Bei Tao

Analysis of Recently Identified Osteoporosis Susceptibility Genes in Han Chinese Women

BACKGROUND In Europeans and populations of European origin, several osteoporosis susceptibility genes, including ZBTB40, RANK, RANKL, OPG, MHC, and ESR1, were recently identified. However, none of these has been fully investigated in Han Chinese populations. OBJECTIVE AND DESIGN In this relatively large cross-sectional sample of 1012 Han Chinese women, 21 single-nucleotide polymorphisms (SNPs) within 11 candidate genes that were newly identified in Europeans were tested, and their associations with bone mineral densities (BMDs) and osteoporotic fracture were investigated. RESULTS A total of 21 SNPs were genotyped. Five SNPs in four genes [ZBTB40 (rs7524102, rs6696981), ESR1 (rs9479055), OPG (rs6469804), and RANK (rs3018362)] were found to be associated with lumbar spine BMD. Seven SNPs in five genes [ZBTB40 (rs7524102, rs6696981), OPG (rs6993813, rs6469804), RANK (rs3018362), LRP5 (rs3736228), and SOST (rs1513670)] were found to be associated with total hip BMD. SPTBN1 (rs11898505) and SOST (rs1107748) were associated with osteoporotic fracture. A significant gene-gene interaction for osteoporotic fracture involving rs1107748 in SOST and rs6469804 in OPG gene was identified from generalized multifactor dimensionality reduction analysis. CONCLUSIONS Our study provides an independent replication of the associations between several SNPs in ZBTB40, ESR1, OPG, RANK, LRP5, and SOST with lumbar spine and/or total hip BMDs in a large sample of Han Chinese women. The results of this study further support the significant associations found between osteoporotic fracture and SNPs in SPTBN1 and SOST. Our results suggest that these variants represent osteoporosis susceptibility genes in both Han Chinese and European populations.

The Changing Clinical Patterns of Primary Hyperparathyroidism in Chinese Patients: Data from 2000 to 2010 in a Single Clinical Center

CONTEXT In Western countries, most patients with primary hyperparathyroidism (PHPT) are asymptomatic. The incidence of parathyroid cancer is as low as 1% but is trending upward. The clinical outlook for Chinese patients with PHPT is unclear. OBJECTIVE Our objective was to describe the changing clinical patterns of benign and malignant PHPT in Chinese patients from 2000 to 2010. DESIGN AND SETTING This was a cross-sectional study. SUBJECTS A total of 249 patients with PHPT were studied. MAIN OUTCOME MEASURES The clinical manifestations and biochemical abnormalities of PHPT were analyzed. RESULTS Of our patients with PHPT, 61.4% were symptomatic, but asymptomatic PHPT has increased from <21% in 2000-2006 to 42.4% to 52.5% in 2007-2010. Of asymptomatic patients, 48.9% came to our center because of elevation of serum calcium levels, and another 46.9% came because of parathyroid nodule(s) incidentally discovered by thyroid ultrasonography, with a steady increase from 18.3% before 2007 to 35.7% in 2007-2008 and 61.5% in 2009-2010. Serum calcium and PTH concentrations greater than 2.77 mmol/L (area under the curve, 0.995; P < .001) and 316.3 pg/dL (area under the curve, 0.842; P < .001), respectively, are responsible for symptom development. The occurrence of parathyroid carcinoma was as high as 5.96%, but a trend downward from 10.53% to 4.44% was observed. CONCLUSIONS The overall clinical and biochemical features of PHPT in Chinese patients are still classic, but the disease is now evolving into a more asymptomatic type. The incidental parathyroid lesion captured by routine neck ultrasonography was the leading cause for such a dramatic change. The high incidence of parathyroid carcinoma is now decreasing.

Glucagon-like peptide-1 receptor agonist Liraglutide has anabolic bone effects in ovariectomized rats without diabetes.

