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1.
Clin Pharmacol Ther ; 99(5): 555-61, 2016 May.
Article in English | MEDLINE | ID: mdl-26599303

ABSTRACT

Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.


Subject(s)
Agranulocytosis/chemically induced , Antithyroid Agents/adverse effects , Carbimazole/adverse effects , HLA-B Antigens/genetics , Methimazole/adverse effects , Agranulocytosis/genetics , Antithyroid Agents/administration & dosage , Carbimazole/administration & dosage , Case-Control Studies , Female , Genome-Wide Association Study , Humans , Linkage Disequilibrium/genetics , Methimazole/administration & dosage , Polymorphism, Single Nucleotide , Predictive Value of Tests , Propylthiouracil/administration & dosage , Propylthiouracil/adverse effects
2.
Osteoporos Int ; 27(5): 1747-54, 2016 May.
Article in English | MEDLINE | ID: mdl-26659066

ABSTRACT

UNLABELLED: The study aimed to prospectively evaluate if serum calcium is related to diabetes incidence in Hong Kong Chinese. The results showed that serum calcium has a significant association with increased risk of diabetes. The result of meta-analysis reinforced our findings. INTRODUCTION: This study aimed to evaluate the association of serum calcium, including serum total calcium and albumin-corrected calcium, with incident diabetes in Hong Kong Chinese. METHODS: We conducted a retrospective cohort study in 6096 participants aged 20 or above and free of diabetes at baseline. Serum calcium was measured at baseline. Incident diabetes was determined from several electronic databases. We also searched relevant databases for studies on serum calcium and incident diabetes and conducted a meta-analysis using fixed-effect modeling. RESULTS: During 59,130.9 person-years of follow-up, 631 participants developed diabetes. Serum total calcium and albumin-corrected calcium were associated with incident diabetes in the unadjusted model. After adjusting for demographic and clinical variables, the association remained significant only for serum total calcium (hazard ratio (HR), 1.32 (95 % confidence interval (CI), 1.02-1.70), highest vs. lowest quartile). In a meta-analysis of four studies including the current study, both serum total calcium (pooled risk ratio (RR), 1.38 (95 % CI, 1.15-1.65); I (2) = 5 %, comparing extreme quantiles) and albumin-corrected calcium (pooled RR, 1.29 (95 % CI, 1.03-1.61); I (2) = 0 %, comparing extreme quantiles) were associated with incident diabetes. Penalized regression splines showed that the association of incident diabetes with serum total calcium and albumin-correlated calcium was non-linear and linear, respectively. CONCLUSIONS: Elevated serum calcium concentration is associated with incident diabetes. The mechanism underlying this association warrants further investigation.


Subject(s)
Calcium/blood , Diabetes Mellitus, Type 2/blood , Adult , Aged , Aged, 80 and over , Diabetes Mellitus, Type 2/epidemiology , Hong Kong/epidemiology , Humans , Incidence , Middle Aged , Observational Studies as Topic , Retrospective Studies , Risk Factors , Serum Albumin/analysis , Young Adult
4.
Osteoporos Int ; 25(3): 1017-23, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24196720

