinuses. This retrospective study included patients diagnosed with TIO who underwent tumor resection at Peking Union Medical College Hospital between January 2016 and December 2023. Patients with lesions in NC and IC structures were defined as the study group, while those with sinus lesions served as the control group. Clinical characteristics, biochemical parameters, and surgical outcomes were systematically analyzed and compared between groups. TIO lesions in NC and IC structures were distributed across the skull base, temporal region, sellar region, frontal lobe, and occipital region. Compared with sinus lesions, patients with NC and IC lesions showed comparable clinical and biochemical profiles but exhibited significantly worse outcomes, including higher rates of non-remission and tumor recurrence. These findings suggest increased difficulty in complete tumor resection and disease control in this subgroup. TIO lesions in NC and IC structures are associated with poorer surgical outcomes and higher recurrence rates despite similar baseline characteristics. These results highlight the need for improved localization strategies and tailored management approaches for this challenging subgroup.

OBJECTIVE:Osteoporosis in men is a common but often neglected health problem. We aim to compare the efficacy and safety of denosumab, zoledronic acid and alendronate in men with osteoporosis. METHODS:In this randomized, comparative, open-label study, 390 men with osteoporosis or osteopenia were included. They were randomized to receive the treatment of denosumab, alendronate, or zoledronic acid for 12 months. The percentage changes in bone mineral density (BMD), trabecular bone score (TBS) and bone turnover biomarkers (BTMs) during the treatment were evaluated. Safety parameters were observed. RESULTS:The baseline characteristics were well balanced among the three groups. After 12 months of treatment, denosumab, alendronate and zoledronic acid significantly increased BMD by 4.83 ± 0.89%, 4.32 ± 0.77%, 5.18 ± 0.73% at lumbar spine, by 2.75 ± 0.51%, 2.50 ± 0.61% and 2.83 ± 0.59% at total hip, TBS was significantly increased by 2.44 ± 0.52%, 2.00 ± 0.64%, 2.29 ± 0.55%, respectively, without significant differences among the three groups. Serum levels of BTMs decreased significantly and similarly in all three groups (all P < .05 vs. baseline). Denosumab and alendronate group had fewer adverse events than zoledronic acid group. Denosumab had similar efficacy in patients with different gonadal functions. In patients previously receiving bone resorption inhibitors, denosumab continued to increase BMD and TBS, but the increments were reduced by approximately 30% in BMD at lumbar spine compared with treatment-naive patients. CONCLUSION:Denosumab, alendronate and zoledronic acid significantly and similarly reduced BTMs, increased BMD and TBS in men with osteoporosis, whether the gonadal function of patients was normal or decreased. Previous anti-bone resorption therapy may partially diminish the efficacy of denosumab.

ContextFibrous Dysplasia/McCune-Albright Syndrome (FD/MAS) is a rare skeletal disorder frequently manifesting in childhood, often leading to progressive bone lesions, pain and functional impairment. Denosumab as a monoclonal antibody targeting RANKL has emerged as a potential therapeutic option, while its safety and efficacy in pediatric population remains poorly defined.ObjectiveInvestigate the efficacy and safety of denosumab in pediatric FD/MAS population.Design12-month single-arm study.SettingSingle center study at Peking Union Medical College Hospital.PatientsFD/MAS patients under 18.InterventionsDenosumab 1mg/kg with a maximum dosage of 60mg every 3 months for 12-month follow-up.Main outcome measuresFD-related bone pain, bone turnover markers, 99mTc-MDP bone scintigraphy, bone mineral density.ResultsIn 5 pediatric FD/MAS patients treated with denosumab, significant clinical improvements were observed, including alleviation of FD-associated bone pain, reductions in bone turnover markers, and regression of FD lesions. Alkaline phosphatase levels dropped to an average of 41.8% of baseline, accompanied by concurrent reductions in C-terminal telopeptide and type 1 N-terminal pro-peptide levels. Adverse events particularly hypercalcemia following treatment cessation occurred in 2 of the 5 patients, indicating a relatively high incidence of rebound hypercalcemia and highlighting the need for careful monitoring and cautious use of denosumab in pediatric patients.ConclusionsDenosumab appears to be effective in pediatric FD/MAS patients, however safety concerns remain. Comprehensive pre-treatment evaluation and close monitoring throughout the treatment course are essential. Further prospective studies and randomized controlled trials are needed to determine optimal dosing strategies and establish long-term safety in this population.