Recently, a number of studies have demonstrated the potential beneficial role for novel anti-diabetic GLP-1 receptor agonists (GLP-1RAs) in the skeleton metabolism in diabetic rodents and patients. In this study, we evaluated the impacts of the synthetic GLP-1RA Liraglutide on bone mass and quality in osteoporotic rats induced by ovariectomy (OVX) but without diabetes, as well as its effect on the adipogenic and osteoblastogenic differentiation of bone marrow stromal cells (BMSCs). Three months after sham surgery or bilateral OVX, eighteen 5-month old female Wistar rats were randomly divided into three groups to receive the following treatments for 2 months: (1) Sham + normal saline; (2) OVX + normal saline; and (3) OVX + Liraglutide (0.6 mg/day). As revealed by micro-CT analysis, Liraglutide improved trabecular volume, thickness and number, increased BMD, and reduced trabecular spacing in the femurs in OVX rats; similar results were observed in the lumbar vertebrae of OVX rats treated with Liraglutide. Following in vitro treatment of rat and human BMSCs with 10 nM Liraglutide, there was a significant increase in the mRNA expression of osteoblast-specific transcriptional factor Runx2 and the osteoblast markers alkaline phosphatase (ALP) and collagen α1 (Col-1), but a significant decrease in peroxisome proliferator-activated receptor γ (PPARγ). In conclusion, our results indicate that the anti-diabetic drug Liraglutide can exert a bone protective effect even in non-diabetic osteoporotic OVX rats. This protective effect is likely attributable to the impact of Liraglutide on the lineage fate determination of BMSCs.

The effects of bisphenol A (BPA) exposure on fat mass and serum leptin concentrations have no impact on bone mineral densities in non-obese premenopausal women

OBJECTIVES Bisphenol A (BPA) exposure may promote obesity, but its effect on bone mineral density (BMD) has not been reported in humans. We aimed to examine the relationships between BPA exposure, body composition, serum estradiol, leptin, osteocalcin levels and BMDs in healthy premenopausal women. DESIGN AND METHODS In this cross-sectional study, a total of 246 healthy premenopausal women aged 20 years and older with regular menstrual cycles were investigated. Body mass index (BMI), fat mass, fat-free mass and BMDs were measured by DXA. Serum estradiol, leptin, osteocalcin, urinary BPA and NTx levels were also tested. RESULTS Urinary BPA levels were positively associated with fat mass (r=0.193, p=0.006) and leptin (r=0.236, p=0.001) but not with fat-free mass after adjusting for age and BMI. BPA was not associated with serum estradiol levels, BMDs, or bone resorption marker NTx and bone formation parameter osteocalcin, either. A multivariate stepwise regression analysis confirmed that serum leptin levels were positively influenced by fat mass (β=0.746, p<0.001) and BPA (β=0.127, p=0.01) but negatively correlated with fat-free mass (β=-0.196, p<0.001). However, the changes of BMDs at the lumbar spine (β=0.298, p<0.001) and femoral neck (β=0.305, p<0.001) were primarily explained by fat-free mass, and were irrelevant of the fat mass, leptin or BPA exposure. CONCLUSIONS Although BPA exposure is related with increased amount of fat mass and elevated serum leptin levels, it has neutral effect on BMDs in premenopausal women, possibly due to the exclusive role of fat-free mass, which is unrelated to BPA in determining BMDs.

An assessment of the use of quantitative ultrasound and the Osteoporosis Self-Assessment Tool for Asians in determining the risk of nonvertebral fracture in postmenopausal Chinese women

This cross-sectional study aims to assess the effectiveness of a simple, noninvasive scoring system, the Osteoporosis Self-Assessment Tool for Asians (OSTA), and quantitative bone ultrasound (QUS) in assessing nonvertebral fracture risk in Chinese postmenopausal women. A group of 513 community-dwelling women including 271 postmenopausal individuals participated in this study. Speed of sound (SOS m/s) at the radius, phalanx, and tibia were assessed by using the Omnisense prototype (Sunlight Ltd., Israel). Body height and weight were measured, and body mass index (BMI) and OSTA indices were calculated. Self-reported fractures were identified using a structured questionnaire. Phalanx SOS was significantly lower among postmenopausal women with a history of nonvertebral fracture occurred after menopause than those without (3755 m/s vs. 3841 m/s, P = 0.017, adjusted for age and weight), with an AUC of 0.66. The AUC of the OSTA for predicting nonvertebral fracture occurred after menopause was 0.64. SOS at the radius, phalanx, and tibia showed a positive correlation with OSTA index (r = 0.376–0.401, P < 0.001). The prevalence of nonvertebral fractures also increased significantly with the decreasing order of OSTA index (χ2 = 5.432, P = 0.02). The OSTA values of ≤−1 and phalanx QUS T-score of ≤−1.95 can differentiate postmenopausal nonvertebral fracture with sensitivity of 75% and 81%, respectively, and specificity of 48% and 40%, respectively. Combining OSTA and phalanx QUS yielded a sensitivity of 83% and a specificity of 84% to detect postmenopausal nonvertebral fracture, with an AUC of 0.64. We conclude that OSTA and phalanx QUS are simple and effective clinical tools for identifying postmenopausal women at increased risk of nonvertebral fractures and can thereby facilitate the appropriate and more cost-effective use of bone densitometry to prevent osteoporotic fractures in developing countries.