ABSTRACT

SUMMARY: A total of 2,266 postmenopausal Chinese women were followed for 4.5 years to determine the incidence of new fractures. The positive predictive value, negative predictive value, sensitivity and specificity of different treatment strategies were compared. Using a fixed optimal threshold calculated from receiver operating characteristics (ROC) curve had the highest sensitivity but lowest specificity. INTRODUCTION: There is no specific intervention threshold based on FRAX to guide treatment for Asian populations. This prospective study sought to determine the impact of applying different intervention thresholds to a cohort of Chinese postmenopausal women. METHODS: This study was part of the Hong Kong Osteoporosis Study. A total of 2,266 treatment-naïve postmenopausal women underwent clinical risk factor and BMD assessments. The subjects were followed to assess fractures. We calculated the FRAX probability of major osteoporotic fractures corresponding to women with prior fractures but no other clinical risk factors. Different treatment strategies which include treating women with prior fractures, women with age-specific FRAX probability corresponding to those with prior fractures, women with osteoporosis as well as women with FRAX probability above a fixed cut-off based on optimizing sensitivity and specificity on the ROC curve were compared. RESULTS: The mean age at baseline was 62.1 ± 8.5 years, and the mean follow-up time was 4.5 ± 2.8 years. One hundred six new major osteoporotic fractures were reported. An optimal (FRAX, with BMD) cut-off point of 9.95 % was identified. All strategies had negative predictive value of >90 %. Using a fixed cut-off had the highest sensitivity (62.3 %) but lowest specificity (73.5 %) and positive predictive value (10.3 %). Using a fixed cut-off would direct treatment from younger women with lower absolute risk to elderly women with higher absolute risk. CONCLUSION: Targeting only women with prior fractures is unlikely to reduce fracture burden. Other treatment strategies with higher sensitivity need to be considered but they have different shortcomings.


Subject(s)
Osteoporotic Fractures/prevention & control , Absorptiometry, Photon/methods , Adult , Aged , Aged, 80 and over , Bone Density/physiology , Cohort Studies , Decision Support Techniques , Female , Hong Kong/epidemiology , Humans , Middle Aged , Osteoporosis, Postmenopausal/diagnosis , Osteoporosis, Postmenopausal/epidemiology , Osteoporosis, Postmenopausal/physiopathology , Osteoporosis, Postmenopausal/therapy , Osteoporotic Fractures/epidemiology , Osteoporotic Fractures/etiology , Osteoporotic Fractures/physiopathology , Predictive Value of Tests , Risk Assessment/methods , Risk Factors
5.
Osteoporos Int ; 23(7): 1877-87, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22215184

ABSTRACT

SUMMARY: Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future. INTRODUCTION: The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis. METHODS: We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA). RESULTS: Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the -2,327 bp upstream (P = 6.8 × 10(-4)) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA. CONCLUSIONS: Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.


Subject(s)
Bone Density/genetics , Cell Adhesion Molecules/genetics , Homeodomain Proteins/metabolism , Osteoporotic Fractures/genetics , Spinal Fractures/genetics , Adult , Aged , Binding Sites/genetics , Cell Adhesion Molecules/metabolism , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Osteoporotic Fractures/physiopathology , Polymorphism, Single Nucleotide , Protein Binding/genetics , Spinal Fractures/physiopathology
6.
Osteoporos Int ; 23(1): 131-42, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21927923

ABSTRACT

UNLABELLED: Gene-based association approach could be regarded as a complementary analysis to the single SNP association analysis. We meta-analyzed the findings from the gene-based association approach using the genome-wide association studies (GWAS) data from Chinese and European subjects, confirmed several well established bone mineral density (BMD) genes, and suggested several novel BMD genes. INTRODUCTION: The introduction of GWAS has greatly increased the number of genes that are known to be associated with common diseases. Nonetheless, such a single SNP GWAS has a lower power to detect genes with multiple causal variants. We aimed to assess the association of each gene with BMD variation at the spine and hip using gene-based GWAS approach. METHODS: We studied 778 Hong Kong Southern Chinese (HKSC) women and 5,858 Northern Europeans (dCG); age, sex, and weight were adjusted in the model. The main outcome measure was BMD at the spine and hip. RESULTS: Nine genes showed suggestive p value in HKSC, while 4 and 17 genes showed significant and suggestive p values respectively in dCG. Meta-analysis using weighted Z-transformed test confirmed several known BMD genes and suggested some novel ones at 1q21.3, 9q22, 9q33.2, 20p13, and 20q12. Top BMD genes were significantly associated with connective tissue, skeletal, and muscular system development and function (p < 0.05). Gene network inference revealed that a large number of these genes were significantly connected with each other to form a functional gene network, and several signaling pathways were strongly connected with these gene networks. CONCLUSION: Our gene-based GWAS confirmed several BMD genes and suggested several novel BMD genes. Genetic contribution to BMD variation may operate through multiple genes identified in this study in functional gene networks. This finding may be useful in identifying and prioritizing candidate genes/loci for further study.


