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Osteoclastic activity is mainly assessed by measurement of urinary markers (eg C-terminal cross-linked telopeptides of type I collagen, N-terminal cross-linked telopeptides of type I collagen etc), the levels of which could often be affected by renal clearance. Recently, serum tartrate-resistant acid phosphatase 5b (TRACP5b) has been used as an alternative serum marker to evaluate osteoclastic activity. We investigated the age-related changes of TRACP5b level and its association with bone mineral density (BMD) in Chinese women. Seven-hundred and twenty-two Chinese mainland women aged 20–79 years were recruited in the study. Serum TRACP5b level was measured using immunoassay to evaluate the state of bone resorption. Bone mineral density (BMD) (g/cm2) at lumbar spine 1–4 and proximal femur were measured by duel-energy X-ray absorptiometry. The serum TRACP5b level reached a bottom value in premenopausal women aged 30–39, gradually increased in women aged 40–49, rapidly rose in women aged 50–59, and culminated with a maximum value in women aged 60–69 before a slow drop in women aged 70–79. The average level of TRACP5b was significantly higher in postmenopausal women [(3.29±1.07) U/L] than in premenopausal women ([1.70±0.59] U/L). The levels of TRACP5b were inversely correlated with BMD at all measured sites (P

Aim: To establish bone mineral density (BMD) reference database in healthy Chinese men of Han ethnicity, and to estimate the prevalence of osteoporosis in the population. Methods: The BMD in the lumbar spine 1-4 (L1-4) and proximal femur was measured using dual energy X-ray absorptiometry in a total of 1 385 healthy Chinese men of Han ethnicity aged 20–89 years old in Shanghai. Results: The highly significant negative correlation between age and BMD at any sites of proximal femur was found in the studied population, wheras no correlation between age and BMD at lumbar spine was observed. The peak BMD of the lumbar spine and any sites of hip in Chinese men was defined as the mean BMD for the subjects aged 20–39 years. According to World Health Organization (WHO) criteria, the BMD cut-off values for osteoporosis of the L1-4, total hip, femoral neck, trochanter and intertrochanter in Chinese men are 0.719, 0.638, 0.575, 0.437 and 0.725 g/cm 2 , respectively. Using the current Chinese reference data, the prevalence of osteoporosis at the L1-4, total hip, femoral neck, trochanter and intertrochanter is 5.4%, 3.8%, 6.3%, 1.8% and 2.8% in 1 084 men aged 50 years or older, respectively. However, using a database for US non-Hispanic white men (NHANES III), the prevalence of osteoporosis or osteopenia at any sites of the hip was significantly higher than that while using the current Chinese reference data. Conclusion: The BMD reference database was established in healthy Chinese men of Han ethnicity, and will facilitate more accurate diagnosis of osteoporosis in Chinese men. (Asian J Androl 2006 Jul; 8: 419–427)

To investigate the possible association of Q89R, N740N and A1330V polymorphisms in low-density lipoprotein receptor-related protein 5 (LRP5) gene with bone mineral density (BMD) in postmenopausal Chinese women. Q89R, N740N and A1330V genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 647 unrelated healthy postmenopausal Han Chinese women aged 43–76 years in Shanghai. BMD at lumbar spine 1–4 and the left proximal femur including the femoral neck, trochanter and Ward's triangle were measured by dual-energy X-ray absorptionmetry in all subjects. The distribution of the Q89R, N740N and A1330V genotypes in this population was as follows: QQ 80.5%, QR 18.7%, and RR 0.8%; TT 66.9%, TC31.1%, and CC2.0%; AA 68.0%, AV 29.7%, and VV 2.3%. The frequencies of the Q89R, N740N and A1330V genotypes and alleles did not deviate from the Hardy-Weinberg equilibrium. We found that the Q89R and A1330V polymorphisms were in linkage disequilibrium in our population (χ2=13.50, P

Objectives: To determine the heritability of BMI and to examine the mode of inheritance of BMI variation in Chinese. Research Methods and Procedures: Familial correlation and complex segregation analyses for BMI were undertaken in a Chinese sample composed of 392 nuclear families, with 1190 total individuals. Results: A moderate heritability was found for BMI (h2 = 0.419-0.492). The obtained results do not support a major gene for BMI in our samples. BMI may be inherited in a complex and non-Mendelian manner in Chinese. Discussion: The findings of this study suggest that identification of specific genes for BMI in Chinese, at least within the same data set, is a serious challenge because of the lack of evidence of a major gene for BMI in our Chinese sample.

