Publications by authors named "Weibo Xia"

156 Publications

Efficacy of generic teriparatide and alendronate in Chinese postmenopausal women with osteoporosis: a prospective study.

Arch Osteoporos 2022 07 28;17(1):103. Epub 2022 Jul 28.

Department of Endocrinology, Key Laboratory of Endocrinology, NHC, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

The efficacy of generic teriparatide in improving BMD at lumbar spine in patients with osteoporosis was similar to that of alendronate. It provided a new choice for osteoporosis treatment in Chinese population.

Introduction: To determine whether the efficacy of generic teriparatide is noninferior to alendronate for Chinese postmenopausal women with osteoporosis.

Methods: Eligible patients were randomly assigned (2:1) in a 48-week, open-label design to receive 20 µg sc daily teriparatide or 70 mg oral weekly alendronate. Primary outcome was percentage change in BMD at the lumbar spine from baseline to 48 weeks and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint.

Results: Three hundred ninety-one and 196 participants were randomly assigned to the teriparatide or alendronate group, of whom 379 and 194 receiving at least one dose of teriparatide and alendronate treatment were eligible for the efficacy analysis. Teriparatide was non-inferior to alendronate for BMD change at lumbar spine (treatment difference: 0.7%, 95% CI: - 0.3 to 1.7%), which excluded the predefined non-inferiority margin of - 1.5%. However, teriparatide was not statistically superior to alendronate in improving BMD at lumbar spine (P = 0.169). At 48 weeks, changes in BMD at total hip were - 1.0% and 2.2% in teriparatide and alendronate group, respectively (P < 0.001). The incidence of new fracture showed no statistical difference between groups (P = 0.128). Serum P1NP and β-CTX levels significantly increased in the teriparatide group and markedly decreased in alendronate group (all P < 0.001 vs baseline). The adverse events (AEs) and serious AEs were more common in the teriparatide group than in the alendronate group, which were mainly teriparatide-related hypercalcemia, elevated alkaline phosphatase or parathyroid hormone, dizziness, and arthralgia.

Conclusions: Teriparatide was not inferior to alendronate in increasing BMD at lumbar spine in Chinese postmenopausal women, and they achieved these effects through different mechanisms.
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http://dx.doi.org/10.1007/s11657-022-01131-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334369PMC
July 2022

Targeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation.

Nat Commun 2022 Jul 22;13(1):4241. Epub 2022 Jul 22.

Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.

Sclerostin negatively regulates bone formation by antagonizing Wnt signalling. An antibody targeting sclerostin for the treatment of postmenopausal osteoporosis was approved by the U.S. Food and Drug Administration, with a boxed warning for cardiovascular risk. Here we demonstrate that sclerostin participates in protecting cardiovascular system and inhibiting bone formation via different loops. Loop3 deficiency by genetic truncation could maintain sclerostin's protective effect on the cardiovascular system while attenuating its inhibitory effect on bone formation. We identify an aptamer, named aptscl56, which specifically targets sclerostin loop3 and use a modified aptscl56 version, called Apc001PE, as specific in vivo pharmacologic tool to validate the above effect of loop3. Apc001PE has no effect on aortic aneurysm and atherosclerotic development in ApoE mice and hSOST.ApoE mice with angiotensin II infusion. Apc001PE can promote bone formation in hSOST mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation.
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http://dx.doi.org/10.1038/s41467-022-31997-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307627PMC
July 2022

Bone Microarchitecture in Obese Postmenopausal Chinese Women: The Chinese Vertebral Osteoporosis Study (ChiVOS).

Front Endocrinol (Lausanne) 2022 5;13:891413. Epub 2022 Jul 5.

Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Background: Obesity is associated with improved bone mass and microarchitecture in Caucasian individuals, but evidence in obese Asian individuals is lacking.

Objective: To analyze the areal bone mineral density (aBMD) and bone microarchitecture in normal-weight, overweight, and obese postmenopausal Chinese women.

Methods: A total of 243 postmenopausal women from the Chinese Vertebral Osteoporosis Study (ChiVOS) were included and were divided into three groups (OB, obese group; OW, overweight group; NW, normal weight group) by BMI level. aBMD, trabecular bone score (TBS), and appendicular lean mass (ALM) were measured by dual-energy X-ray absorptiometry (DXA). Bone microarchitecture was measured by HR-pQCT at the distal radius and tibia. X-ray was performed to confirm vertebral fractures (VFs). Multiple linear regression was used to evaluate the correlations between bone parameters and ALM after adjusting for confounding variables.

Results: The prevalence of VFs and clinical fractures were similar among the groups. Participants in the OB group showed a lower level of osteocalcin with comparable levels of other bone turnover markers (BTMs). The aBMD at several skeletal sites was higher in the OB group than in the NW group after adjusting for age (<0.01 for all comparisons). At the radius, the OB group had a higher Ct.Ar, Tb.vBMD, Tb.BV/TV, Tb.N, Tb.Th, and Ct.Th than the NW group after adjusting for covariates (<0.05 for all). Differences of a similar magnitude were found at the distal tibia. There was a trend of decreasing trend in Tb.Sp, Tb.1/N/SD, and Ct.Po among groups at both sites. However, the bone microarchitecture did not differ between participants with severe obesity (BMI≥35.0kg/m) and those with 30.0≤BMI<35 kg/m. Multiple linear regression revealed that the associations between ALM and most of the bone microarchitecture parameters at both sites were much stronger than the association between body weight and bone parameters.

Conclusion: We have observed significant improvements in aBMD, bone geometry, and bone microarchitecture in obese postmenopausal Chinese women. Except for a lower level of osteocalcin in the OB group, no significant differences in BTMs were found among the groups. Compared with body weight, ALM may explain greater variance in the improvement of bone microarchitecture parameters.
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http://dx.doi.org/10.3389/fendo.2022.891413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294215PMC
July 2022

Tumor-Induced Osteomalacia: A Systematic Clinical Review of 895 Cases.

Calcif Tissue Int 2022 Jul 20. Epub 2022 Jul 20.

Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months-90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ - 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.
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http://dx.doi.org/10.1007/s00223-022-01005-8DOI Listing
July 2022

Identification of six novel variants from nine Chinese families with hypophosphatemic rickets.

BMC Med Genomics 2022 07 16;15(1):161. Epub 2022 Jul 16.

Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.

Background: Hypophosphatemic rickets (HR) is a rare genetic disorder associated with renal phosphate wasting and characterized by bone defects. Inactivating mutations in the phosphate regulating endopeptidase homolog X‑linked gene (PHEX) account for most cases of HR. The aim of this study was to identify causative variants in nine unrelated Chinese families associated with HR, and to determine potential pathogenicity of the identified variants.

