Paget's disease of bone (PDB) is a late‐onset chronic progressive bone disease characterized by abnormal activation of osteoclasts that results in bone pain, deformities, and fractures. PDB is very rare in Asia. A subset of PDB patients have early onset and can develop malignant giant cell tumors (GCTs) of the bone (PDB/GCTs), which arise within Paget bone lesions; the result is a significantly higher mortality rate. SQSTM1, TNFRSF11A, OPG, VCP and HNRNPA2B1 have been identified as pathogenic genes of PDB, and ZNF687 is the only confirmed gene to date known to cause PDB/GCT. However, the molecular mechanism underlying PDB/GCT has not been fully elucidated. Here, we investigate an extended Chinese pedigree with 8 individuals affected by early‐onset and polyostotic PDB, two of whom developed GCTs. We identified a heterozygous 4‐bp deletion in the Profilin 1 (PFN1) gene (c.318_321delTGAC) by genetic linkage analysis and exome sequencing for the family. Sanger sequencing revealed another heterozygous 1‐bp deletion in PFN1 (c.324_324delG) in a sporadic early‐onset PDB/GCT patient, further proving its causative role. Interestingly, a heterozygous missense mutation of PFN1 (c.335 T > C) was identified in another PDB/GCT family, revealing that not only deletion but also missense mutations in PFN1 can cause PDB/GCT. Furthermore, we established a Pfn1‐mutated mouse model (C57BL/6J mice) and successfully obtained Pagetic phenotypes in heterozygous mice, verifying loss of function of PFN1 as the cause of PDB/GCT development. In conclusion, our findings reveal mutations in PFN1 as the pathological mechanism in PDB/GCT, and we successfully established Pfn1‐mutated mice as a suitable animal model for studying PDB‐associated pathological mechanisms. The identification of PFN1 mutations has great diagnostic value for identifying PDB individuals predisposed toward developing GCTs.

The lack of DXA has made the diagnosis and treatment of osteoporosis extremely difficult in the vast rural areas of China, which has the largest population with high risks of osteoporosis. The aims of this cross-sectional study were to evaluate the association between the osteoporosis self-assessment tool for Asians (OSTA) and calcaneus quantitative ultrasound (QUS) in populations residing in Shanghai, China, and their assessment in predicting osteoporotic fractures and falls. A population of 12,033 participants, including 1272 males (average age 68.3 ± 9.8 years, range 28–100 years) and 10,761 females (average 56.8 ± 11.4 years, range 23–99 years), was gathered. OSTA and calcaneus QUS (Sonost 2000, OsteoSys) values were measured. Spearman’s correlation and Cohen’s kappa were used to determine the association and agreement between the OSTA and QUS. Receiver operating characteristic (ROC) curves were adapted to assess the performance and optimal cutoff values for the OSTA and QUS in osteoporotic fracture and fall screening. In total, the prevalence of osteoporotic fractures (low-trauma fractures including fractures of the spine, hip, forearm, humerus and ribs) was 15.2% in women, and 17.7% reported a history of falls (falling from standing height more than once in the past year). The percentages of men with the same history were 8.4% and 11.7%, respectively. The association between the OSTA and QUS was found to be r_s = 0.393, κ = 0.137, p < 0.001. The OSTA (cutoff < −1) revealed an area under ROC curve (AUC) of 0.590 in identifying female individuals with moderate or high risk of osteoporosis defined by QUS (T-score < −1). The QUS T-score lower than −1.55 or −1.40 in postmenopausal women may lead to an increased risk of falls or osteoporotic fractures, respectively. The agreement between QUS and the OSTA seemed to be limited in determining individuals at risk of osteoporosis. Measuring bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) may still be necessary in the clinical diagnosis of osteoporosis. OSTA and QUS T-scores less than the respective cutoff values may indicate an increased risk of osteoporotic fractures and falls that individual should be further treated and screened by DXA.

Objective: Primary hyperparathyroidism (PHPT) is a common endocrine disorder of calcium metabolism. However, data concerning a large cohort of PHPT patients in the Chinese population are scarce. Thus, the objective of this study was to determine the general clinical signatures of 457 Chinese PHPT patients and explore the clinical characteristic differences between benign and malignant PHPT.Methods: A single-center retrospective study was designed. Medical records between preoperation and postoperative follow-up, were assessed and statistical analysis of the clinical data was performed.Results: Patients with PHPT aged 12–87 years, with a mean onset age of 56.16 ± 14.60 years, were included. Most patients (68.7%) in our center had symptomatic patterns described as bone pain (74.8%), urolithiasis (25.5%), fatigue (17.5%), and pathological fracture (13.1%), but an increasing tendency has been established in the proportion of patients with asymptomatic forms. Correlation analysis revealed that patients with higher serum levels of parathyroid hormone (PTH) and calcium presented higher serum levels of bone turnover markers (BTMs) and lower 25-hydroxy-vitamin D (25OHD) values (P<0.001). Gains in bone mineral density (BMD) at L1–4, the femoral neck and the total hip were observed 1–2 years after parathyroidectomy (9.6, 5.9, and 6.8%). Parathyroid carcinoma patients presented prominently higher serum PTH and calcium levels and BTMs and lower BMD at femoral neck and total hip than benign PHPT patients (P<0.05), while no significant differences in age, sex, and serum 25OHD concentration were observed between benign and malignant PHPT patients.Conclusions: PHPT should be paid attention to in the patients with bone pain. While, BMD and BTMs can differentiate parathyroid carcinoma from parathyroid adenoma and hyperplasia to some extent. In addition, anti-osteoporosis drugs could be used when necessary to avoid hip fractures in patients with parathyroid carcinoma.