Adult height (stature), as a complex quantitative trait, has been studied in different populations. However, few genetic studies on height were performed on the Chinese, the largest population in the world. In this study, familial correlation and segregation analyses were carried out for adult height in a Chinese sample composed of 385 nuclear families with a total of 1,169 informative individuals. The results suggest that a major gene with a recessive effect accounts for about 17.2% of the total adult height variation in the Chinese. Significant familial residual effects are found. The heritability (+/-SE) of height is estimated to be 0.647 (+/-0.122). This study, for the first time, provides evidence for the high degree of genetic determination of adult height in the Chinese population and furnishes a valuable reference for further mapping and identification of adult height genes in the Chinese.

PBD is an important determinant of osteoporotic fractures. Few studies were performed to search for genes underlying PBD variation in Chinese populations. We tested linkage and/or association of the estrogen receptor alpha gene polymorphism with PBD in 401 Chinese nuclear families. This study suggests the ER-alpha gene may have some minor effects on PBM variation in the Chinese population. Low peak bone density (PBD) in adulthood is an important determinant of osteoporotic fractures in the elderly. PBD variation is mainly regulated by genetic factors. Extensive molecular genetics studies have been performed to search for genes underlying PBD variation, largely in whites. Few studies were performed in Chinese populations. In this study, we simultaneously test linkage and/or association of the estrogen receptor alpha (ER-alpha) gene polymorphism with PBD in 401 Chinese nuclear families (both parents plus their female children) of 1260 subjects, with the 458 children generally between 20 and 40 years of age. All the subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) at polymorphic PvuII and XbaI sites inside the ER-alpha gene. Bone mineral density was measured at the lumbar spine (L1-L4) and hip (femoral neck, trochanter, and intertrochanteric region). Raw bone mineral density values were adjusted by age, height, and weight as covariates. We detected marginally significant results for within-family association (transmission disequilibrium; p = 0.054) between the spine bone mineral density variation and the ER-alpha XbaI genotypes. For the hip bone mineral density variation, significant (p < 0.05) linkage results were generally found for the two intragenic markers. Analyses of the haplotypes defined by the two markers confer further evidence for linkage of the ER-alpha with the hip PBD variation. In conclusion, this study suggests that the ER-alpha gene may have minor effects on PBD variation in our Chinese population.

To investigate whether the polymorphism of osteoprotegerin (OPG) gene is associated with the change of BMD (bone mineral density) after alendronate therapy in postmenopausal women with osteoporosis and determine the correlation between genotypes and therapeutic effect.Eighty postmenopausal osteoporotic patients were recruited with an average age of (64.2 +/- 7.7) years old. Every patient took oral alendronate (Fosamax) 70 mg weekly and Caltrate 600 mg daily for 12 months. At pre- and post-treatment, BMD was measured at lumbar spine 2 - 4 and hip sites. PCR-RFLP was performed for three polymorphisms at the promoter site of OPG gene (A163G, T245G and T950C).One-year therapy was accomplished in 67 patients. Patients with G allele (genotype AG and GG) of site A163G, the baseline BMD of vertebral L2-4, inter-troche and total hip were lower than genotype AA [(0.732 +/- 0.113) g/cm(2) vs (0.819 +/- 0.157) g/cm(2), (0.775 +/- 0.101) g/cm(2) vs (0.843 +/- 0.124) g/cm(2) and (0.667 +/- 0.105) g/cm(2) vs (0.725 +/- 0.091) g/cm(2)]. Patients with G allele (genotype TG and GG) of site T245G, baseline BMD of vertebral L2-4, inter-troche and total hip were lower than genotype TT [(0.723 +/- 0.111) g/cm(2) vs (0.819 +/- 0.155) g/cm(2), (0.776 +/- 0.102) g/cm(2) vs (0.840 +/- 0.124) g/cm(2) and (0.670 +/- 0.109) g/cm(2) vs (0.721 +/- 0.091) g/cm(2)]. After one-year therapy, at site A163G, the percentage of BMD change at inter-troche was higher in genotype AA than in genotypes AG and GG [2.50 (3.47)% vs 0.88% (3.47%)%, P = 0.014]. While at site T245G, the percentage of BMD change at inter-troche and total hip were higher in genotype TT than in genotype TG and GG 2.50% (3.47%) vs 0.61% (3.31%), P = 0.011; 2.72% (2.68%) vs 0.89 (3.01%), P = 0.046].The G allele of sites A163G and T245G may be the risk allele of postmenopausal osteoporosis. Furthermore, patients with genotypes AA (A163G) and (T245G) show a better therapeutic effect to alendronate.