Methods: Genomic DNA was isolated from the peripheral blood of HR patients and their healthy relatives, followed by next-generation sequencing and/or Sanger sequencing. In silico prediction combined with conservation analysis was performed to assess the effects of the variants, and 3D protein modeling was conducted to predict the functional effects on the encoded protein.

Results: All HR patients recruited in this study displayed bone deformities and tooth agenesis, as well as reduced serum phosphate levels and elevated urine phosphate levels. Nine PHEX variants were identified in eight families, including four novel variants (c.1661_1726del, c.980A > G, c.1078A > T, and c.1017_1051dup). Of the nine identified PHEX variants, five caused a truncated protein, two caused an altered amino acid, and the other two were the canonical splicing variants. Novel variants c.1336G > A and c.1364 T > C in SLC34A3 were also found in one family. Conservation analysis showed that all the amino acids corresponding to the missense variants were highly conserved. In silico analysis and 3D protein structure modeling confirmed the pathogenicity of these variants.

Conclusions: This study identified four novel variants in PHEX and two novel variants in SLC34A3 in a Chinese cohort with HR. Our findings highlight the dominant role of PHEX in HR, and expand the genotypic and phenotypic spectra of this disorder.
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http://dx.doi.org/10.1186/s12920-022-01305-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287957PMC
July 2022

A Novel Synonymous Variant of PHEX in a Patient with X-Linked Hypophosphatemia.

Calcif Tissue Int 2022 Jul 14. Epub 2022 Jul 14.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, People's Republic of China.

X-linked dominant hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets/osteomalacia, is caused by loss-of-function phosphate-regulating endopeptidase homolog X-linked gene (PHEX) variants. However, synonymous PHEX variants are rare in XLH. We report a 7-year-old boy with hypophosphatemia, short stature, and lower limb deformity. Whole-exome sequencing, reverse transcription-polymerase chain reaction, and Sanger sequencing were performed to identify the pathogenicity of the variant. A novel synonymous PHEX variant (NM_000444.4:c.1530 C>T, p.Arg510Arg) was detected in the proband. Further analysis revealed a 58-bp deletion at the 5' site of exon 14 during splicing. This study extends the genetic spectrum of XLH and confirms the rarity and significance of synonymous PHEX variants.
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http://dx.doi.org/10.1007/s00223-022-01003-wDOI Listing
July 2022

Improvement of Bone Health and Initiation of Puberty Development in Camurati-Engelmann Disease With Glucocorticoid and Losartan Treatment: A Case Report and Review of Literature.

Front Endocrinol (Lausanne) 2022 17;13:882144. Epub 2022 Jun 17.

Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.

Camurati-Engelmann Disease (CED) is a rare sclerosing bone disease, sometimes associated delayed puberty. The treatment effect of glucocorticoid and angiotensin II receptor blocker (ARB) in bone health and puberty development remain unclear. We report a case of an 18-year-old girl who presented for a history of an enlarged head, pain of lower limbs, and no menstrual onset or breast development. Radiographs revealed thickening of skull and cortices in the diaphysis but sparse bone trabeculae in the spine and metaphysis. Sanger sequencing detected a mutation of c. 652C>T (p. R218C) in the gene and confirmed the diagnosis of CED. After treatment of a medium-to-small dosage of prednisone and losartan for 28 months, we observed improvement of bone mass in spine and hip and body fat mass and found initiation of puberty development. By a systemic review of current treatment strategies in patients with CED, we found that most cases reported relief of bone pain with treatment of glucocorticoid or ARB, but none has reported the outcome of hypogonadotropic hypogonadism. We propose that long-term use of glucocorticoid combined with ARB may inhibit the activation of TGFβ1 in CED, improve adipogenesis, and thus initiate puberty development and improve the bone mass in spine and hip.
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http://dx.doi.org/10.3389/fendo.2022.882144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9247158PMC
June 2022

Bone Volumetric Density, Microarchitecture, and Estimated Bone Strength in Tumor-Induced Rickets/Osteomalacia X-linked Hypophosphatemia in Chinese Adolescents.

Front Endocrinol (Lausanne) 2022 13;13:883981. Epub 2022 Jun 13.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.

Tumor-induced rickets/osteomalacia (TIR/O) severely impairs bone microarchitecture and bone strength. However, no study has described the microarchitectural quality of bone in adolescent patients with TIR/O. TIR/O affects bone quality more severely than the inherited causes of hypophosphatemia, the most common form of which is X-linked hypophosphatemia (XLH). Nevertheless, differences of the microarchitectural quality of the bone between TIR/O and XLH have never been clarified. Therefore, in this study, we used high-resolution peripheral quantitative computed tomography to assess bone microarchitecture in five Chinese adolescent TIR/O patients, and these were compared with 15 age- and gender-matched XLH patients as well as 15 age- and gender-matched healthy controls. Compared with the healthy controls, the TIR/O patients presented with significantly lower volumetric bone mineral densities (vBMDs), severely affected bone microarchitecture, and profoundly weaker bone strength. The distal tibia was more severely affected than the distal radius. Compared with the XLH patients, the TIR/O patients showed deteriorated bone quality notably at the distal tibia and in the cancellous compartment, reflected by 45.9% lower trabecular vBMD ( = 0.029), 40.2% lower trabecular fraction ( = 0.020), 40.6% weaker stiffness ( = 0.058), and 42.7% weaker failure load ( = 0.039) at the distal tibia. The correlation analysis showed that a higher level of serum FGF23 and a lower level of serum phosphate were associated with a poorer bone microarchitecture and a weaker estimated bone strength in the hypophosphatemic patients of our study. In conclusion, our study demonstrated significantly lower vBMDs, severely impaired bone microarchitecture, and profoundly weaker bone strength in Chinese adolescent patients with TIR/O, notably at the distal tibia, compared with the same parameters in age- and sex-matched healthy controls and XLH patients, which was possibly caused by excessive FGF23 production and secretion, chronically severe hypophosphatemia, and weak mechanical stimulus at the lower extremities. These findings further our understanding of the impact of different kinds of hypophosphatemic rickets/osteomalacia on bone quality.
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http://dx.doi.org/10.3389/fendo.2022.883981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234144PMC
July 2022

Na-Cl Co-transporter (NCC) gene inactivation is associated with improved bone microstructure.

Osteoporos Int 2022 Jun 29. Epub 2022 Jun 29.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Shuaifuyuan No.1, Wangfujing Street, Dongcheng District, Beijing, 100730, China.