Differences between Measurements of Bone Mineral Densities by Quantitative Ultrasound and Dual-Energy X-Ray Absorptiometry in Type 2 Diabetic Postmenopausal Women

CONTEXT Quantitative ultrasound (QUS) may be more helpful than dual-energy X-ray absorptiometry (DXA) in detecting bone deficits in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE The objective of the study was to compare differences in bone mass measurement by DXA and QUS in T2DM and nondiabetic postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS This clinical investigation was a cross-sectional study in 76 patients with T2DM and 86 nondiabetic postmenopausal women. MAIN OUTCOME MEASURES The primary outcomes were speed of sound (SOS) at the radius, phalanx, and tibia measured by QUS and bone mineral density (BMD) at the lumbar spine (LS), femoral neck (FN), and total hip (TH) measured by DXA. RESULTS BMDs in T2DM patients were higher (LS, 1.06 +/- 0.12 vs. 0.90 +/- 0.23 g/cm(2); FN, 0.80 +/- 0.13 vs. 0.74 +/- 0.12 g/cm(2); TH, 0.87 +/- 0.14 vs. 0.80 +/- 0.13 g/cm(2), respectively, P < 0.001), whereas SOSs were lower than those in nondiabetics (radius, 4044 +/- 178 vs. 4129 +/- 182 m/sec; phalanx, 3902 +/- 207 vs. 3999 +/- 214 m/sec, respectively, P < 0.001). The positive relationships between SOS and BMD (r = 0.26-0.75, P < 0.05) in nondiabetics were not observed in women with T2DM. T2DM impacted negatively on SOSs (radius, beta= -0.223, P <0.01; phalanx, beta= -0.219, P <0.01) but positively on BMDs (LS, beta = 0.314, P < 0.001; FN, beta = 0.173, P < 0.05; TH, beta = 0.203, P <0.01). CONCLUSIONS Differences in bone mass as measured by DXA and QUS in postmenopausal T2DM and nondiabetic women do not change in parallel. QUS can provide useful information in the skeletal assessment of patients with T2DM.

Higher Serum Uric Acid Is Associated with Higher Bone Mineral Density in Chinese Men with Type 2 Diabetes Mellitus

Accumulating evidence suggests that oxidative stress is associated with osteoporosis. Serum uric acid (UA) is a strong endogenous antioxidant. Therefore, we investigated the relationship between the serum UA and BMD in Chinese men with T2DM. In this cross-sectional study of 621 men with T2DM, BMDs at lumbar spine (L2–4), femoral neck (FN), and total hip (TH) were measured by dual-energy X-ray absorptiometry (DXA). Serum levels of UA, calcium (Ca), 25-OH vitamin D3 (vitD3), parathyroid hormone (PTH), and creatinine (Cr) were also tested. Data analyses revealed that serum UA levels were positively associated with BMD at all sites (p < 0.05) in men with T2DM after adjusting for multiple confounders. The serum UA levels were positively correlated with body weight (r = 0.322), body mass index (BMI) (r = 0.331), Ca (r = 0.179), and Cr (r = 0.239) (p < 0.001) and were also positively associated with the concentrations of PTH (r = 0.10, p < 0.05). When compared with those in the lowest tertile of UA levels, men with T2DM in the highest tertile had a lower prevalence of osteoporosis or osteopenia (adjusted odds ratio 0.54, 95% confidence interval [CI] 0.31–0.95). These data suggest that higher serum levels of UA are associated with higher BMDs and lower risks of osteoporosis in Chinese men with T2DM.