To develop a simple screening tool for low bone mass of postmenopausal women.405 postmenopausal women in Shanghai who visited the department of osteoporosis consecutively, aged 62.8 +/- 8.0 (47 approximately 90), underwent questionnaire survey on the risk factors of osteoporosis and fracture. Dual energy X-ray absorptiometry (DXA) was conducted on the left or right femoral neck to measure the bone mineral density (BMD) to identify osteoporosis (T-scoreor= -2.5). Univariate linear regression was conducted to identify the variables with significant association with the femoral neck BMD to be used in multiple variable regression analysis. The screening index was obtained by the formula: index = independent variable X corresponding weight. A receiver operating characteristic (ROC) curve was drawn with the sensitivity (true positive rate) as the vertical coordinate and 1-specificity (false positive rate) as the horizontal coordinate. The area under the ROC curve (AUC ROC) was calculated so as to establish a parsimonious model.The final tool was based only on age and body weight. The formula of screening index was: index = 2 x weight (kg)/10 + [-1 x age (year)/10]. The risk index thus obtained had a sensitivity of 93.4%, a specificity of 52.6%, and an AUC ROC of 0.818 (95% CI for the mean: 0.766 approximately 0.870). 58% of the high-risk women had osteoporosis, compared with 26% and 2% of the intermediate and low-risk women respectively.The established and verified screening tool can easily predict the bone mass status in the postmenopausal women, thus screening the high-risk population and saving the cost of BMD measurement unnecessary for the low-risk population.

To construct an A20 expression vector under the control of mouse osteocalcin promoter (OC-A20), and investigate osteoblastic MC3T3-E1 cell line, which stably overexpresses A20 protein prevented tumor necrosis factor (TNF)-alpha-induced apoptosis.OC-A20 vector was constructed by fusing a fragment of the mouse osteocalcin gene-2 promoter with human A20 complementary DNA. Then the mouse MC3T3-E1 cell line, stably transfected by A20, was established. The expression of A20 mRNA and A20 protein in the cells were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. To determine the specificity of A20 expression in osteoblast, the mouse osteoblastic MC3T3-E1 cell line and mouse embryo fibroblast NIH3T3 cell line were transiently transfected with OC-A20. The anti-apoptotic role of A20 in MC3T3-E1 cells was determined by Flow cytometric analysis (FACS), terminal dUTP nick endo-labeling (TUNEL) and DNA gel electrophoresis analysis (DNA Ladder), respectively.Weak A20 expression was found in MC3T3-E1 cells with the primers of mouse A20. A20 mRNA and A20 protein expression were identified in MC3T3-E1 cells transfected with OC-A20 using RT-PCR and Western blot analysis. Only A20 mRNA expression was found in MC3T3-E1 cell after MC3T3-E1 cells and NIH3T3 cells were transient transfected with OC-A20. A decrease obviously occurred in the rate of apoptosis in the OC-A20 group compared with the empty vector (pcDNA3) group by FACS (P0.001). A significant increase in TUNEL positive staining was found in the pcDNA group compared with OC-A20 group (P0.001). Simultaneously, similar effects were demonstrated in DNA gel electrophoresis analysis.We constructed an osteoblast-specific expression vector that expressed A20 protein in MC3T3-E1 cells and confirmed that A20 protects osteoblast against TNF-alpha-induced apoptosis.