Gitelman syndrome (GS) is the disease model of the inactivation of thiazide-sensitive sodium chloride cotransporter (NCC), which is believed to benefit bone mass and reduce fracture risk. In this study, we found that GS patients have superior bone microarchitecture, which is associated with the disease status. Several decreased bone parameters with aging in healthy controls were reversed in GS patients to a certain extent.

Purpose: To evaluate the impact of the inactivation of NCC on bone turnover and microarchitecture in Gitelman syndrome patients.

Methods: A cross-sectional study was conducted in 45 GS patients (25 males and 20 females). Serum procollagen type 1 N-terminal propeptide (P1NP), β-carboxy-terminal crosslinked telopeptide of type 1 collagen (β-CTX), and osteocalcin were measured. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in GS patients and age- and sex-matched healthy controls. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously.

Results: GS patients had a relatively lower level of β-CTX. aBMD at several skeletal sites was improved in GS patients. HR-pQCT assessment revealed that GS patients had slightly thinner but significantly more compact trabecular bone (increased trabecular number and decreased thickness), notably decreased cortical porosity, and increased volume BMD (vBMD) at both the radius and tibia compared with controls. The disease severity, represented as the relationship with the minimum level of magnesium during the course and standard base excess, was associated with bone microarchitecture parameters after adjusting for age, sex, and BMI. The decreased vBMD and Tb.BV/TV, and increased Tb.Sp and Ct.Po with aging, were reversed in GS patients to a certain extent.

Conclusion: GS patients have superior bone microarchitecture, which suggests that the inactivation of NCC might be beneficial for avoiding osteoporosis.
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http://dx.doi.org/10.1007/s00198-022-06471-2DOI Listing
June 2022

Relationship of pathogenic mutations and responses to zoledronic acid in a cohort of osteogenesis imperfecta children.

J Clin Endocrinol Metab 2022 Jun 21. Epub 2022 Jun 21.

Department of Endocrinology, Key Laboratory of Endocrinology of National Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.

Context: Osteogenesis imperfecta (OI) is a rare, heterogeneous genetic disorder characterized by bone fragility and recurrent fractures. Bisphosphonates (BPs) are the most commonly used medications for OI, but their efficacy has great variability.

Objective: We investigate the relationship of pathogenic gene mutations and responses to zoledronic acid (ZOL) in a large cohort of OI children.

Methods: Children with OI were included who received ZOL treatment and followed up for at least one year. Bone mineral density (BMD), serum levels of β-isomerized carboxy-telopeptide of type I collagen (β-CTX, bone resorption marker) were measured at baseline and during follow-up. Causative mutations of OI were identified using next-generation sequencing and Sanger sequencing.

Results: 201 OI children were included who initiated ZOL treatment at a median age of 5 years, with mutations identified in 11 genes. After 3 years of treatment, the increase of femoral neck BMD Z-score in OI patients with autosomal dominant inheritance (AD) was greater than that in patients with autosomal recessive or X-linked inheritance (non-AD) (4.5±2.9 vs. 2.0±1.0, P<0.001). Collagen structural defects were negatively correlated with the increase of femoral neck BMD Z-score. Patients with collagen structural defects had higher incidence of new fracture (35.1% vs. 18.4%, Relative risk 0.52, P=0.044) and less decline in β-CTX level than those with collagen quantitative reduction. Increase in lumbar spine BMD as well as change in height Z-score was not associated with the genotype of OI children.

Conclusion: OI patients with non-AD inheritance or with pathogenic mutations leading to collagen structural defects may have relatively poor responses to ZOL treatment, which is possibly associated with their more severe phenotypes. New therapeutic agents are worth developing in these patients.
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http://dx.doi.org/10.1210/clinem/dgac366DOI Listing
June 2022

Unusual Presentation and Surgical Treatment of a Phosphaturic Mesenchymal Tumor in a Knee.

Front Surg 2022 25;9:746623. Epub 2022 May 25.

Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

A 30-year-old woman presented to our hospital with an 11-year history of gradually enlarging masses around the left knee and 2-year history of progressively worsening bone pain. Tumor-induced osteomalacia (TIO), a rare paraneoplastic syndrome caused by phosphaturic mesenchymal tumors (PMTs) was suspected, but the postoperative pathology of her two operations was both reported as tenosynovial giant cell tumor (TGCT), making its diagnosis confusing. The possibility of hypophosphatemia, insufficient blood supply, innervation of the left lower limbs, as well as the unclear pathology, make it unreasonable to perform tumor-type knee prosthesis replacement directly. Finally, we placed static polymethylmethacrylate (PMMA) spacer at first, then when the concentration of blood phosphorus level rose to the normal range, the pathology was confirmed to be TIO, the blood supply and innervation was satisfying, tumor-type knee prosthesis replacement was performed. She was discharged post operative day 15 after the prothesis implantation without incident. One and a half years after her surgery, the concentration of blood phosphorus was still in the normal range, the symptom of systemic bone pain had improved significantly, the prosthesis was still in a good position and no recurrence was caught.
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http://dx.doi.org/10.3389/fsurg.2022.746623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174667PMC
May 2022

[Identification of c.196C>T nonsense RUNX2 variant in a Chinese patient with cleidocranial dysplasia].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2022 May;39(5):526-529

Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.

Objective: To detect the genetic variant of a child with cleidocranial dysplasia (CCD) and to find out the causation of the illness.

Methods: Gene variant was identified by the second generation targeted sequencing and Sanger sequencing.

Results: The gene sequencing revealed that the RUNX2 gene had c.196C>T(p.Glu66*) nonsense variant, which was predicted to be a pathogenic variant according to the ACMG guidelines(PVS1+PS2).

Conclusion: The variant of c.196C > T in the RUNX2 gene may be the cause of the child with CCD, and the novel variant enriches the RUNX2 gene variant spectrum.
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http://dx.doi.org/10.3760/cma.j.cn511374-20210119-00055DOI Listing
May 2022

Overview of the clinical efficacy and safety of eldecalcitol for the treatment of osteoporosis.

Arch Osteoporos 2022 05 5;17(1):74. Epub 2022 May 5.

Department of Endocrinology, First Medical Center, General Hospital of the People's Liberation Army of China, Beijing, 100039, China.

Eldecalcitol (ELD) is a new oral analog of the active form of vitamin D with anti-resorptive properties. We conducted a meta-analysis to investigate the efficacy and safety of ELD in osteoporosis. Compared with alfacalcidol, ELD significantly lowered vertebral facture risk, increased bone mineral density, but also had a higher risk of hypercalciuria.

Purpose: This study aimed to investigate the efficacy and safety of eldecalcitol (ELD) in osteoporosis by examining fracture rates, bone mineral density (BMD), bone turnover markers, and adverse events as outcomes.