Sclerostin is an important regulator of bone mass involving Wnt/β-catenin signaling pathway. We aimed to obtain the profile of serum sclerostin level and explore its associations with bone metabolism markers and sex hormones in healthy community-dwelling Chinese elderly individuals and adolescents. A cross-sectional study was performed in three communities in Shanghai. In all, 861 participants, including 574 healthy elderly individuals, and 287 healthy adolescents, were recruited. The levels of serum sclerostin, procollagen type 1 N-terminal propeptide (P1NP), β-CrossLaps of type I collagen containing cross-linked C-telopeptide (β-CTX), parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], estradiol (E₂), testosterone (T), and sex hormone-binding globulin (SHBG) were measured in blood samples from all participants. Median sclerostin level was higher in males than in females and in elderly individuals than in adolescents (elderly males: 54.89 pmol/L, elderly females: 39.95 pmol/L, adolescent males: 36.58 pmol/L, adolescent females: 27.06 pmol/L; both P < 0.05). In elderly individuals, serum sclerostin was positively correlated with age (β = 0.176, P < 0.001) and T (β = 0.248, P = 0.001), but negatively associated to P1NP (β = −0.140, P = 0.001). In adolescents, circulating sclerostin was significantly and positively associated with P1NP (β = 0.192, P = 0.003). The directions of the association between sclerostin and P1NP were opposite in Chinese elderly individuals and adolescents, which may reflect that sclerostin plays distinct roles in different functional states of the skeleton. Our findings revealed the rough profile of circulating sclerostin level in general healthy Chinese population and its associations with bone metabolism markers and sex hormones, which may provide a clue to further elucidate the cross action of sclerostin in bone metabolism and sexual development.

X-linked hypophosphatemia (XLH) is caused by inactivating mutations in thephosphate-regulating endopeptidase homolog, X-linked(PHEX) gene, resulting in an excess of circulating intact fibroblast growth factor-23 (iFGF-23) and a waste of renal phosphate. In the present study, we retrospectively reviewed the clinical and molecular features of 153 Chinese patients, representing 87 familial and 66 sporadic cases with XLH. A total of 153 patients with XLH presented with signs or symptoms at a median age of 18.0 months (range, 9.0 months–26.0 years). Lower-limb deformity was the most frequent clinical manifestation, accounting for 79.1% (121/153). Biochemical screening showed increased serum levels of iFGF23 in patients with XLH, with a wide variation ranging from 14.39 to 730.70 pg/ml. Median values of serum iFGF23 in pediatric and adult patients were 94.87 pg/ml (interquartile range: 74.27–151.86 pg/ml) and 72.82 pg/ml (interquartile range: 39.42–136.00 pg/ml), respectively. Although no difference in circulating iFGF23 levels between these two groups was observed (P= 0.062), the proportion of patients with high levels of circulating iFGF23 (>42.2 pg/ml) was greater in the pediatric group than in the adult group (P= 0.026). Eighty-eight different mutations in 153 patients were identified, with 27 (30.7%) being novel. iFGF23 levels and severity of the disease did not correlate significantly with truncating and non-truncating mutations or N-terminal and C-terminalPHEXmutations. This study provides a comprehensive description of the clinical profiles, circulating levels of iFGF23 and gene mutation features of patients with XLH, further enriching the genotypic spectrum of the diseases. The findings show no evident correlation of circulating iFGF23 levels with the age or disease severity in patients with XLH.

Bone organoids, as three-dimensional (3D) biomimetic constructs, have emerged as a promising platform for studying bone development, disease modeling, drug screening, and regenerative medicine. This review comprehensively explores innovative strategies driving bone organoid advancements, emphasizing the integration of cutting-edge technologies such as bioprinting, artificial intelligence, assembloids, and gene editing. While 3D bioprinting enhances spatial precision and structural complexity, artificial intelligence accelerates organoid optimization through data-driven approaches. Assembloids enable the assembly of multicellular systems to better replicate bone tissue microenvironments, whereas gene editing refines disease modeling and functional modifications. Despite these advancements, challenges remain, including the lack of vascularization, insufficient mechanical stimulation, and standardization issues across different models. Also, the clinical translation of bone organoids necessitates the establishment of rigorous evaluation frameworks, ethical guidelines, and regulatory policies to ensure their reproducibility and safety. Looking ahead, interdisciplinary convergence will be critical for constructing physiologically relevant “ex vivo skeletal systems”, advancing bone biology, precision medicine, and biomaterial testing. This review highlights the transformative potential of bone organoid technology and its future applications in personalized orthopedics and bone disease intervention. This review provides a comprehensive overview of cutting-edge strategies for constructing bone organoids, emphasizing their integration with advanced technologies such as bioprinting, artificial intelligence, assembloids, and gene editing. By systematically discussing their applications in bone development, disease modeling, drug screening, and regenerative medicine, this article bridges the gap between experimental models and clinical translation. The insights into vascularization, skeletal patterning, and high-throughput screening platforms offer a foundation for developing physiologically relevant bone organoids with enhanced fidelity and functionality. These advancements hold significant potential for accelerating personalized medicine, facilitating preclinical evaluation of therapeutics, and ultimately improving treatment outcomes for skeletal diseases.