To determine whether premenopausal daughters of women with postmenopausal osteoporosis have lower peak bone mass than the daughters of normal women the same age, and to analyze the related risk factors affecting bone mass variation.126 pairs of mother with postmenopausal osteoporosis and her premenopausal daughter, and 136 pairs of normal postmenopausal mother and her premenopausal daughter selected for 410 core families including one healthy premenopausal daughter aged 20 - 40, all of Han ethnicity living in Shanghai recruited by advertisement and lectures. A questionnaire survey was conducted to investigate their dietary custom, Dual-energy X-ray absorptiometry at lumber spine 1 - 4 (L(1 - 4)) and proximal femur was conducted to measure the values of bone mineral density (BMD).The BMD values in L(1 - 4), femoral neck, and greater trochanter of the daughters of mothers with osteoporosis were 0.68 g/cm(2) +/- 0.07 g/cm(2), 0.59 g/cm(2) +/- 0.08 g/cm(2), and 0.47 g/cm(2) +/- 0.07 g/cm(2) respectively, all significantly lower than those of the daughters of normal mothers (0.86 g/cm(2) +/- 0.14 g/cm(2), 0.70 g/cm(2) +/- 0.11 g/cm(2), and 0.57 g/cm(2) +/- 0.10 g/cm(2) respectively, all P0.001). The average body weight of the daughters of mothers with osteoporosis was lighter then that of the daughters of normal mothers by 4.8% (P0.05). Multivariate regression analysis showed that age, body height, age of menarche, and milk intake were not influencing factors of BMD value, however, body weight was most significantly associated with BMD of the premenopausal daughters, contributing to the BMD variation at L(1 - 4), femoral neck, and greater trochanter by 9.4%, 16.5%, and 16.6% respectively. When body weight was excluded in the model, lower BMD of mother became the most important factors affecting the BMD variation, contributing to the BMD variation at L(1 - 4), femoral neck, and greater trochanter by 5.1%, 5.3%, and 4.2% respectively.The daughters of mothers with osteoporosis have reduced peak bone mass. It is likely due to the lower body weight of the daughter and the lower bone mass of the mother.

To investigate the correlation between calcium treatment in postmenopausal women and estrogen receptor-alpha (ER-alpha) Xba I and Pvu II genotype and vitamin D receptor (VDR) Apa I genotype.One hundred fifteen postmenopausal Chinese women of Han population were enrolled and treated with calcichew-D3 (1000 mg calcium and 400 U vitamin D3) daily for 1 year. At entry and after 1 year treatment, the bone mineral density (BMD), serum and urinary bone turnover biochemical markers were evaluated. ER-alpha and VDR genotype were analyzed using PCR-restriction fragment length polymorphism.After 1 year of calcium supplementation, a significant increase of BMD and a marked reduction in serum ALP and PTH levels, and a significant increase of serum 25-(OH) vitamin D level were observed (P0.01 or P0.05). At entry and after 1 year of treatment, no significant association was found between Xba I, Pvu II, and Apa I genotypes and BMD in L1-4, Neck, and Troch, and all bone turnover marker levels. However, the percentage of change (median, QR) in Neck BMD was significantly different in homozygous XX [-4.14 (from -6.54 to -1.34)] in comparison with Xx [1.72 (from -1.12 to 3.20)] (P0.001) or xx [1.22 (from -1.74 to 3.06)] Xba I ER-alpha genotype (P=0.001).Women with ER-alpha Xba I genotype XX may have a higher risk of relatively fast bone mass loss in femoral neck after menopause and that they may have a poor responsiveness to calcium supplementation. The changes in BMD are not associated with ER-alpha Pvu II genotype and VDR Apa I genotype after 1 year of calcium supplementation.

Raloxifene has been approved for prevention and treatment of postmenopausal osteoporosis in Caucasian women. It also has some positive effects on serum lipids in Caucasians. The objective of this study was to determine the effect of raloxifene hydrochloride on lumbar spine and total hip bone mineral density (BMD), bone metabolism, and serum lipids in Chinese postmenopausal women with osteoporosis.This was a multi-center, randomized, double-blind, placebo-controlled clinical trial in which 204 postmenopausal Chinese women with osteoporosis were assigned to receive raloxifene (60 mg) or placebo treatment daily for 12 months. BMD, serum bone metabolism markers, and serum lipids were measured before and after drug administration. BMD was measured by Dual-Energy X-Ray Absorptiometry (DEXA) and bone metabolism markers were analyzed by one-step enzyme-linked immunosorbent assay. Serum lipids were measured by enzymatic analysis.At the end of the 12-month study, lumbar spine BMD increased in both groups with a mean increase of (3.3 +/- 4.8)% in the raloxifene group and (1.0 +/- 4.9)% in the placebo group (P0.001). There was a mean increase in total hip BMD of (1.4 +/- 4.8)% in the raloxifene group and a mean decrease of (0.9 +/- 5.0)% in the placebo group (P0.001). No subject in the raloxifene group had a new vertebral fracture and 5 placebo subjects had new fractures (P0.05). In the raloxifene group, the median decreases in the biochemical markers of bone metabolism serum osteocalcin and C-telopeptide were 41.7% and 61.5%, respectively. These changes were statistically significant compared with those in the placebo group (10.6% and 35.6%, P0.001, respectively). Both total cholesterol and low-density lipoprotein cholesterol decreased significantly in the raloxifene group compared with those in the placebo group (P0.001, respectively) and there was no significant effect of raloxifene on high-density lipoprotein cholesterol and triglycerides compared with placebo.Raloxifene 60 mg/d for 12 months significantly increases lumbar spine and total hip BMD, significantly decreases bone turnover, and has favourable effects on serum lipids in Chinese postmenopausal women with osteoporosis.