Methods: PubMed, EMBASE, and Cochrane Library were searched up to July 20, 2020, to identify eligible randomized controlled trials. The odds ratio (OR) or weighted mean difference (WMD) with 95% confidence interval was calculated by the random-effects model.

Results: ELD significantly increased lumbar BMD (WMD: 2.80; 95% CI: 1.60, 4.00; P < 0.001, 2 studies involved), total hip BMD (WMD: 2.11; 95% CI: 0.68, 3.55; P = 0.004, 2 studies involved), and femoral neck BMD (WMD: 1.78; 95% CI: 0.76, 2.79; P = 0.001, 1 study involved) compared with alfacalcidol. Moreover, ELD caused a significantly lower rate of vertebral fracture (OR: 0.52; 95% CI: 0.29-0.95; P = 0.034, 2 studies involved) than alfacalcidol, but did not lower the rate of non-vertebral facture (OR: 0.44; 95% CI: 0.06-3.05; P = 0.405, 2 studies involved) compared with alfacalcidol. ELD significantly reduced the percentage change in bone-specific alkaline phosphatase (WMD: - 15.40; 95% CI: - 20.30, - 10.60; P < 0.001, 1 study involved) and serum type I collagen C-telopeptide (WMD: - 38.50; 95% CI: - 50.00, - 27.10; P < 0.001, 1 study involved) as compared with alfacalcidol. ELD was also associated with higher risk of hypercalciuria compared with alfacalcidol (OR: 1.64; 95% CI: 1.22, 2.20; P = 0.001, 2 studies involved).

Conclusions: This systematic review indicated that ELD was superior than alfacalcidol for improving vertebral fracture risk and BMD. Further large-scale trials should be conducted to verify the long-term effects and safety of ELD in osteoporosis.

Prospero Registration Number: CRD42020147518.
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http://dx.doi.org/10.1007/s11657-022-01071-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072485PMC
May 2022

[Prevalence of osteoporosis and related factors in postmenopausal women aged 40 and above in China].

Zhonghua Liu Xing Bing Xue Za Zhi 2022 Apr;43(4):509-516

Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.

To understand the prevalence of osteoporosis and related factors in postmenopausal women aged ≥40 years in China and provide scientific evidence for osteoporosis prevention and control. Data of this study were from the 2018 China Osteoporosis Epidemiological Survey, covering 44 counties (districts) in 11 provinces in China. Related variables were collected by questionnaire survey and physical measurement, and the BMD of lumbar spine and proximal femur was measured by dual-energy X-ray absorption method. The prevalence of osteoporosis and its 95% in postmenopausal women aged ≥40 years were estimated with complex sampling weights. A total of 5 728 postmenopausal women aged ≥40 years were included in the analysis and the prevalence of osteoporosis was 32.5% (95%: 30.3%-34.7%). The prevalence of osteoporosis in postmenopausal women aged 40-49 years, 50-59 years, 60-69 years, 70-79 years, and ≥80 years were 16.0% (95%:4.5%-27.5%), 18.4% (95%:15.9%-20.8%), 37.5% (95%:34.5%-40.4%), 52.9% (95%: 47.5%-58.3%), and 68.0% (95%:55.9%-80.1%) respectively. The prevalence of osteoporosis was higher (<0.001) in those with education level of primary school or below (47.2%, 95%: 43.0%-51.3%) and in those with individual annual income less than 10 000 Yuan, (40.3%, 95%: 36.9%-43.7%). The prevalence of osteoporosis was 35.1% in rural areas (95%: 32.0%-38.1%), which was higher than that in urban areas (<0.001). The prevalence of osteoporosis in low weight, normal weight, overweight and obese groups were 69.9% (95%: 59.0%-80.8%), 42.2% (95%: 38.7%-45.7%), 24.2% (95%: 21.3%-27.1%) and 14.6% (95%: 11.1%-18.0%), respectively. The prevalence of osteoporosis in those with menstrual maintenance years ≤30 years and in those with menopause years ≥11 years were 46.1% (95%:40.8%-51.3%) and 48.2% (95%:45.0%-51.3%), respectively. Multivariate logistic analysis showed that age ≥60 years, education level of primary school or below, annual household income per capita less than 10 000 Yuan, low body weight, menstrual maintenance years ≤30 years, menopause years ≥11 years were risk factors of osteoporosis in postmenopausal women in China. The prevalence of osteoporosis was high in postmenopausal women aged ≥40 years in China, and there were differences in osteoporosis prevalence among different socioeconomic groups. Effective interventions should be taken for the prevention and control of osteoporosis in key groups in the future.
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http://dx.doi.org/10.3760/cma.j.cn112338-20210826-00680DOI Listing
April 2022

Bone microstructure evaluated by TBS and HR-pQCT in Chinese adults with X-linked hypophosphatemia.

Bone 2022 07 18;160:116423. Epub 2022 Apr 18.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. Electronic address:

X-linked hypophosphatemia (XLH) is the most common form of heritable hypophosphatemic rickets. Although generalized mineralization defects have been observed, elevated areal bone mineral density (aBMD) in the lumbar spine measured by dual-energy X-ray absorptiometry (DXA) has also been found in XLH. In contrast, high-resolution peripheral quantitative computed tomography (HR-pQCT) revealed lower volumetric BMD (vBMD) and damaged bone microstructure in the peripheral bone in XLH. Trabecular bone score (TBS), which can assess the trabecular microstructure in the lumbar spine, has not been explored in XLH. This study aimed to explore TBS and its correlations with biochemical indices and HR-pQCT parameters in adult XLH patients. A total of 66 patients with XLH (26 men and 40 women) aged 29.6 ± 9.6 years and 66 age- and sex-matched healthy controls were included. Z score of lumbar spine aBMD was relatively high [2.0 (0.6, 3.7)], with normal TBS (1.475 ± 0.129) in the XLH patients. HR-pQCT revealed larger total and trabecular area in the peripheral bone in the XLH group compared with the control group. In addition, lower trabecular and cortical vBMD, lower trabecular number with greater separation, and lower bone strength at both the radius and tibia were found in the XLH group compared with the control group. Smaller cortical area, lower thickness and higher porosity in the XLH group compared with controls were only found at the radius. TBS was not associated with any biochemical indices, while better HR-pQCT parameters correlated with higher serum phosphate and lower ALP levels. TBS was positively related with aBMD but not HR-pQCT parameters. In conclusion, adult patients with XLH had high bone mass and normal TBS in the lumbar spine but compromised microarchitecture and bone strength in the peripheral bone. This finding indicated a site-specific effect of the disease on the skeleton in the XLH patients.
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http://dx.doi.org/10.1016/j.bone.2022.116423DOI Listing
July 2022

Biocompatible tumor-targeted GQDs nanocatalyst for chemodynamic tumor therapy.

