Wei Yu

Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature.

Tumor‐induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult‐onset hypophosphatemic osteomalacia were seen over a 6‐year period (January, 2004 to May, 2010) in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium‐99m octreotide scintigraphy (99Tcm‐OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in 99Tcm‐OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by 99Tcm‐OCT. The gender distribution was equal (M/Fu2009=u200919/20). Average age was 42u2009±u200914 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5u2009±u20093.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult‐onset hypophosphatemia in China. 99Tcm‐OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long‐term follow‐up.

The levels of bone turnover markers in Chinese postmenopausal women: Peking Vertebral Fracture study.

Objective:The aim of this study was to evaluate serum N-aminoterminal propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (&bgr;-CTX), and vitamin D status in healthy Chinese postmenopausal women. The study was also designed to investigate their possible relationships with osteoporosis phenotypes. Methods:A community-based population of 1,724 postmenopausal women in Beijing was randomly selected. Serum bone turnover markers and 25-hydroxyvitamin D [25(OH)D] were tested by an automated Roche electrochemiluminescence system. Dual-energy x-ray absorptiometry was used to measure bone mineral density (BMD). Results:The mean (SD) values of serum &bgr;-CTX and P1NP were 0.439 (0.210) and 56.7 (27.9) ng/mL, respectively. The 25(OH)D level of postmenopausal women in Beijing was remarkably low (13.2 ± 5.4 ng/mL). Serum &bgr;-CTX and P1NP levels were negatively correlated with BMDs of lumbar spine, femoral neck, and total hip (all P < 0.01). The cubic regression model better fitted the relationships of BMD and bone turnover markers. Serum &bgr;-CTX levels were significantly higher in women with sustained osteoporotic fracture or vertebral fracture (P = 0.006 and 0.012, respectively). No association between P1NP and fracture or vertebral fracture was detected. The same situation applied to 25(OH)D. 25(OH)D was negatively correlated with &bgr;-CTX and P1NP (r = −0.073 and −0.088, P = 0.002 and <0.001, respectively). Conclusions:Serum &bgr;-CTX and P1NP levels were negatively correlated with BMD. &bgr;-CTX was significantly higher in postmenopausal women with sustained fracture or vertebral fracture. Vitamin D deficiency was highly prevalent in postmenopausal women in Beijing.

The efficacy and safety of calcitriol and/or Caltrate D in elderly Chinese women with low bone mass.

AbstractAim:To observe the efficacy and safety of Rocaltrol (calcitriol) and/or Caltrate D (calicum carbonate plus vitamin D) in elderly Chinese women with osteopenia or osteoporosis.Methods:One hundred fifty Chinese women aged over 65 years with osteopenia or osteoporosis from three centers were randomly divided into two groups. Seventy-six participants received Caltrate D as one pill daily; the other 74 participants received 0.25 μg Caltrate D plus Rocaltrol daily. The changes in bone mineral density (BMD) served as primary end-points. Height changes, the presence of new vertebral fractures, muscle strength and balance were evaluated.Results:The following are the mean percentage changes (and SD) in BMD over 12 months: at L2-L4, 0.83±3.88 in the Caltrate D group and 2.84±4.04 in the Rocaltrol+Caltrate D group (P=0.003, by ANCOVA); at the femoral neck, 0.04±3.94 in the Caltrate D group and 2.01±5.45 in the Rocaltrol+Caltrate D group (P=0.085, by ANCOVA); and in the trochanter, 1.59±4.57 in the Caltrate D group and 3.76±6.25 in the Rocaltrol+Caltrate D group (P=0.053, by ANCOVA). The stand and maximal forward reach test (SMFRT) was significantly enhanced in both groups during the 12 months of treatment, but no significant differences were found between these two groups. No severe adverse event related to these medications occurred throughout the study.Conclusion:Treatment with Rocaltrol plus Caltrate D or Caltrate D for 12 months in elderly Chinese postmenopausal women effectively increased BMD at the lumbar spine. Rocaltrol plus Caltrate D was more effective at the lumbar spine than Caltrate D alone.