To investigate if vitamin D receptor (VDR) gene Apa I polymorphism and estrogen receptor-alpha (ER-alpha) gene Pvu II, Xba I polymorphisms are related to bone mineral density (BMD), bone mineral content (BMC) and bone size in premenopausal Chinese women.The VDR Apa I genotype and ER-alpha Pvu II, Xba I genotype were determined by PCR-restriction fragment length polymorphism (RFLP) in 493 unrelated healthy women aged 20-40 years of Han nationality in Shanghai city. BMD (g/cm(2)), BMC (g), and bone areal size (BAS, cm(2) ) at lumbar spine 1-4 (L(1-4)) and proximal femur (femoral neck, trochanter and Ward's triangle) were measured by duel-energy X-ray absorptionmetry.All allele frequencies did not deviate from Hardy-Weinberg equilibrium. After phenotypes were adjusted for age, height, and weight, a significant association was found between VDR Apa I genotype and BMC variation at L(1-4) and Ward's triangle (P0.05), but not in BMD or BAS at lumbar spine and proximal femur. ER-a Pvu II, Xba I genotype was not related to BMC, BMD, and BAS at all sites.The study suggested that Apa I polymorphism in VDR gene may influence on attainment and maintenance of peak bone mass in premenopausal Chinese women.

To determine the effect of raloxifene hydrochloride (RLX) on the lumbar spine and total hip bone mineral density (BMD), bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis.204 Chinese postmenopausal women with osteoporosis from 3 hospitals in Beijing and Shanghai were randomly divided into 2 groups of 102 women: RLX group (RLX of the dosage of 60 mg/day was given for 12 months) and placebo group. In addition, 500 mg of elemental calcium and 200 units of vitamin D were given daily to all women. BMD, serum bone markers and lipids were measured before and after drug administration. The BMD of lumber spine and hip was measured by dual-energy X-ray absorptiometry (DEXA). Serum bone gamma-carboxyglutamic acid-containing protein (BGP) and C-teloppeptide were analyzed by one-step ELISA. Serum lipids were measured by enzymatic method.By the end of the 12-month study period, the lumbar spine BMD was increased by 3.3% +/- 4.8% in the RLX group and 1.0% +/- 4.9% in the placebo group (P0.001); the hip BMD was increased by 1.4% +/- 4.8%in the RLX group and decreased by 0.9% +/- 5.0% in the placebo group (P0.01). New vertebral fracture occurred in none of the subjects in the RLX group and in 5 subjects of the placebo group (P = 0.059). The serum BGP and CTX decreased by 41.7% and 61.5% respectively in the RLX group, both significantly more than those in the placebo group (10.6% and 35.6% respectively, both P0.001). Both the total cholesterol and low-density lipoprotein cholesterol were significantly lower in the RLX group than in the placebo group (both P0.001), however, there were no significant differences in high-density lipoprotein cholesterol and triglycerides between these two groups. One subject in the RLX group and 5 subjects in the placebo group discontinued the study due to adverse events. There were no differences in the number of subjects with hot flushes (3 in the RLX group and 1 in the placebo group) and the number of subjects with leg cramps (9 in the RLX group and 4 in the placebo group). No venous thromboembolic event was reported.RLX of the dosage of 60 mg/day for 12 months significantly increases the lumbar spine and total hip bone BMD, significantly decreases bone turnover and has favorable effects on serum lipids in Chinese postmenopausal women with osteoporosis.