Objective: Pseudohypoparathyroidism (PHP) is a rare disorder characterized by hypocalcemia and elevated PTH. Although short stature is a key feature, especially in PHP type 1 (PHP1), growth data in Chinese patients remained limited. Methods: Clinical data, including height, age, and biochemical indices, were retrospectively collected from PHP1 patients at Peking Union Medical College Hospital. Molecular diagnosis was performed using MS-MLPA, Sanger sequencing, and WES. Growth charts for height, weight, and BMI in underage patients were constructed. Results: A total of 92 PHP1 patients (58 males, 34 females), including 32 pseudohypoparathyroidism type 1A (PHP-1A), 49 sporadic pseudohypoparathyroidism type 1B (PHP-S1B), and 11 autosomal dominant pseudohypoparathyroidism type 1B (PHP-AD1B), were recruited. Growth velocity peaked at 12 years in males and 5 years in females, with height plateau at 14 and 13 years, respectively. Adult height was 160.0 cm (SDS −1.04) in males and 155.0 cm (SDS −0.52) in females. PHP-1A patients had significantly shorter adult height than PHP-1B (male: 157.0 ± 6.9 vs 171.9 ± 8.9, P = 0.004; female: 146.8 ± 10.2 vs 156.2 ± 4.9, P = 0.007). PHP-1A showed early-onset weight gain from age 1, persisting into adulthood. Adult Wt-SDS was 1.67 vs 1.55 in males and 2.00 vs 3.10 in females (PHP-1A vs PHP-1B). Weight curves exceeded population P50 in most groups, with no significant differences in adult weight, Wt-SDS, BMI, or obesity prevalence between subtypes. Conclusion: Chinese PHP1 patients show early growth plateau and short stature, more severe in PHP-1A. Obesity varies by subtype and sex, with earlier and more persistent weight gain in PHP-1A. These growth charts may aid clinical management.

Background Insights into basic bone biology and genetic disorders have led to advances in the treatment of osteoporosis. However, new drugs for the treatment of osteoporosis in men remain insufficient. We investigated the efficacy of a novel anti-Dkk1 monoclonal antibody (Dkk1-mAb) and its sequential alendronate treatment in a mouse model of osteoporosis induced by orchiectomy. Methods A specific Dkk1-mAb was generated using the hybridoma technology. A total of 40 male C57BL/6 mice aged 12 weeks underwent orchidectomy or sham surgery. At 8 weeks postoperatively, the orchiectomized mice were randomly divided into 4 groups (8 in each group) to receive treatment of Dkk1-mAb, alendronate, Dkk1-mAb followed by alendronate, or placebo. After 8 weeks of treatment, the mice were euthanized, and bone mineral density (BMD), skeletal mechanical properties, bone histology, bone turnover biomarkers, serum levels of Dkk1 and sclerostin, muscle properties, and activity of the Wnt signaling were evaluated. Results After 8 weeks of treatment, serum Dkk1 levels were lower in Dkk1-mAb and sequential groups than placebo group (P < 0.001, P < 0.05). L1-5 BMD was higher in Dkk1-mAb, alendronate, and sequential groups by 11.9 %, 22.8 %, and 23.1 % than placebo group (P < 0.05 or P < 0.001), with BMD at left femur increased by 12.8 % and 21.0 % in alendronate and sequential groups than placebo group (P < 0.05 or P < 0.001). The sequential group exhibited higher vertebral trabecular volume/total volume (39.9 %), bone surface/total volume (25.8 %), trabecular BMD (4.0 %), and trabecular thickness (13.1 %) than Dkk1-mAb group (P < 0.01 or P < 0.001), and higher cortical BMD, thickness than Dkk1-mAb (2.9 %, P < 0.01; 6.6 %, P < 0.05) and alendronate (2.2 %, 5.7 %, all P < 0.05) groups. All treatment groups showed greater bone strength, cross-sectional area of muscle, and grip strength than placebo group. The expression of Lef1 was significantly increased in bones of Dkk1-mAb and sequential groups. No pathological abnormalities in vital organs were found in all groups, suggesting that Dkk1-mAb had a good safety profile. Conclusions The novel Dkk1-mAb has therapeutic potential in osteoporosis, which can increase BMD and bone strength, improve bone microarchitecture and muscle performance of orchiectomy-induced osteoporotic mice through activating the WNT pathway, and its sequential treatment with alendronate achieves additive benefits. The Translational Potential of this Article This study found that the novel Dkk1-mAb can increase BMD and bone strength, improve bone microarchitecture and muscle performance of orchiectomy-induced osteoporosis mice, and sequential treatment with Dkk1-mAb and alendronate achieves additive benefits. Dkk1-mAb has translational potential for the treatment of osteoporosis.