The Pilot Study of DXA Assessment in Chinese HIV-Infected Men With Clinical Lipodystrophy

The aim of this study was to evaluate human immunodeficiency virus (HIV)-infected patients body composition changes by dual-energy X-ray absorptiometry (DXA) and to analyze factors associated with lipodystrophy (LD). Total-body composition was measured by DXA in HIV-infected men and healthy men. HIV-infected men were divided into LD patients and non-LD patients according to whether they were complicated with LD. Healthy men were selected as controls. Fat mass (FM) of HIV-infected patients correlated negatively with the duration of HIV infection and with the duration of highly active antiretroviral therapy regimen (r(s)=-0.448 and -0.563; p=0.032 and 0.000, respectively). Multiple linear regression results showed that FM had positive correlation with weight and bone mineral content (BMC) and had negative correlation with lean mass (LM). Total body and regional FMs were found to be significantly different among LD patients, non-LD patients, and controls-the lowest in LD patients and the highest in controls (p<0.05). Total body, trunk, and leg BMCs of LD patients were lower than those of controls (p<0.05). Lumbar bone mineral density of LD patients was lower than that of non-LD patients and controls (p=0.04 and 0.007). LM of LD patients was higher than that of non-LD patients, and trunk LM had statistical difference between the 2 groups (p=0.003). Applying DXA to assess HIV-infected patients body composition changes could provide objective information for physicians to prevent LD and osteoporosis.

Association of genetic variants of vit D binding protein (DBP/GC) and of the enzyme catalyzing its 25-hydroxylation (DCYP2R1) and serum vit D in postmenopausal women

OBJECTIVE: To determine if GC (group-specific component globulin) and CYP2R1 genetic variants have an association with serum 25-OHD3 levels, BMD or bone turnover markers in a population of Chinese postmenopausal women. DESIGN: We randomly selected 1494 postmenopausal women of the Han ethnic group from seven communities in Beijing. BMD was determined by dual energy X-ray absorptiometry; serum bone turnover markers and 25-OHD3 were measured by the automated Roche electrochemiluminescence system; genotypes of GC and CYP2R1 were detected by the TaqMan allelic discrimination assay. Multiple statistic methods were used to test the associations of SNP genotypes and vitamin D levels. RESULTS: In our sample, 89.6% women had vitamin D deficiency and another 9.8% had vitamin D insufficiency. The variants of rs2298849 (β=0.105, P < 0.001) in GC were significantly associated with serum 25-OHD3 levels. Allele G of rs2298849 might be protective for serum 25-OHD3 level. Among the haplotypes of rs222020-rs2298849, CG (β = 0.104, P=0.001) corresponded to increasing serum 25-OHD3 concentrations. CYP2R1 polymorphisms showed some significant association with serum β-CTX and P1NP levels. CONCLUSIONS: We found that GC variants had a significant association with serum 25-OHD3 levels among postmenopausal women of the Han ethnic group in Beijing, while CYP2R1 variants were not found to be significant.

Correction to: Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing

SummaryThe achievement of more accurate diagnosis would greatly benefit the management of patients with osteogenesis imperfecta (OI). In this study, we present the largest OI sample in China as screened by next generation sequencing. In particular, we successfully identified 81 variants, which included 45 novel variants. We further did a genotype-phenotype analysis, which helps make a better understanding of OI.IntroductionThis study aims to reveal the gene mutation spectrum and the genotype-phenotype relationship among Chinese OI patients by next generation sequencing (NGS).MethodsWe developed a NGS-based panel for targeted sequencing of all exons of 14 genes related to OI, and performed diagnostic gene sequencing for a cohort of 103 Chinese OI patients from 101 unrelated families. Mutations identified by NGS were further confirmed by Sanger sequencing and co-segregation analysis.ResultsOf the 103 patients from 101 unrelated OI families, we identified 79 mutations, including 43 novel mutations (11 frameshift, 17 missense, 5 nonsense, 9 splice site, and 1 chromosome translocation) in 90 patients (87.4%). Mutations in genes encoding type I collagen, COL1A1 (nxa0=xa037), and COL1A2 (nxa0=xa029) accounts for 73.3% of all molecularly diagnosed patients, followed by IFITM5 (nxa0=xa09, 10%), SERPINF1 (nxa0=xa04, 4.4%), WNT1 (nxa0=xa04, 4.4%), FKBP10 (nxa0=xa03, 3.3%), TMEM38B (nxa0=xa03, 3.3%), and PLOD2 (nxa0=xa01, 1.1%). This corresponds to 75 autosomal dominant inherited (AD) OI patients and 15 autosomal recessive (AR) inherited patients. Compared with AD inherited OI patients, AR inherited patients had lower bone mineral density (BMD) at spine (Pxa0=xa00.05) and less frequent blue sclera (Pxa0=xa00.001). Patients with type I collagen qualitative defects had lower femoral neck BMD Z-score (Pxa0=xa00.034) and were shorter compared with patients with type I collagen quantitative defects (Pxa0=xa00.022).ConclusionWe revealed the gene mutation spectrum in Chinese OI patients, and novel mutations identified here expanded the mutation catalog and genotype and phenotype relationships among OI patients.