Subject(s)
Asian People/genetics , Bone Density/genetics , Genome-Wide Association Study , Osteoporosis/genetics , White People/genetics , Adult , Aged , Female , Femur Neck/physiology , Gene Regulatory Networks , Genetic Predisposition to Disease , Genotype , Hong Kong/epidemiology , Humans , Iceland/epidemiology , Lumbar Vertebrae/physiology , Middle Aged , Osteoporosis/ethnology , Osteoporosis/physiopathology , Polymorphism, Single Nucleotide
7.
Osteoporos Int ; 23(3): 879-85, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21461720

ABSTRACT

UNLABELLED: Vertebral fractures are the most common osteoporotic fractures. Data on the vertebral fracture risk in Asia remain sparse. This study observed that Hong Kong Chinese and Japanese populations have a less dramatic increase in hip fracture rates associated with age than Caucasians, but the vertebral fracture rates were higher, resulting in a high vertebral-to-hip fracture ratio. As a result, estimation of the absolute fracture risk for Asians may need to be readjusted for the higher clinical vertebral fracture rate. INTRODUCTION: Vertebral fractures are the most common osteoporotic fractures. Data on the vertebral fracture risk in Asia remain sparse. The aim of this study was to report the incidence of clinical vertebral fractures among the Chinese and to compare the vertebral-to-hip fracture risk to other ethnic groups. METHODS: Four thousand, three hundred eighty-six community-dwelling Southern Chinese subjects (2,302 women and 1,810 men) aged 50 or above were recruited in the Hong Kong Osteoporosis Study since 1995. Baseline demographic characteristics and medical history were obtained. Subjects were followed annually for fracture outcomes with a structured questionnaire and verified by the computerized patient information system of the Hospital Authority of the Hong Kong Government. Only non-traumatic incident hip fractures and clinical vertebral fractures that received medical attention were included in the analysis. The incidence rates of clinical vertebral fractures and hip fractures were determined and compared to the published data of Swedish Caucasian and Japanese populations. RESULTS: The mean age at baseline was 62 ± 8.2 years for women and 68 ± 10.3 years for men. The average duration of follow-up was 4.0 ± 2.8 (range, 1 to 14) years for a total of 14,733 person-years for the whole cohort. The incidence rate for vertebral fracture was 194/100,000 person-years in men and 508/100,000 person-years in women, respectively. For subjects above the age of 65, the clinical vertebral fracture and hip fracture rates were 299/100,000 and 332/100,000 person-years, respectively, in men, and 594/100,000 and 379/100,000 person-years, respectively, in women. Hong Kong Chinese and Japanese populations have a less dramatic increase in hip fracture rates associated with age than Caucasians. At the age of 65 or above, the hip fracture rates for Asian (Hong Kong Chinese and Japanese) men and women were less than half of that in Caucasians, but the vertebral fracture rate was higher in Asians, resulting in a high vertebral-to-hip fracture ratio. CONCLUSIONS: The incidences of vertebral and hip fractures, as well as the vertebral-to-hip fracture ratios vary in Asians and Caucasians. Estimation of the absolute fracture risk for Asians may need to be readjusted for the higher clinical vertebral fracture rate.


Subject(s)
Osteoporotic Fractures/ethnology , Spinal Fractures/ethnology , Age Distribution , Aged , Aged, 80 and over , Anthropometry/methods , Asian People/statistics & numerical data , Female , Hip Fractures/ethnology , Hong Kong/epidemiology , Humans , Incidence , Japan/epidemiology , Male , Middle Aged , Prospective Studies , Sex Distribution , Sweden/epidemiology , White People/statistics & numerical data
8.
Osteoporos Int ; 23(1): 351-63, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21779819

