Purposes: In order to investigate the association between serum periostin levels and the variation of its encoding gene POSTN and the prevalence of vertebral fractures and bone mineral density (BMD) in Chinese postmenopausal women, an association study was performed. Materials and Methods: 385 postmenopausal women were recruited. For participants without a history of vertebral fracture, lateral X-rays of the spine covering the fourth thoracic spine to the fifth lumbar spine were performed to detect any asymptomatic vertebral fractures. Ten tag-single nucleotide polymorphisms (SNP) of POSTN were genotyped. Serum periostin levels, biochemical parameters, and BMD were measured individually. Results: rs9603226 was significantly associated with vertebral fractures. Compared to allele G, the minor allele A carriers of rs9603226 had a 1.722-fold higher prevalence of vertebral fracture (p = 0.037). rs3923854 was significantly associated with the serum periostin level. G/G genotype of rs3923854 had a higher serum periostin level than C/C and C/G (67.26 ± 19.90 ng/mL vs. 54.57 ± 21.44 ng/mL and 54.34 ± 18.23 ng/mL). Furthermore, there was a negative correlation between the serum level of periostin and BMD at trochanter and total hip. Conclusion: Our study suggested that genetic variation of POSTN could be a predicting factor for the risk of vertebral fractures. The serum level of periostin could be a potential biochemical parameter for osteoporosis in Chinese postmenopausal women.

Hypophosphatasia (HPP) is an inherited disease caused by ALPL mutation, resulting in decreased alkaline phosphatase (ALP) activity and damage to bone and tooth mineralization. The clinical symptoms of adult HPP are variable, making diagnosis challenging. This study aims to clarify the clinical and genetic characteristics of HPP in Chinese adults. There were 19 patients, including 1 with childhood-onset and 18 with adult-onset HPP. The median age was 62 (32–74) years and 16 female patients were involved. Common symptoms included musculoskeletal symptoms (12/19), dental problems (8/19), fractures (7/19), and fatigue (6/19). Nine patients (47.4%) were misdiagnosed with osteoporosis and six received anti-resorptive treatment. The average serum ALP level was 29.1 (14–53) U/L and 94.7% (18/19) of patients had ALP levels below 40 U/L. Genetic analysis found 14 ALPL mutations, including three novel mutations—c.511C>G (p.His171Ala), c.782C>A (p.Pro261Gln), and 1399A>G (p.Met467Val). The symptoms of two patients with compound heterozygous mutations were more severe than those with heterozygous mutations. Our study summarized the clinical characteristics of adult HPP patients in the Chinese population, expanded the spectrum of pathogenic mutations, and deepened clinicians’ understanding of this neglected disease.

Background: Autosomal dominant osteopetrosis II (ADO II, MIM166600) is a sclerosing bone disorder caused by CLCN7 mutation. The main clinical characteristics include minor trauma-related fracture and hip osteoarthritis, whereas cranial nerve palsy and bone marrow failure rarely develop. Although it is generally believed that ADO II has a relatively benign course, the natural course of the disease in Chinese patients remains unclear.Materials and Methods: Thirty-six patients diagnosed with ADO II in Shanghai Jiao Tong University Affiliated Sixth People’s Hospital from 2008 to 2021 were studied retrospectively. Among them, 15 patients were followed for an average of 6.3 years (1-14 years).Results: In this study, minor trauma-related fractures of the limb were the most typical clinical manifestations. Visual loss (1/36) and bone marrow failure (2/36), was rare in this study. The condition of ADO II seems to be stable in most patients. There were no correlations between markedly elevated bone mineral density (BMD) and minor trauma-related fractures. In total, 21 diseases causing mutations were detected. Among them, the mutation c.2299C>T (p.Arg767Trp) was the most common (16.67%), and mutation c.937G>A [p.(Glu313Lys)] was associated with severe fractures, haematological defects and cranial palsy.Conclusions: Minor trauma-related fracture is the most typical clinical manifestation of ADO II and always occurs in. The mutation c.2299C>T (p.Arg767Trp) is in general a relatively common variant, while the mutation c.937G>A [p.(Glu313Lys)] seems to be associated with severe phenotype. In our study, ADO II seems to remain stable over time.