J Mater Chem B 2022 05 11;10(18):3567-3576. Epub 2022 May 11.

State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.

To deal with the complex tumor microenvironment (TME), chemodynamic therapy (CDT) has been developed, which uses nanocatalysts simulating peroxidase to convert high concentration hydrogen peroxide (HO) into highly toxic hydroxyl radicals (˙OH) and effectively kills tumor cells. Due to the low catalytic activity of traditional nanocatalysts, the present CDT treatment has to be combined with other anti-tumor therapies, which increases the complexity and uncertainty of the treatment. Thus, developing new nanocatalysts with stable and high enzymatic activity is the key point to CDT treatment. Graphene quantum dots (GQDs) are important metal-free catalysts with intrinsic peroxidase-like activity due to their excellent electron transport performance. Here, we prepare a nitrogen-doped GQD (NGOD) nanocatalyst, which displays much higher peroxidase activity than known metal nanocatalysts. The NGQD nanocatalyst is further grafted with RGDS peptide-modified polyethylene glycol (PEG), which guides the nanocatalyst to the tumor area and increases its circulation time in blood. The as-produced [email protected] nanocatalyst displays stable and high peroxidase activity, which achieves the conversion of HO → ˙OH in the TME. Through an study it has been observed that [email protected] obviously inhibit tumor growth without combining with other treatment methods and show excellent biocompatibility, which provides a unique idea for the application of GQDs in CDT.
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http://dx.doi.org/10.1039/d1tb02734dDOI Listing
May 2022

Head-to-Head Comparison of Ga-DOTA-TATE and Ga-DOTA-JR11 PET/CT in Patients With Tumor-Induced Osteomalacia: A Prospective Study.

Front Oncol 2022 24;12:811209. Epub 2022 Feb 24.

Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: The purpose of this study is to compare the sensitivity of Ga-DOTA-JR11 and Ga-DOTA-TATE PET/CT for detecting the responsible tumor of tumor-induced osteomalacia (TIO) and investigate if Ga-DOTA-JR11 PET/CT can identify the culprit tumor of TIO in multiple suspicious lesions in Ga-DOTA-TATE PET/CT.

Methods: A total of 19 patients with suspected TIO were prospectively recruited in this study. Each patient underwent whole-body PET/CT scan 40-60 min postinjection using Ga-DOTA-TATE and Ga-DOTA-JR11 on the same PET/CT, respectively in sequence, and on consecutive days. The diagnosis of TIO was confirmed by the combination of the postsurgical pathological results of the tumor and clinical information.

Results: Among the 19 patients with TIO who were included in this study, culprit tumors from all patients were confirmed pathologically. Ga-DOTA-TATE PET/CT positively identified the causative tumor in 18/19 patients, whereas Ga-DOTA-JR11 PET/CT was positive in 11/19 patients (94.7% vs. 57.9%, respectively; < 0.05). Ga-DOTA-TATE PET/CT demonstrated more than one increased focal activity in 7 patients for a total of 16 lesions (3 lesions each in 2 patients and 2 lesions each in the rest 5 patients). However, seven of these 16 lesions showed concordant results on Ga-DOTA-JR11 PET/CT by demonstrating increased activity (one lesion in each of the 7 patients). The surgical specimens of the lesions in these 7 patients confirmed the phosphaturic mesenchymal tumor. A total of 11 culprit tumors were positive in both Ga-DOTA-TATE and Ga-DOTA-JR11 PET/CT. The SUVmax of 11 culprit tumors was significantly higher on Ga-DOTA-TATE PET/CT compared with that on Ga-DOTA-JR11 PET/CT (17.8 ± 12.5 vs. 6.8 ± 6.2; < 0.05).

Conclusions: Ga-DOTA-TATE PET/CT is more sensitive to Ga-DOTA-JR11 PET/CT in the detection of the culprit tumor of TIO. However, Ga-DOTA-JR11 PET/CT might be helpful to identify the tumor in multiple suspicious lesions in Ga-DOTA-TATE PET/CT.

Clinical Trial Registration: clinicaltrials.gov, identifier NCT04689893.
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http://dx.doi.org/10.3389/fonc.2022.811209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8913035PMC
February 2022

Correction to: Oxygen content-related DNA damage of graphene oxide on human retinal pigment epithelium cells.

J Mater Sci Mater Med 2022 Feb 9;33(2):23. Epub 2022 Feb 9.

State Key Laboratory of Ophthalmology, Optometry and Visual Science, Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, China.

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http://dx.doi.org/10.1007/s10856-021-06634-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828594PMC
February 2022

An adult patient of X-linked hypophosphatemia with joint manifestation mimicking spondylarthritis.

Chin Med J (Engl) 2022 05 20;135(10):1255-1257. Epub 2022 May 20.

State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Beijing 100730, China.

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http://dx.doi.org/10.1097/CM9.0000000000002000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337256PMC
May 2022

A robust method for simultaneous measurement of serum 25(OH)D, 1,25(OH) D, and 24,25(OH) D by liquid chromatography-tandem mass spectrometry with efficient separation of 3-epi analogs, 23R,25(OH) D , and 4β,25(OH) D.

J Mass Spectrom 2022 Jan;57(1):e4792

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.

Background: This study aimed to establish a robust, simple method to detect 25-hydroxyvitamin D (25(OH)D ), 25-hydroxyvitamin D (25(OH)D ), 1,25-dihydroxyvitamin D (1,25(OH) D ), 1,25-dihydroxyvitamin D (1,25(OH) D ), 24,25-dihydroxyvitamin D (24,25(OH) D ), and 24,25-dihydroxyvitamin D (24,25(OH) D ) simultaneously with efficient separation of 3-epi 25(OH)D , 3-epi 24,25(OH) D , 23R,25(OH) D , and 4β,25-dihydroxyvitamin D (4β,25(OH) D ) by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Method: This method was validated according to procedures established by Clinical and Laboratory Standards Institute (CLSI) and then applied in healthy population to determine the distribution of the vitamin D metabolites by LC-MS/MS.