ABSTRACT

UNLABELLED: In this 2-year extension of a 3-year study, bazedoxifene showed sustained efficacy in preventing new vertebral fractures in postmenopausal women with osteoporosis and in preventing non-vertebral fractures in higher-risk women. Bazedoxifene significantly increased bone mineral density and reduced bone turnover versus placebo and was generally safe and well tolerated. INTRODUCTION: This study evaluated the efficacy and safety of bazedoxifene for the treatment of postmenopausal osteoporosis over 5 years. METHODS: A total of 4,216 postmenopausal women with osteoporosis were enrolled in this 2-year extension of a 3-year, randomized, double-blind, placebo-controlled, phase 3 trial. In the core study (N = 7,492), subjects received bazedoxifene 20 or 40 mg/day, raloxifene 60 mg/day, or placebo. The raloxifene arm was discontinued after 3 years; subjects receiving bazedoxifene 40 mg were transitioned to bazedoxifene 20 mg after 4 years. Five-year findings are reported for bazedoxifene 20 and 40/20 mg and placebo. Endpoints included incidence of new vertebral fractures (primary) and non-vertebral fractures, and changes in bone mineral density (BMD) and bone turnover markers. RESULTS: At 5 years, the incidence of new vertebral fractures in the intent-to-treat population was significantly lower with bazedoxifene 20 mg (4.5%) and 40/20 mg (3.9%) versus placebo (6.8%; P < 0.05), with relative risk reductions of 35% and 40%, respectively. Non-vertebral fracture incidence was similar among groups. In a subgroup of higher-risk women (n = 1,324; femoral neck T-score ≤-3.0 and/or ≥ 1 moderate or severe or ≥ 2 mild vertebral fracture[s]), bazedoxifene 20 mg reduced non-vertebral fracture risk versus placebo (37%; P = 0.06); combined data for bazedoxifene 20 and 40/20 mg reached statistical significance (34% reduction; P < 0.05). Bazedoxifene significantly increased BMD and reduced bone turnover versus placebo (P < 0.05) and was generally safe and well tolerated. CONCLUSIONS: The findings support a sustained anti-fracture effect of bazedoxifene on new vertebral fractures in postmenopausal osteoporotic women and on non-vertebral fractures in the higher-risk subgroup of women.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Indoles/therapeutic use , Osteoporosis, Postmenopausal/drug therapy , Osteoporotic Fractures/prevention & control , Aged , Bone Density/drug effects , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/adverse effects , Bone Remodeling/drug effects , Dose-Response Relationship, Drug , Double-Blind Method , Female , Follow-Up Studies , Humans , Indoles/administration & dosage , Indoles/adverse effects , Middle Aged , Osteoporosis, Postmenopausal/complications , Osteoporotic Fractures/etiology , Placebos , Selective Estrogen Receptor Modulators/administration & dosage , Selective Estrogen Receptor Modulators/adverse effects , Selective Estrogen Receptor Modulators/therapeutic use , Spinal Fractures/etiology , Spinal Fractures/prevention & control , Treatment Outcome
9.
Osteoporos Int ; 22(11): 2799-807, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21234548

ABSTRACT

UNLABELLED: This prospective study aimed to determine the risk factors and the 10-year probability of osteoporotic fracture in Southern Chinese men. The findings show substantial population differences in fracture incidence and risk prediction compared to the FRAX(TM) model, and the addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men. INTRODUCTION: Clinical risk factors with or without bone mineral density (BMD) measurements are increasingly recognized as reliable predictors of fracture risk. Prospective data on fracture incidence in Asian men remain sparse. This prospective study aimed to determine the risk factors and the 10-year absolute fracture risk in Southern Chinese men. METHODS: This is a part of the Hong Kong Osteoporosis Study. One thousand eight hundred ten (1,810) community-dwelling, treatment-naive men aged 50 years or above were evaluated. Baseline demographic characteristics, clinical risk factors and BMD were recorded. Ten-year risk of osteoporotic fracture was calculated using Cox proportional hazards models. RESULTS: The mean age of subjects was 68.0 ± 10.3 years. After a mean follow-up period of 3.5±2.9 years (range 1 to 14 years), 37 incident low-trauma fractures were recorded. The incidence for all osteoporotic fractures and hip fractures was 635/100,000 and 123/100,000 person-years, respectively. The most significant predictors of osteoporotic fracture were history of fall (RR 14.5), femoral neck BMD T-score < -2.5 (RR 13.8) and history of fracture (RR 4.4). Each SD reduction in BMD was associated with a 1.8 to 2.6-fold increase in fracture risk. Subjects with seven clinical risk factors and BMD T-score of -1 had an absolute 10-year risk of osteoporotic fracture of 8.9%, but this increased to 22.7% if they also had a femoral neck BMD T-score of -2.5. CONCLUSIONS: These findings show substantial population differences in fracture incidence and risk prediction. The addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men.