Association of GALNT3 gene polymorphisms with bone mineral density in Chinese postmenopausal women: the Peking Vertebral Fracture study.

ObjectiveGALNT3 gene encodes the glycosyltransferase polypeptide N-acetylgalactosaminyltransferase-3 (ppGalNacT3), which initiates the O-glycosylation of fibroblast growth factor 23 (FGF23) that is important in phosphorous regulation. Inactivating mutations of the GALNT3 gene can cause familial tumoral calcinosis. The aim of present study is to investigate the association of GALNT3 polymorphisms with osteoporosis phenotypes in Chinese postmenopausal women. MethodsA community-based population of 1,353 postmenopausal women was randomly selected in Beijing. Bone mineral densities (BMDs) of the lumbar spine, femoral neck (FN), and total hip (TH) were measured by dual-energy x-ray absorptiometry. Vertebral fracture phenotypes were ascertained by vertebral x-ray reading. Osteoporotic fracture phenotypes were obtained from questionnaires. Single nucleotide polymorphisms of GALNT3 were determined by TaqMan allelic discrimination assay. Differences in BMD, serum phosphorus, or serum calcium across diverse genotypes or haplotypes were analyzed by general linear model analysis of covariance. Linear regression or logistic regression was used for association analyses of different osteoporosis phenotypes, phosphorous, or calcium. Partial correlation was used to investigate the relationship between phosphorus or calcium and BMD. ResultsWe found that polymorphisms of rs1863196, rs6710518, and rs13429321 were significantly associated with FN BMD (P values of 0.002, 0.003, and 0.002, respectively). Polymorphisms of rs1863196, rs6710518, rs4667492, rs13429321, and rs6721582 were associated with TH BMD (P values of 0.002, 0.004, 0.037, 0.005, and 0.014, respectively). Haplotype-1 additive and dominant models were found to be associated with TH BMD (P values of 0.035 and 0.024, respectively). Haplotype-2 dominant model was found to be associated with FN BMD (P = 0.003) and TH BMD (P = 0.001). ConclusionsGALNT3 may play a role in genetic susceptibility to osteoporosis among Chinese postmenopausal women. Efforts should be exerted to replicate our findings in other similar and ethnically diverse populations.

Familial Early-Onset Paget’s Disease of Bone Associated with a Novel hnRNPA2B1 Mutation

Paget disease of bone (PDB) is a common metabolic bone disease characterized by increased bone resorption and disorganized bone formation which affect single or multiple sites of bones. Although the exact cause of PDB is still controversial, genetic factors are considered to play an important role in PDB. Several genes involved in the differentiation or function of osteoclast were shown to be associated with PDB or related syndrome such as SQSTM1, TNFRSF11A, TNFRSF11B, and ZNF687. Multisystem proteinopathy (MSP), a newly proposed syndrome including inclusion body myopathy (IBM), PDB, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), is mainly caused by mutation in VCP gene. In 2013, a new casual gene for MSP was identified as hnRNPA2B1 gene. This may partly account for the inherited PDB traits which is however negative for mutation in already known causative PDB genes. We investigated a Chinese family with multiple affected individuals with PDB, but none of the members showed symptoms of IBM, FTD, or ALS. Three patients were evaluated clinically, biochemically, and radiographically. To screen for the responsible mutation, whole-exome sequencing was conducted in the proband, another patient, as well as a normal individual from the family. This revealed a novel heterozygous missense mutation of hnRNPA2B1 gene (c.929C>T, p. P310L) in the two patients which was then verified in all affected individuals. We describe here a novel missense mutation in hnRNPA2B1 gene in a large pedigree affected with PDB with members who do not present other manifestations of multisystem proteinopathy, such as IBM, FTD, and ALS.