Results: The total-run CV% of 25(OH)D , 25(OH)D , 24,25(OH) D , 24,25(OH) D , 1,25(OH) D , and 1,25(OH) D were 6.30%-8.40%, 5.00%-8.40%, 5.90%-9.00%, 5.60%-9.00%, 5.60%-8.00%, and 7.00%-9.70%, respectively. The linearity correlation coefficients r of these six vitamin D metabolites were >0.99. The matrix effects of 25(OH)D , 25(OH)D , 24,25(OH) D , 24,25(OH) D , 1,25(OH) D , and 1,25(OH) D were 90.6%-103.3%, 97.3%-106.3%, 90.7%-106.3%, 100.7%-114.5%, 97.9%-104.6%, and 97.0%-111.0%. The trueness values of 25(OH)D , 25(OH)D , and 24,25(OH) D were 93.8%-103.0%, 101.0%, and 96.3%-100%, respectively.

Conclusion: This study successfully established an efficient, accurate, robust method for simultaneous measurement of serum 25(OH)D, 1,25(OH) D, and 24,25(OH) D by LC-MS/MS with efficient separation of 3-epi analogs, 23R,25(OH) D , and 4β,25(OH) D .
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http://dx.doi.org/10.1002/jms.4792DOI Listing
January 2022

Serum Metabolomics Reveals Dysregulation and Diagnostic Potential of Oxylipins in Tumor-induced Osteomalacia.

J Clin Endocrinol Metab 2022 04;107(5):1383-1391

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.

Context: Excessive production of fibroblast growth factor 23 (FGF23) by a tumor is considered the main pathogenesis in tumor-induced osteomalacia (TIO). Despite its importance to comprehensive understanding of pathogenesis and diagnosis, the regulation of systemic metabolism in TIO remains unclear.

Objective: We aimed to systematically characterize the metabolome alteration associated with TIO.

Methods: By means of liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 96 serum samples (32 from TIO patients at initial diagnosis, pairwise samples after tumor resection, and 32 matched healthy control (HC) subjects). In order to screen and evaluate potential biomarkers, statistical analyses, pathway enrichment and receiver operating characteristic (ROC) were performed.

Results: Metabolomic profiling revealed distinct alterations between TIO and HC cohorts. Differential metabolites were screened and conducted to functional clustering and annotation. A significantly enriched pathway was found involving arachidonic acid metabolism. A combination of 5 oxylipins, 4-HDoHE, leukotriene B4, 5-HETE, 17-HETE, and 9,10,13-TriHOME, demonstrated a high sensitivity and specificity panel for TIO prediction screened by random forest algorithm (AUC = 0.951; 95% CI, 0.827-1). Supported vector machine modeling and partial least squares modeling were conducted to validate the predictive capabilities of the diagnostic panel.

Conclusion: Metabolite profiling of TIO showed significant alterations compared with HC. A high-sensitivity and high-specificity panel with 5 oxylipins was tested as diagnostic predictor. For the first time, we provide the global profile of metabolomes and identify potential diagnostic biomarkers of TIO. The present work may offer novel insights into the pathogenesis of TIO.
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http://dx.doi.org/10.1210/clinem/dgab885DOI Listing
April 2022

Bone Geometry, Density, Microstructure, and Biomechanical Properties in the Distal Tibia in Patients With Primary Hypertrophic Osteoarthropathy Assessed by Second-Generation High-Resolution Peripheral Quantitative Computed Tomography.

J Bone Miner Res 2022 03 3;37(3):484-493. Epub 2022 Jan 3.

Department of Endocrinology, Key Laboratory of Endocrinology, NHC, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Periosteosis refers to pathological woven bone formation beneath the cortical bone of the long bones. It is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO) and also considered as one of the major diagnostic criteria of PHO patients. Up to date, detailed information on bone quality changes in long bones of PHO patients is still missing. This study aimed to evaluate bone microarchitecture and bone strength in PHO patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT). The study comprised 20 male PHO patients with the average age of 27.0 years and 20 age- and sex-matched healthy controls. The areal bone mineral density (aBMD) was assessed at the lumbar spine (L -L ) and hip (total hip and femoral neck) by dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric bone mineral density (vBMD), and microstructure parameters at the distal tibia were evaluated by using HR-pQCT. Bone strength was evaluated by finite element analysis (FEA) based on HR-pQCT screening at distal tibia. Urinary prostaglandin E (PGE ), serum phosphatase (ALP), beta-C-telopeptides of type I collagen (β-CTX), soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and neuronal calcitonin gene-related peptide (CGRP) were investigated. As compared with healthy controls, PHO patients had larger bone cross-sectional areas; lower total, trabecular, and cortical vBMD; compromised bone microstructures with more porous cortices, thinned trabeculae, reduced trabecular connectivity, and relatively more significant resorption of rod-like trabeculae at distal tibia. The apparent Young's modulus was significantly lower in PHO patients. The concentration of PGE , biomarkers of bone resorption (β-CTX and sRANKL/OPG ratio), and the neuropeptide CGRP were higher in PHO patients versus healthy controls. PGE level correlated negatively with vBMD and estimated bone strength and positively with bone geometry at distal tibia. The present HR-pQCT study is the first one illustrating the microarchitecture and bone strength features in long bones. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4488DOI Listing
March 2022

Clinical, Biochemical, Radiological, and Genetic Analyses of a Patient with VCP Gene Variant-Induced Paget's Disease of Bone.

Calcif Tissue Int 2022 04 20;110(4):518-528. Epub 2021 Nov 20.

Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Shuaifuyuan No.1, Dongcheng District, Beijing, 100730, China.

Paget's disease of bone (PDB) is a rare metabolic bone disorder, which is extremely rare in Asian population. This study aimed to investigate the phenotypes and the pathogenic mutations of woman with early-onset PDB. The clinical features, bone mineral density, x-ray, radionuclide bone scan, and serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and β-carboxy-terminal cross-linked telopeptide of type 1 collagen (β-CTX) were measured in detail. The pathogenic mutations were identified by whole-exon sequencing and confirmed by Sanger sequencing. We also evaluated the effects of intravenous infusion of zoledronic acid on the bones of the patient and summarized the phenotypic characteristics of reported patients with mutation at position 155 of the valosin-containing protein (VCP). The patient only exhibited bone pain as the initial manifestation with vertebral compression fracture and extremely elevated ALP, P1NP, and β-CTX levels; she had no inclusion body myopathy and frontotemporal dementia. The missense mutation in exon 5 of the VCP gene (p.Arg155His) was identified by whole-exome sequencing and further confirmed by Sanger sequencing. No mutation in candidate genes of PDB, such as SQSTM1, CSF1, TM7SF4, OPTN, PFN1, and TNFRSF11A, were identified in the patient by Sanger sequencing. Rapid relief of bone pain and a marked decline in ALP, P1NP, and β-CTX levels were observed after zoledronic acid treatment. Previously reported patients with VCP missense mutation at position 155 (R155H) always had myopathy, frontotemporal dementia, and PDB, but the patient in this study exhibited only PDB. This was the first report of R155H mutation-induced early-onset in the VCP gene in Asian population. PDB was the only manifestation having a favorable response to zoledronic acid treatment. We broadened the genetic and clinical phenotype spectra of the VCP mutation.
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http://dx.doi.org/10.1007/s00223-021-00929-xDOI Listing
April 2022

Bone Impairment in a Large Cohort of Chinese Patients With Tumor-Induced Osteomalacia Assessed by HR-pQCT and TBS.