To characterize the clinical and genetic features of Chinese FHH type 1 (FHH1) patients and evaluate biochemical discriminators between FHH1 and sporadic primary hyperparathyroidism (s-PHPT). This retrospective study included 11 genetically confirmed FHH1 and 55 s-PHPT patients. Their clinical, biochemical, and imaging data were compared. Genetic testing was conducted via targeted next-generation or whole-exome sequencing. The key discriminators were assessed by receiver operating characteristic (ROC) analysis. Among the 11 FHH1 patients, 63.6

Introduction Osteoporosis (OP) is a systemic skeletal disorder that increases fragility and susceptibility to fractures. Despite the availability of teriparatide for the treatment of patients with acute fractures with better efficacy, its long-term daily injection and high cost limit its broader use among a wider patient population, especially for those living in low- and middle-income countries. This study aims to evaluate the efficacy of a novel sequential treatment with teriparatide daily for 6 months followed by denosumab every 6 months for another 18 months, in comparison with denosumab monotherapy every 6 months for 24 months, in reducing the risk of fractures in patients with newly diagnosed osteoporotic fractures. The study will also explore the possible difference between two sequential treatments (shifting to denosumab treatment at 6 or 12 months) in their effect on increasing bone mineral density (BMD).Methods and analysis This study is designed as a multicentre, open-label, randomised controlled trial among 2478 patients with newly diagnosed osteoporotic fractures from 58 hospitals across China. Participants will be randomly assigned in a 10:10:1 ratio to three treatment groups: 24 months of denosumab monotherapy, early sequential treatment (teriparatide for 6 months followed by denosumab for 18 months) and late sequential treatment (teriparatide for 12 months followed by denosumab for 12 months). The primary outcome is the incidence of vertebral fractures over 24 months of treatment. Secondary outcomes include changes in BMD at the lumbar spine, total hip and femoral neck, changes in bone turnover markers (β-carboxy-terminal telopeptide of type 1 collagen and procollagen type 1 N-terminal propeptide), treatment adherence and cost-effectiveness. Follow-up assessments are scheduled at 3, 6, 9, 12, 18 and 24 months post-randomisation for primary and secondary outcomes, and biannually afterwards for the primary outcome.Ethics and dissemination The study protocol has been registered on ClinicalTrials.gov and has received ethical approval from the Peking Union Medical College Hospital Medical Science Research Ethics Committee (1-22PJ939). The findings will be disseminated through peer-reviewed scientific journals.Trial registration number NCT05866029.