An Independent Positive Relationship Between the Serum Total Osteocalcin Level and Fat-Free Mass in Healthy Premenopausal Women

CONTEXT It is widely reported that osteocalcin is negatively associated with fat mass. However, there are few reports describing its correlation with fat-free mass, particularly in women. OBJECTIVES The objective of the current study was to investigate the possible relationship between osteocalcin and fat-free mass in healthy, nonobese women. DESIGN AND SETTING This study was performed in a tertiary university teaching hospital. SUBJECTS A total of 504 healthy women aged 20-75 years were enrolled. MAIN OUTCOME MEASURES Body composition was measured using a bioelectronics impedance analyzer. The serum concentrations of total osteocalcin, estradiol, leptin, osteoprotegerin, the receptor activator of nuclear factor-κB ligand, IGF-I, fasting plasma glucose, and urinary N-terminal telopeptide of type I collagen were tested. The bone mineral densities (BMDs) at the lumbar spine and proximal femoral neck were measured by dual-energy X-ray absorptiometry. RESULTS The serum total osteocalcin level had a significant positive association with fat-free mass (r = 0.168, P = .007) after adjusting for age, fat mass, menopausal status, estradiol, fasting glucose, leptin, osteoprotegerin, receptor activator of nuclear factor-κB ligand, IGF-I, N-terminal telopeptide of type I collagen, BMDs, and waist and hip circumference. Analysis in pre- and postmenopausal women demonstrated that this association was only present in premenopausal women (r = 0.190, P = .005). The multiple stepwise regression analysis revealed that hip circumference, femoral neck-BMD, fat mass, leptin, osteocalcin, and age are the contributors to the changes in fat-free mass in premenopausal women (adjusted R(2) = 0.521, P < .001). CONCLUSION The serum level of total osteocalcin was positively associated with fat-free mass independent of age, fat mass, leptin, and other confounders in premenopausal women.

Primary Hyperparathyroidism: A Tale of Two Cities Revisited — New York and Shanghai

In the 1970s, with the advent of biochemical multichannel screening in the United States and other western countries, the clinical presentation of primary hyperparathyroidism (PHPT) changed from a symptomatic to an asymptomatic disorder. However, in Asian countries, like China, PHPT did not show this evolution, but rather continued to be a symptomatic disease with target organ involvement. In this paper, we revisit the clinical features of PHPT in New York and Shanghai, representative United States and Chinese cites, over the past decade. The questions we address are whether the disease evolved in China to a more asymptomatic one and, whether in the United States further changes are evident. The results indicate that while PHPT continues to present primarily as an asymptomatic disease in the United States, a new phenotype characterized by normal serum calcium and high parathyroid hormone levels, normocalcemic PHPT, has emerged. Data from Shanghai demonstrates a trend for PHPT to present more commonly as an asymptomatic disorder in China. However, most patients with PHPT in China still manifest classical symptoms, i.e. nephrolithiasis and fractures. A comparison of the two cohorts shows that Chinese patients with PHPT are younger, with higher serum calcium and PTH levels, and lower 25-hydroxyvitamin D levels than patients in New York. Normocalcemic PHPT has not yet been recognized in Shanghai. In summary, although the phenotypes of PHPT in both cities are evolving towards less evident disease, sharp clinical and biochemical differences are still apparent in PHPT as expressed in China and the United States.

Interactions of osteoporosis candidate genes for age at menarche, age at natural menopause, and maximal height in Han Chinese women.

Objective:Age at menarche (AAM), age at natural menopause (ANM), and maximal height are closely related to bone mineral densities and osteoporosis. It is still unclear whether osteoporosis susceptibility genes are also associated with AAM, ANM, and maximal height in Chinese women. Methods:In this relatively large cross-sectional sample of 722 Han Chinese postmenopausal women, 22 single nucleotide polymorphisms (SNPs) within 12 osteoporosis candidate genes that were identified from genome-wide association studies and replicated in our previous study were studied. The effects of a single gene on the AAM, ANM, and maximal height were investigated by linear regression analysis, whereas the gene-gene interactions were determined by a generalized multifactor dimensionality reduction method. Results:It was revealed that the major histocompatibility complex (MHC) gene (rs3130340) was associated with ANM even after Bonferroni correction (P = 0.001). A significant gene-gene interaction for ANM involving rs3130340 in MHC, rs1038304 and rs4870044 in estrogen receptor-&agr; gene (ESR1), and a significant three-SNP interaction model (SNP rs2273061 in jagged1, SNP rs6929137 in ESR1, and SNP rs2306033 in low-density lipoprotein receptor-related protein 4) for maximal height were identified. No single or combined effect of tested SNPs on AAM was discovered. Conclusions:Our study indicates that osteoporosis susceptibility SNPs, such as ESR1 (rs1038304, rs4870044, rs6929137), MHC (rs3130340), low-density lipoprotein receptor-related protein 4 (rs2306033), and jagged1 (rs2273061), might independently and/or in an interactive manner influence ANM and maximal height. All the SNPs tested had no association with AAM.