Surgical Treatments of Tumor-Induced Osteomalacia Lesions in Long Bones: Seventeen Cases with More Than One Year of Follow-up.

BACKGROUNDnTumor-induced osteomalacia is a rare and fascinating paraneoplastic syndrome usually caused by a small, benign phosphaturic mesenchymal tumor. Most tumors are treated surgically, but we are unaware of any reports that compare the results of curettage and segmental resection for lesions in long bones.nnnMETHODSnSeventeen patients (ten male and seven female) with tumor-induced osteomalacia lesions in long bones, who underwent surgical treatment from December 2004 to August 2013 in our hospital, were included in this retrospective study. The mean follow-up (and standard deviation) was 35 ± 27 months (range, twelve to 116 months). The characteristics of the tumor and the effects of different surgical treatments (curettage compared with segmental resection) were evaluated.nnnRESULTSnAll patients showed typical clinical characteristics of tumor-induced osteomalacia, including elevated serum fibroblast growth factor-23 (FGF-23); 82% of tumors were in the epiphysis, and 82% grew eccentrically. The mean maximum diameter of the tumors was 2.4 ± 2.0 cm. The complete resection rates were similar for curettage (67%) and segmental resection (80%). However, the recurrence rate after curettage (50%) was higher than that after segmental resection (0%). The complete resection rate for secondary segmental resection (75%) was not different from that for primary segmental resection (83%). All of our cases of tumor-induced osteomalacia were caused by phosphaturic mesenchymal tumors. After successful removal of tumors, serum FGF-23 returned to normal within twenty-four hours and serum phosphorus levels returned to normal at a mean of 6.5 ± 3.5 days.nnnCONCLUSIONSnMost lesions in long bones are located in the epiphysis, so curettage is first suggested to maintain joint function. If curettage is incomplete or there is a recurrence, secondary segmental resection should be considered curative. Changes of serum FGF-23 and phosphorus levels before and after the operation may be of prognostic help.

Low-dose adefovir dipivoxil may induce Fanconi syndrome: clinical characteristics and long-term follow-up for Chinese patients.

BACKGROUNDnAdefovir dipivoxil (ADV) nephrotoxicity is well known at a dose of 60 mg day(-1) or 120 mg day(-1). However, renal toxicity at a low-dose of 10 mg ADV for HBV-infected patients is not fully described. Our objective was to analyse the clinical features and outcomes of ADV-related Fanconis syndrome in the Chinese population.nnnMETHODSnThis was a retrospective study. A total of 35 patients with ADV-related Fanconis syndrome were studied. Clinical manifestations and biochemical parameters were analysed. 19 patients were from Peking Union Medical College Hospital (PUMCH) included from August 2010 to December 2012. A total of 16 patients were eligible from case reports in the Chinese population retrieved in PUBMED, WANFANG and CNKI database. Bone mineral density and biochemical parameters including serum phosphate, calcium, creatinine, alkaline phosphatase (ALP) were measured before and after ADV cessation and during the follow-up.nnnRESULTSnAll recruited patients had hypophosphataemia, increased urinary phosphate excretion and elevated alkaline phosphatase. Serum phosphate levels rapidly increased especially within the 4 weeks after ADV cessation. Serum creatinine remained high or at the upper limit of normal range even after ADV cessation for 1 year. ALP increased in the first three months of ADV cessation and decreased at the 24th week. Bone mineral density was significantly improved after 6 months cessation of ADV.nnnCONCLUSIONSnADV can be nephrotoxic at prolonged low doses of 10 mg. For those who take ADV long term, regular monitoring of serum phosphate, creatinine levels and urine routine tests are required.