Purpose:Neural EGF-like 1 (Nell-1), originally implicated in craniosynostosis, has been identified as a key regulator in osteogenic processes. While preclinical data were encouraging, clinical studies correlating serum Nell-1 levels with osteoporosis remain scarce. This study aims to investigate the relationship between circulation Nell-1 level and bone turnover markers, bone mineral density (BMD), bone microstructure, muscle strength, fall risk, and fractures in Chinese postmenopausal women. Methods:Serum Nell-1 levels were measured in 123 Chinese postmenopausal women. Muscle function was evaluated through grip strength tests, the Short Physical Performance Battery (SPPB), and the Timed Up and Go (TUG) test. Dual-energy X-ray absorptiometry was used to assess areal bone mineral density (aBMD), lumbar trabecular bone score (TBS), and muscle mass. High-resolution peripheral quantitative computed tomography (HR-pQCT) was applied to determine volumetric bone mineral density (vBMD), analyze bone microarchitecture, and estimate bone strength. Result:Postmenopausal women with higher serum Nell-1 levels had higher aBMD and total volumetric bone mineral density (Tot.vBMD) at the distal tibia, larger cortical area (Ct.Ar) and thicker cortical thickness (Ct.Th) at the distal tibia, and higher bone strength. There was a significant negative association between serum Nell-1 levels and C-terminal cross-linking telopeptide of type I collagen (β-CTX), while no significant correlations were observed between serum Nell-1 levels and muscle mass or function. Conclusion:Postmenopausal women with higher serum Nell-1 levels exhibited higher BMD and bone strength, indicating its potential as a therapeutic invention for osteoporosis.

Background: Precise preoperative imaging localization of parathyroid tumors is critical in primary hyperparathyroidism (PHPT) for choosing proper surgical methods and ensuring successful surgery, but may be challenging due to the variable size, number, and location of parathyroid tumors. This study aimed to investigate the association between biochemical indices and intraoperative parathyroid tumor size, number, location, and imaging results in a cohort of PHPT patients, and to explore whether these indices can assist in preoperative localization of PHPT. Methods: A total of 462 patients with surgically confirmed PHPT were enrolled in this study retrospectively. Preoperative biochemical indices, including serum parathyroid hormone (PTH), plasma ionized calcium (iCa), and serum calcium (Ca), as well as the intraoperative size, number, location, and imaging results of the parathyroid tumor, were reviewed and analyzed. The correlation between preoperative biochemical indices and intraoperative parathyroid tumor size was investigated using Spearman's rank correlation. The comparison of preoperative biochemical indices between single-gland disease (SGD) and multi-gland disease (MGD), orthotopic and ectopic hyperparathyroidism, as well as imaging true positive (TP) and false negative (FN) groups, was performed using the Mann-Whitney U test. Results: The Spearman's rank correlation coefficient (r(s)) of serum PTH, plasma iCa, and serum Ca with intraoperative parathyroid tumor maximum diameter were 0.352, 0.342, and 0.224, respectively. The r(s) of serum PTH, plasma iCa, and serum Ca with intraoperative parathyroid tumor volume were 0.394, 0.355, and 0.256, respectively. Serum PTH and plasma iCa levels were weakly correlated with intraoperative parathyroid tumor size (P<0.001), while no correlation was found between serum Ca levels and intraoperative parathyroid tumor size (P<0.001). Serum PTH levels were significantly higher in ectopic hyperparathyroidism than in orthotopic hyperparathyroidism (204.8 vs. 139.7 pg/mL, P<0.001). However, plasma iCa (1.38 vs. 1.36 mmol/L, P=0.76) and serum Ca levels (2.74 vs. 2.71 mmol/L, P=0.82) were not significantly different between them. No significant differences were found in these indices between SGD and MGD (P=0.10-0.84), as well as imaging TP and FN groups (P=0.10-0.88). Conclusions: Serum PTH and plasma iCa levels were weakly correlated with intraoperative parathyroid tumor size. Higher serum PTH levels tend to be associated with ectopic hyperparathyroidism. The ability of biochemical indices to reliably predict parathyroid tumor anatomical features (size, number, or location of glands) appears to be limited.