Subject(s)
Hip Fractures/epidemiology , Osteoporosis/epidemiology , Osteoporotic Fractures/epidemiology , Absorptiometry, Photon , Aged , Aged, 80 and over , Algorithms , Asian People/ethnology , Bone Density , Femur Neck/diagnostic imaging , Follow-Up Studies , Hip/diagnostic imaging , Hong Kong/epidemiology , Humans , Incidence , Lumbar Vertebrae/diagnostic imaging , Male , Middle Aged , Osteoporotic Fractures/ethnology , Prospective Studies , Risk Factors
10.
Osteoporos Int ; 22(2): 667-74, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20503038

ABSTRACT

UNLABELLED: This study evaluated the characteristics of patients with vertebral fractures and examined the discriminative ability of clinical risk factors. The findings provide further insights into possible development of a simple, cost-effective scheme for fracture risk assessment using clinical risk factors to identify high-risk patients for further evaluation. INTRODUCTION: Vertebral fractures are the most common complication of osteoporosis. The aim of this study was to evaluate the characteristics of patients with vertebral fractures and to determine the discriminative ability of bone mineral density (BMD) and other clinical risk factors. METHODS: Postmenopausal Southern Chinese women (2,178) enrolled in the Hong Kong Osteoporosis Study since 1995 were prospectively followed up for fracture outcome. Subjects (1,372) with lateral spine radiographs were included in this study. Baseline demographic, BMD, and clinical risk factor information were obtained from a structured questionnaire. RESULTS: Subjects (299; 22%) had prevalent vertebral fractures. The prevalence of vertebral fractures increased with increasing age, number of clinical risk factors, and decreasing BMD. The odds of having a prevalent vertebral fracture per SD reduction in BMD after adjustment for age in Hong Kong Southern Chinese postmenopausal women was 1.5 for the lumbar spine and femoral neck. Analysis of the receiver operating characteristic curve revealed that bone mineral apparent density did not enhance fracture risk prediction. Subjects with ≥ 4 clinical risk factors had 2.3-fold higher odds of having a prevalent vertebral fracture while subjects with ≥ 4 clinical risk factors plus a low BMD (i.e., femoral neck T-score < -2.5) had 2.6-fold. Addition of BMD to clinical risk factors did not enhance the discriminative ability to identify subjects with vertebral fracture. CONCLUSIONS: Based on these findings, we recommend that screening efforts should focus on older postmenopausal women with multiple risk factors to identify women who are likely to have a prevalent vertebral fracture.


Subject(s)
Bone Density/physiology , Spinal Fractures/epidemiology , Absorptiometry, Photon , Aged , Asian People/ethnology , Female , Femur Neck/diagnostic imaging , Hong Kong/epidemiology , Humans , Lumbar Vertebrae , Middle Aged , Postmenopause , Prevalence , Prospective Studies , Risk Factors
11.
Osteoporos Int ; 21(Suppl 4): S529-34, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21057992

ABSTRACT

The effect of delay of surgery on the geriatric hip fractures has been a subject of interest in the past two decades. While the elderly patients will not tolerate long periods of immobilization, it is still unclear how soon these surgeries need to be performed. A review of existing literature was performed to examine the effect of timing of surgery on the different outcome parameters of these patients. Although there is conflicting evidence that early surgery would improve mortality, there is widespread evidence in the literature that other outcomes including morbidity, the incidence of pressure sores, and the length of hospital stay could be improved by shortening the waiting time of hip fracture surgery. We concluded that it is beneficial to the elderly patients to receive surgical treatment as an urgent procedure as soon as the body meets the basic anesthetic requirements.