J Bone Miner Res 2022 03 3;37(3):454-464. Epub 2022 Jan 3.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Previous studies have revealed generalized mineralization defects and low areal bone mineral density (aBMD) in TIO. However, data on the bone microarchitecture in TIO are limited. In this study, we evaluated the microarchitecture in the peripheral (distal radius and tibia) and axial (lumbar spine) skeleton using high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) and investigated related factors in a large cohort of Chinese patients with TIO. A total of 186 patients with TIO who had undergone dual-energy X-ray absorptiometry (DXA) or HR-pQCT scans were enrolled. Compared with age-, sex-, and body mass index (BMI)-matched healthy controls, TIO patients (n = 113) had lower volumetric BMD, damaged microstructure, and reduced bone strength in the peripheral skeleton, especially at the tibia. The average TBS obtained from 173 patients was 1.15 ± 0.16. The proportion of patients with abnormal TBS (<1.35) was higher than that with low L to L aBMD Z-score (Z ≤ -2) (43.9% versus 89.6%, p < 0.001). Higher intact fibroblast growth factor 23 (iFGF23), intact parathyroid hormone (iPTH), alkaline phosphatase, and β-isomerized C-terminal telopeptide of type I collagen (β-CTx) levels, more severe mobility impairment, and a history of fracture were associated with poorer HR-pQCT parameters but not with lower TBS. However, greater height loss and longer disease duration were correlated with worse HR-pQCT parameters and TBS. Moreover, TBS was correlated with both trabecular and cortical HR-pQCT parameters in TIO. In conclusion, we revealed impaired bone microarchitecture in the axial and peripheral skeleton in a large cohort of Chinese TIO patients. HR-pQCT parameters and TBS showed promising advantages over aBMD for assessing bone impairment in patients with TIO. A longer follow-up period is needed to observe changes in bone microarchitecture after tumor resection. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4476DOI Listing
March 2022

A novel long-range deletion spanning CDC73 and upper-stream genes discovered in a kindred of familial primary hyperparathyroidism.

Endocrine 2022 Mar 2;75(3):907-915. Epub 2021 Nov 2.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100032, China.

Purpose: To confirm the exact break-point of a novel long-range deletion discovered in one female parathyroid carcinoma (PC) patient who has a strong family history suggesting familial hyperparathyroidism, and to investigate the expression of parafibromin in the patient's affected lesion.

Methods: Clinical information of one female patient as well as five of her relatives was collected. Their genomic DNA extracted from peripheral blood went through Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). After completing whole genome sequencing (WGS), clone sequencing was also performed, whose result was aligned with standard human genome database after Sanger sequencing.

Results: The medical history of recurrent hypercalcemia after parathyroidectomy and histopathological investigation confirmed that the female patient was diagnosed with PC. WGS displayed a novel 130 kb long-range deletion spanning UCHL5 to CDC73 that was later confirmed by clone sequencing. MLPA showed similar results in four of her five relatives, suggesting these people to be carriers of the same long-range deletion, and three among them had a history of primary hyperparathyroidism (PHPT) ahead of the proband's first visit.

Conclusions: We discovered a novel 130 kb long-range deletion spanning CDC73 in a family of 5 persons, and the existence of the deletion was related to PHPT and PC. Our discovery validated the role of CDC73 mutation in the occurrence of PHPT and PC, which provided new information to the genetic studies of PC.
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http://dx.doi.org/10.1007/s12020-021-02917-5DOI Listing
March 2022

Clinical, Biochemical, Radiological, Genetic and Therapeutic Analysis of Patients with COMP Gene Variants.

Calcif Tissue Int 2022 03 28;110(3):313-323. Epub 2021 Oct 28.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient's condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r =  - 0.603, p = 0.01) and the clinical manifestation score (r =  - 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p < 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874T>C, c.1123_1134del, c.1531G>A, and c.1576G>T. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce "spondyloepiphyseal dysplasia, COMP type". Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity.
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http://dx.doi.org/10.1007/s00223-021-00920-6DOI Listing
March 2022

The Negative Impacts of Acromegaly on Bone Microstructure Not Fully Reversible.

Front Endocrinol (Lausanne) 2021 15;12:738895. Epub 2021 Sep 15.

Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Purpose: This study aimed to evaluate the bone turnover markers and bone microarchitecture parameters derived from high-resolution peripheral quantitative computed tomography (HR-pQCT) in active and controlled acromegaly patients.

Methods: This cross-sectional study involved 55 acromegaly patients from a tertiary hospital (23 males and 32 females, aged 45.0 ± 11.6 years). Firstly, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and markers for bone turnover were assessed. Next, we derived peripheral bone microstructure parameters and volumetric bone mineral density (vBMD) through HR-pQCT. These parameters were compared between acromegaly patients and 110 healthy controls, as well as between 27 active and 28 controlled acromegaly patients. Moreover, the relationship between GH/IGF-1 and bone microstructure parameters was analyzed through multiple linear regression.

Results: As compared with healthy controls, acromegaly patients exhibited elevated cortical vBMD, reduced trabecular vBMD, and increased trabecular inhomogeneity in the distal radius and tibia. While controlled acromegaly patients had slower bone turnover, they did not necessarily have better bone microstructure relative to active patients in intergroup comparison. Nevertheless, multiple regression indicated that higher IGF-1 was associated with lower tibial stiffness and failure load. Additionally, males with higher IGF-1 typically had larger trabecular separation, lower trabecular number, and larger cortical pores in the radius. Moreover, patients with elevated GH typically had more porous cortical bone in the radius and fewer trabeculae in the tibia. However, the compromised bone strength in active patients was partially compensated by increased bone thickness. Furthermore, no significant linkage was observed between elevated GH/IGF-1 and the most important HR-pQCT parameters such as trabecular volumetric bone density.

Conclusion: Acromegaly adversely affected bone quality, even in controlled patients. As the deterioration in bone microstructure due to prolonged GH/IGF-1 exposure was not fully reversible, clinicians should be aware of the bone fragility of acromegaly patients even after they had achieved biochemical remission.
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http://dx.doi.org/10.3389/fendo.2021.738895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479105PMC
February 2022

Molecular Characterization of an Aquaporin-2 Mutation Causing Nephrogenic Diabetes Insipidus.