Context: Cutaneous-skeletal hypophosphatemia syndrome (CSHS) is a rare mosaic RASopathy characterized by epidermal or melanocytic nevi, skeletal dysplasia, and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets. However, its bone microarchitectural features remain underdefined.Objectives: The study aimed to characterize the clinical, genetic, and skeletal microarchitectural features of CSHS.Methods: We summarized clinical findings of 6 CSHS patients with genetically confirmed somatic RAS mutations. Skeletal involvement was assessed by whole-body bone scintigraphy. High-resolution peripheral quantitative computed tomography parameters at the distal radius and tibia were compared with age- and sex-matched XLH controls (1:3). Literature review of 20 genetically confirmed CSHS patients was performed to assess genotype-phenotype correlation.Results: All patients were confirmed to carry somatic HRAS or NRAS mutation in affected skin. Hypophosphatemia, elevated alkaline phosphatase and FGF23 were found in all patients. Genotype-phenotype correlation analysis did not identify any significant biochemical or systemic burden differences across 3 genotypes. Compared with XLH controls, CSHS patients exhibited significantly reduced total and trabecular volumetric BMD (vBMD), with relatively preserved cortical vBMD. Bone cross-sectional geometry was less expanded than in XLH at the tibia. In addition, thinner trabeculae with greater separation were found at the radius, and the distal tibia showed thinner and decreased cortical porosity. Estimated bone stiffness and failure load were significantly lower at both the radius and tibia.Conclusions: CSHS is associated with pronounced trabecular microarchitectural impairment and reduced bone strength that exceed the expected effects of FGF23-mediated phosphate wasting alone, supporting a combined contribution of intrinsic skeletal dysplasia and chronic hypophosphatemia.

Pseudohypoparathyroidism type 1 (PHP1), caused by GNAS defects, is associated with metabolic syndrome components like obesity and insulin resistance, potentially involving adipokine dysregulation. This study characterized serum adipokine profiles in PHP1 and elucidated the independent and interactive effects of GNAS defects and obesity. This single-center, cross-sectional study included 60 PHP1 patients with molecularly confirmed GNAS defects (epigenetic or genetic). Controls (n = 60) were matched for body mass index (BMI), age, and sex. Serum adipokines were measured using multiplex enzyme-linked immunosorbent assay. Generalized linear models assessed independent/joint effects of GNAS defects and obesity on adipokines, adjusting for confounders. Overweight/obesity (OW/OB) prevalence was 58.3

ABSTRACT Background Duchenne muscular dystrophy (DMD) is an X‐linked recessive disorder that affects dystrophin production, characterized by progressive neuromuscular dysfunction, often accompanied by osteoporosis. We prospectively evaluate the effects of bisphosphonates on bone micro‐architecture reflected by trabecular bone score (TBS) of patients with DMD. Methods A total of 72 male children or adolescents with DMD were included, with a mean age of 9.5 ± 1.8 years. They were divided into bisphosphonate treatment groups and control group based on areal bone mineral density (aBMD) and history of fragility fractures. Patients in bisphosphonate treatment groups randomly received intravenous infusion of 5 mg zoledronic acid (ZOL) annually or oral 70 mg alendronate weekly for three years. All patients took calcium 600 mg plus 125 IU vitamin D daily and calcitriol 0.25 μg every other day. TBS at the lumbar spine (LS) and aBMD at the LS, femoral neck (FN) and total hip (TH) were measured annually by dual‐energy X‐ray absorptiometry. Serum levels of β‐isomerized carboxy‐telopeptide of type I collagen and alkaline phosphatase were measured annually during the follow‐up. Results A total of 25 (86.2%), 26 (92.9%) and 13 (86.7%) patients in the ZOL, alendronate and control groups completed the study. After 3 years, TBS Z‐score increased from baseline by 1.13 (p < 0.01), 0.68 (p < 0.01) and 0.26 (p > 0.05) in the ZOL, alendronate and control groups, respectively. The mean increase in TBS Z‐score from baseline was significantly greater in both bisphosphonate treatment groups compared to the control group (p < 0.05). No significant difference was found between the ZOL and alendronate groups. LS, FN and TH aBMD increased by 35.8%, 23.7% and 34.5% in the ZOL group (all p < 0.01 vs. baseline and control group) and by 21.5%, 29.3% and 25.0% in the alendronate group (all p < 0.05 vs. baseline and control group). LS and FN aBMD Z‐scores increased by 1.56 and 1.63 in the ZOL group (all p < 0.01 vs. baseline), by 1.32 and 1.48 in the alendronate group (all p < 0.05 vs. baseline). Bisphosphonates demonstrated a favourable safety profile during the study period. Conclusion This relatively long‐term study confirms that zoledronic acid and alendronate are beneficial to improve micro‐architecture reflected by TBS and aBMD of children or adolescents with DMD.