Zoledronic acid (ZOL) is a potent antiresorptive agent that increases bone mineral density (BMD) and reduces fracture risk in postmenopausal osteoporosis (PMOP). The anti-osteoporotic effect of ZOL is determined by annual BMD measurement. In most cases, bone turnover markers function as early indicators of therapeutic response, but they fail to reflect long-term effects. We used untargeted metabolomics to characterize time-dependent metabolic shifts in response to ZOL and to screen potential therapeutic markers. In addition, bone marrow RNA-seq was performed to support plasma metabolic profiling. Sixty rats were assigned to sham-operated group (SHAM, n = 21) and ovariectomy group (OVX, n = 39) and received sham operation or bilateral ovariectomy, respectively. After modeling and verification, rats in the OVX group were further divided into normal saline group (NS, n = 15) and ZOL group (ZA, n = 18). Three doses of 100 μg/kg ZOL were administrated to the ZA group every 2 weeks to simulate 3-year ZOL therapy in PMOP. An equal volume of saline was administered to the SHAM and NS groups. Plasma samples were collected at five time points for metabolic profiling. At the end of the study, selected rats were euthanatized for bone marrow RNA-seq. A total number of 163 compound were identified as differential metabolites between the ZA and NS groups, including mevalonate, a critical molecule in target pathway of ZOL. In addition, prolyl hydroxyproline (PHP), leucyl hydroxyproline (LHP), 4-vinylphenol sulfate (4-VPS) were identified as differential metabolites throughout the study. Moreover, 4-VPS negatively correlated with increased vertebral BMD after ZOL administration as time-series analysis revealed. Bone marrow RNA-seq showed that the PI3K-AKT signaling pathway was significantly associated with ZOL-mediated changes in expression (adjusted-p = 0.018). In conclusion, mevalonate, PHP, LHP, and 4-VPS are candidate therapeutic markers of ZOL. The pharmacological effect of ZOL likely occurs through inhibition of the PI3K-AKT signaling pathway.

Purpose: Optimal dosing of denosumab in osteogenesis imperfecta (OI) remains undefined. This prospective cohort study evaluated the 12-month efficacy and safety of denosumab in OI patients, with a historical control study with alendronate.Materials and methods: Eight pediatric patients (1 mg/kg every 3 months; ≤60 mg/dose) and ten adults (60 mg every 6 months) received denosumab. Outcomes included lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), bone turnover markers (BTMs), vertebral compression fractures (assessed via AI-assisted Genant grading [AI_OVF_SH system]), fracture incidence, height velocity and adverse events. Historical controls (n=25 alendronate-treated OI patients) were analyzed for comparative efficacy. Sensitivity analyses excluded female pediatric participants (n=4) and peri-/post-menopausal adults (n=4) to assess hormonal confounding.Results: Pediatric denosumab recipients exhibited significant LS-BMD (+30.3%, P0.050) but superior pediatric height gain (+5.8% vs. +2.5%, P=0.004). Vertebral area loss decreased significantly with denosumab (-14.6%, P=0.029), unlike alendronate (-8.8%, P=0.296). Adverse events were more frequent with denosumab in children (hypercalcemia: 62.5% vs. 0%, P=0.002).Conclusion: Denosumab demonstrates non-inferior efficacy to alendronate for BMD improvement in OI, with heightened vertebral remodeling and pediatric height gains. However, its overshoot phenomenon in children (rebound hypercalcemia) and hormone-dependent efficacy in adults necessitate risk-stratified use. Age and menopausal status considerations are critical for optimizing denosumab therapy in OI.Clinical trial registration: https://www.chictr.org.cn/bin/project/edit?pid=184231, identifier ChiCTR2300074207.

The aim of this study was to explore the allelic association between genetic polymorphisms of the NF-κB pathway and the variance of clinical effects of zoledronic in postmenopausal Chinese women with osteoporosis. In the study, 110 Chinese postmenopausal women with osteoporosis were recruited. Every patient received zoledronic once a year. BMD was measured at baseline and after one year of treatment. The 13 tagger SNPs of five genes in the NF-κB pathway were genotyped. In the study, 101 subjects completed the one-year follow-up. The ITCTG and DTCTG haplotypes, which are constituted of rs28362491, rs3774937, rs230521, rs230510 and rs4648068 of the NF-κB1 gene, were associated with improvement in BMD at L1-4 and femoral neck (p < 0.001, p = 0.008, respectively). The CGC haplotype, which is constituted of rs7119750, rs2306365 and rs11820062 of the RELA gene, was associated with improvement in BMD at total hip (p < 0.001). After Bonferroni correction, haplotypes ITCTG and CGC still showed significant association with the % change of BMD at L1-4 and total hip. Therefore, NF-κB1 and RELA gene were significantly associated with bone response to the treatment of zoledronic in postmenopausal Chinese women with osteoporosis.