Front Endocrinol (Lausanne) 2021 27;12:665145. Epub 2021 Aug 27.

Department of Endocrinology, Key Laboratory of Endocrinology, NHC, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

The aquaporin 2 (AQP2) plays a critical role in water reabsorption to maintain water homeostasis. AQP2 mutation leads to nephrogenic diabetes insipidus (NDI), characterized by polyuria, polydipsia, and hypernatremia. We previously reported that a novel mutation (G215S) caused NDI in a boy. In this study, we aimed to elucidate the cell biological consequences of this mutation on AQP2 function and clarify the molecular pathogenic mechanism for NDI in this patient. First, we analyzed AQP2 expression in Madin-Darby canine kidney (MDCK) cells by AQP2-G215S or AQP2-WT plasmid transfection and found significantly decreased AQP2-G215S expression in cytoplasmic membrane compared with AQP2-WT, independent of forskolin treatment. Further, we found co-localization of endoplasmic reticulum (ER) marker (Calnexin) with AQP2-G215S rather than AQP2-WT in MDCK cells by immunocytochemistry. The functional analysis showed that MDCK cells transfected with AQP2-G215S displayed reduced water permeability compared with AQP2-WT. Visualization of AQP2 structure implied that AQP2-G215S mutation might interrupt the folding of the sixth transmembrane α-helix and/or the packing of α-helices, resulting in the misfolding of monomer and further impaired formation of tetramer. Taken together, these findings suggested that AQP2-G215S was misfolded and retained in the ER and could not be translocated to the apical membrane to function as a water channel, which revealed the molecular pathogenic mechanism of AQP2-G215S mutation and explained for the phenotype of NDI in this patient.
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http://dx.doi.org/10.3389/fendo.2021.665145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429928PMC
December 2021

Alteration of Bone Density, Microarchitecture, and Strength in Patients with Camurati-Engelmann Disease: Assessed by HR-pQCT.

J Bone Miner Res 2022 01 28;37(1):78-86. Epub 2021 Sep 28.

Department of Endocrinology, Key Laboratory of Endocrinology, NHC, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Camurati-Engelmann disease (CED) is a rare autosomal-dominant skeletal dysplasia caused by mutations in the transforming growth factor-β1 (TGFB1) gene. In this study, a retrospective review of patients with CED evaluated at Peking Union Medical College Hospital in Beijing, China, between November 30, 2000 and November 30, 2020 was conducted. Data including demographic data, manifestations, and examination results were characterized. Furthermore, bone geometry, density, and microarchitecture were assessed and bone strength was estimated by HR-pQCT. Results showed the median age at onset was 2.5 years. Common manifestations included pain in the lower limbs (94%, 17/18), abnormal gait (89%, 16/18), genu valgum (89%, 16/18), reduced subcutaneous fat (78%, 14/18), delayed puberty (73%, 8/11), muscle weakness (67%, 12/18), hearing loss (39%, 7/18), hepatosplenomegaly (39%, 7/18), exophthalmos or impaired vision or visual field defect (33%, 6/18), and anemia (33%, 7/18). Twenty-five percent (4/16) of patients had short stature. Serum level of alkaline phosphatase was elevated in 41% (7/17) of patients whereas beta-C-terminal telopeptide was elevated in 91% of patients (10/11). Among 12 patients, the Z-scores of two patients were greater than 2.5 at the femur neck and the Z-scores of five patients were lower than -2.5 at the femur neck and/or lumbar spine. HR-pQCT results showed lower volumetric BMD (vBMD), altered bone microstructure and lower estimated bone strength at the distal radius and tibia in patients with CED compared with controls. In addition, total volume bone mineral density and cortical volumetric bone mineral density at the radius were negatively correlated with age in patients with CED, but positively correlated with age in controls. In conclusion, the largest case series of CED with characterized clinical features in a Chinese population was reported here. In addition, HR-pQCT was used to investigate bone microstructure at the distal radius and tibia in nine patients with CED, and the alteration of bone density, microstructure, and strength was shown for the first time. © 2021 American Society for Bone and Mineral Research (ASBMR).
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January 2022

Prevalence of Osteoporosis and Fracture in China: The China Osteoporosis Prevalence Study.

JAMA Netw Open 2021 08 2;4(8):e2121106. Epub 2021 Aug 2.

Department of Endocrinology, The First Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.

Importance: The aging of the population is associated with an increasing burden of fractures worldwide. However, the epidemiological features of fractures in mainland China are not well known.

Objective: To assess the prevalence of and factors associated with osteoporosis, clinical fractures, and vertebral fractures in an adult population 40 years or older in mainland China.

Design, Setting. And Participants: This cross-sectional study, the China Osteoporosis Prevalence Study, was conducted from December 2017 to August 2018. A random sample of individuals aged 20 years or older who represented urban and rural areas of China were enrolled, with a 99% participation rate.

Main Outcomes And Measures: Weighted prevalence of osteoporosis, clinical fracture, and vertebral fracture by age, sex, and urban vs rural residence as determined by x-ray absorptiometry, questionnaire, and radiography.

Results: A total of 20 416 participants were included in this study; 20 164 (98.8%; 11 443 women [56.7%]; mean [SD] age, 53 [13] years) had a qualified x-ray absorptiometry image and completed the questionnaire, and 8423 of 8800 (95.7%) had a qualified spine radiograph. The prevalence of osteoporosis among those aged 40 years or older was 5.0% (95% CI, 4.2%-5.8%) among men and 20.6% (95% CI, 19.3%-22.0%) among women. The prevalence of vertebral fracture was 10.5% (95% CI, 9.0%-12.0%) among men and 9.7% (95% CI, 8.2%-11.1%) among women. The prevalence of clinical fracture in the past 5 years was 4.1% (95% CI, 3.3%-4.9%) among men and 4.2% (95% CI, 3.6%-4.7%) among women. Among men and women, 0.3% (95% CI, 0.0%-0.7%) and 1.4% (95% CI, 0.8%-2.0%), respectively, with osteoporosis diagnosed on the basis of bone mineral density or with fracture were receiving antiosteoporosis treatment to prevent fracture.

Conclusions And Relevance: In this cross-sectional study of an adult population in mainland China, the prevalence of osteoporosis and vertebral fracture were high and the prevalence of vertebral fracture and clinical fracture was similarly high in men and women. These findings suggest that current guidelines for screening and treatment of fractures among patients in China should focus equally on men and women and should emphasize the prevention of vertebral fractures.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.21106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369359PMC
August 2021
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