This study estimated FRAX®-based intervention thresholds for initiating osteoporosis treatment in Chinese postmenopausal women, using real-world data from the largest nationally representative osteoporosis survey in China and a validated Markov microsimulation model. Denosumab became cost-effective at a 10-year major osteoporotic fracture probability of 7

PurposeHigh serum periostin is linked to an increased risk of osteoporotic fractures in postmenopausal women. However, the relationships between serum periostin and bone microarchitecture, particularly muscle mass, and muscle function remain unclear. This study aims to investigate the relationships between serum periostin and bone mineral density, bone microarchitecture, muscle mass and function, falls, and fractures in community-dwelling Chinese postmenopausal women.MethodSerum periostin levels were measured in 135 Chinese postmenopausal women. Dual-energy X-ray absorptiometry assessed areal bone mineral density (aBMD), lumbar trabecular bone score (TBS), and muscle mass. High-resolution peripheral quantitative computed tomography (HR-pQCT) evaluated bone microarchitecture. Muscle function and fall risk were assessed using handgrip strength, the Short Physical Performance Battery (SPPB), the Timed Up and Go (TUG) test, and the Falls Risk for Older People in the Community (FROP-Com) screening tool.ResultThe mean serum periostin was 1770.3 ± 440.4 pmol/L. Serum periostin was negatively correlated with bone microarchitecture parameters, total area (Tot.Ar), cortical perimeter (Ct.Pm), trabecular area (Tb.Ar), estimated bone strength stiffness, and failure load. Negative correlations were also found with appendicular skeletal muscle mass (ASM), balance test scores, and gait speed. Conversely, serum periostin was positively correlated with TUG time and FROP-Com scores.ConclusionHigher serum periostin is associated with smaller bone cross-sectional area, lower estimated bone strength, reduced muscle mass, and higher fall risk, indicating its potential as a predictor for assessing skeletal and muscular health in postmenopausal women.

OBJECTIVES:We aimed to systematically evaluate the impact of glucocorticoid (GC) exposure on trabecular bone score (TBS). METHODS:The protocol was registered on PROSPERO (No: CRD420250632403). PubMed/Medline, Embase, OVID, and the Cochrane Library databases were systematically searched until December 2024. Studies that assessed TBS and areal bone mineral density (aBMD) in both GC-treated patients and non-GC controls were included. We assessed risk of bias using the Joanna Briggs Institute Checklist. Data were analyzed using the random effects model. For heterogeneity, we performed subgroup and sensitivity analyses. RESULTS:A total of 8 studies involving 3215 participants were included. Compared to controls, GC-treated patients had significantly lower TBS (SMD = -0.47; 95%CI: [-0.64, -0.31], P < 0.00001) and lumbar spine (LS) aBMD (SMD = -0.1784; 95%CI: [-0.3190, -0.0378], P = 0.01), along with a borderline reduction in total hip aBMD (SMD = -0.2686; 95%CI: [-0.5353, -0.0019], P = 0.05). Femoral neck aBMD showed no significant difference (P = 0.06). Subgroup analyses revealed that TBS was significantly lower regardless of sex, ethnicity, and body mass index. While LS-aBMD showed significantly lower values in females (SMD = -0.25, 95%CI: [-0.39, -0.11], P = 0.0005) and White population (SMD = -0.20, 95%CI: [-0.38, -0.03], P = 0.03). After adjusting for disease-matched controls, confounders, and DXA manufacturer, TBS results remained robust, while aBMD outcomes showed greater variability. CONCLUSION:GC exposure is associated with significant and consistent deterioration in TBS across diverse subgroups. Combining TBS with aBMD is recommended for assessing the bone health in patients treated with GC.

Background: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic disorders characterized by fibro-osseous skeletal lesions and hyperfunctioning endocrinopathies. Large-scale pediatric cohort data from China remain scarce. We aimed to characterize the phenotypic spectrum of Chinese children with FD/MAS and examine cross-sectional associations between skeletal distribution and endocrine phenotypes. Methods: We conducted a nationally representative retrospective cross-sectional study at Peking Union Medical College Hospital. Patients aged ≤18 years diagnosed with FD/MAS between January 1st 2015 and December 31st 2024, with complete baseline data were included. Main outcomes include demographic features, clinical manifestations, skeletal manifestations, endocrine manifestations, and serum profile. Skeletal involvement was categorized by anatomical region and quantified using the Skeletal Burden Score. Associations between skeletal lesion distribution and endocrinopathies were evaluated using odds ratios. Unsupervised hierarchical clustering assessed symptom patterns at onset. Random forest classification models identified baseline features associated with pituitary adenoma and peripheral precocious puberty in girls. Findings: Of 137 screened pediatric patients, 90 were included (56·7% female). Median age at symptom onset was 5·0 years, with a median diagnostic delay of 2·0 years; 21·1% experienced delays exceeding five years. MAS was present in 76·7% of patients, polyostotic FD in 94·4%, and craniofacial involvement in 76·7%. Among MAS cases, peripheral precocious puberty occurred in 52·2%, hyperthyroidism in 29·0%, pituitary adenoma in 21·7%, and hypophosphatemia in 5·8%. Two phenotype clusters were identified at disease onset. Craniofacial involvement was associated with pituitary adenoma (OR 10·71, 95%CI 2·34-49·08), while pelvic involvement in girls was associated with peripheral precocious puberty (OR 20·94, 95% CI 4·52-96·97). Random forest models yielded AUCs of 0·799 (95%CI 0·625-0·973) for pituitary adenoma and 0·917 (95%CI 0·782-1·000) for peripheral precocious puberty. Interpretation​: This national pediatric cohort demonstrates substantial diagnostic delay, high skeletal, and endocrine burden. Anatomical skeletal distribution is cross-sectionally associated with specific endocrinopathies, supporting anatomy-informed surveillance strategies that warrant prospective validation.

Background Periosteosis is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO). Increased level of prostaglandin E2 (PGE2) is the pathogenesis of PHO. PGE2 has been shown to bind its EP4 receptor in sensory nerves to stimulate bone formation. Sensory neuropeptide calcitonin gene-related peptide (CGRP), richer in the periosteum, has been revealed to promote osteogenic differentiation of periosteum-derived stem cells (PDSCs) and contributed to periosteum proliferation at peripheral cortical sites. The study hypothesized that CGRP might have a role in regulating proliferative periosteum formation in PHO through the PGE2/EP4 receptor pathway. Methods We explored the regulatory mechanisms of CGRP in proliferative periosteosis of PGE2 in vivo and in vitro. In vivo, PGE2 at 3 mg/kg/day or vehicle was given by daily subcutaneous injection along the periosteum at bilateral lower extremities to male rats for 30 days. After sacrificing the rats, tibiae and femurs were collected to conduct micro-CT, histopathological, and bone histomorphometric analysis. PDSCs were isolated from PGE2-treated and vehicle-treated rats to analyze osteogenic differentiation. In vitro, PDSCs and bone mesenchymal stem cells (BMSCs) were isolated from the normal rats and treated with PGE2 to evaluate and compare osteogenic differentiation. Results PGE2 administration induced significant bone gain phenotype with higher cortical areas and cortical and trabecular bone volumes at the microarchitectural level. Histological and molecular analysis of the periosteum isolated from the PGE2-treated rats revealed that high CGRP expression in the PGE2/EP4 pathway promoted osteogenesis and mineralization in the peripheral cortex of the femur. Furthermore, in vitro study revealed that PGE2 treatment upregulated the expression of CGRP throughout the osteogenesis differentiation in PDSCs. Conclusion Both in vivo and in vitro evidenced elevated CGRP expression through PGE2/EP4 axis promoted proliferative periosteal formation, suggesting that CGRP might be a potential target for PGE2-induced periosteosis treatment, providing new insight into potential therapies for PHO patients. Translational potential of this study This study identifies CGRP as a key mediator in PGE2/EP4-induced periosteal bone formation, revealing its critical role in the pathogenesis of periosteosis in primary hypertrophic osteoarthropathy (PHO). Targeting the CGRP signaling pathway offers a promising therapeutic strategy to modulate aberrant periosteal proliferation and bone remodeling in PHO patients. These findings pave the way for developing novel treatments aimed at inhibiting CGRP activity to alleviate periosteal hyperplasia and improve clinical outcomes in PHO.

Autosomal dominant hypocalcemia type 1 (ADH1) is rarely reported in Chinese populations except for isolated cases. This study aimed to describe the clinical characteristics of a group of Chinese patients with genetically confirmed childhood-onset ADH1 and compare them with patients diagnosed with idiopathic hypoparathyroidism (IHP). This retrospective study analyzed 210 childhood-onset hypoparathyroidism (HP) cases using targeted next-generation sequencing and TBX1-MLPA. Patients harboring rare variants in the CASR gene were identified as ADH1 cases. In vitro functional tests of the variants were performed using a dual-luciferase reporter assay. Patients without any variants or with only benign/likely benign variants in known HP-related genes were classified as IHP for comparison. Clinical presentation, biochemical parameters, and complications were compared between the ADH1 and IHP groups. Thirteen ADH1 patients carried 10 different CASR mutations, including six novel variants, all of which showed higher NFAT activity in functional tests. Median age at hypocalcemia onset was 0.05 years, with an average diagnostic delay of 12.90 ± 9.90 years. Four of them were familial cases. Compared to 124 IHP patients, ADH1 patients showed significantly earlier onset (0.05 vs. 12.67 years), higher 24 h urinary calcium excretion (0.13 vs. 0.04 mmol/kg/day) despite similar serum calcium levels, more frequent hypomagnesemia (61.54 vs. 13.73

AbtractAimPathogenic variants in NOTCH2 disrupt Notch signalling and give rise to a broad spectrum of skeletal and multisystem disorders, most notably Hajdu–Cheney Syndrome (HCS) and Alagille Syndrome (ALGS). This study aimed to delineate the clinical heterogeneity, genotype–phenotype correlations, and therapeutic responsiveness of NOTCH2-related diseases.MethodsThe genotype of four male patients with NOTCH2 mutations was evaluated through Whole-exome and Sanger sequence, in-silico structural modeling, and the phenotype was assessed including bone mineral density, X ray films and bone turnover biomarkers. A systematic review of literatures from PubMed, Embase, and China National Knowledge Infrastructure was also performed.ResultsAll four cases presented with reduced BMD, ranging from classical HCS skeletal deformities to osteoporosis. Genetic analysis identified one pathogenic truncating variant in the PEST domain and three novel missense variants, of which structural predictions indicated potential disruption of electrostatic interactions or local conformational stability by these variants. Anti-resorptive therapy supplemented with calcium and calcitriol resulted in reduced bone resorption and increased BMD. A systematic review integrating 166 cases (including these four patients) revealed that 96.3% of HCS patients carried exon 34 PEST-domain truncating variants, which were strongly associated with severe skeletal fragility, early pathological fractures, and progressive acral osteolysis. ALGS primarily resulted from loss-of-function variants distributed across multiple exons without hotspots.ConclusionThese findings expand the clinical and genetic spectrum, and clarified the genotype-phenotype correlation of NOTCH2-related diseases. Anti-resorptive therapy could be an effective management for NOTCH2-mediated osteoporosis, and new targeted drugs at the Notch2 pathway should be explored.