Subject(s)
Fracture Fixation/methods , Hip Fractures/surgery , Osteoporotic Fractures/surgery , Aged , Hip Fractures/complications , Hip Fractures/mortality , Humans , Length of Stay , Osteoporotic Fractures/complications , Osteoporotic Fractures/mortality , Pressure Ulcer/etiology , Time Factors , Treatment Outcome
12.
Osteoporos Int ; 21(Suppl 4): S605-14, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21058000

ABSTRACT

Hip fracture is associated with high morbidity, mortality, and economic burden worldwide. It is also a major risk factor for a subsequent fracture. A literature search on the management of osteoporosis in patients with hip fracture was performed on the Medline database. Only one clinical drug trial was conducted in patients with a recent hip fracture. Further studies that specifically address post-fracture management of hip fracture are needed. The efficacy of anti-osteoporosis medication in older individuals and those at high risk of fall is reviewed in this paper. Adequate nutrition is vital for bone health and to prevent falls, especially in malnourished patients. Protein, calcium, and vitamin D supplementation is associated with increased hip BMD and a reduction in falls. Fall prevention, exercise, and balance training incorporated in a comprehensive rehabilitation program are essential to improve functional disability and survival. Exclusion of secondary causes of osteoporosis and treatment of coexistent medical conditions are also vital. Such a multidisciplinary team approach to the management of hip fracture patients is associated with a better clinical outcome. Although hip fracture is the most serious of all fractures, osteoporosis management should be prioritized to prevent deterioration of health and occurrence of further fracture.


Subject(s)
Hip Fractures/rehabilitation , Osteoporosis/drug therapy , Osteoporotic Fractures/rehabilitation , Accidental Falls/prevention & control , Aged , Aged, 80 and over , Bone Density Conservation Agents/therapeutic use , Female , Hip Fractures/prevention & control , Hospitalization , Humans , Male , Osteoporotic Fractures/prevention & control , Secondary Prevention
13.
Osteoporos Int ; 21(6): 1009-20, 2010 Jun.
Article in English | MEDLINE | ID: mdl-19727905

ABSTRACT

SUMMARY: We performed an association study of five candidate genes within chromosome 3p14-25 in 1,080 Chinese female subjects. Polymorphisms in FLNB/CRTAP are associated with bone mineral density (BMD) in Chinese. INTRODUCTION: Chromosomal region 3p14-25 has shown strong evidence of linkage to BMD in genome-wide linkage scans. The variants responsible for this linkage signal, nonetheless, remain obscure. METHODS: Thirty SNPs in five positional and functional candidate genes within 3p14-25 (PPARG, CRTAP, TDGF1, PTHR1, and FLNB) and rs7646054 in the ARHGEF3 gene were genotyped in a case-control cohort of 1,080 Chinese females. Allelic and haplotypic association were tested using logistic regression analysis implemented in PLINK software. Potential transcription factor binding sites were predicted with MatInspector. RESULTS: Multiple SNPs and haplotypes in FLNB were significantly associated with BMDs, with the strongest association between lumbar spine BMD and rs9828717 (p = 0.005). SNP rs7623768 and the haplotype G-C of rs4076086-rs7623768 in CRTAP were associated with femoral neck BMD (p = 0.009 and p = 0.003, respectively). PTHR1 showed haplotypic associations with lumbar spine and femoral neck BMD (p = 0.02 and p = 0.044, respectively). Nevertheless, the association between rs7646054 in ARHGEF3 and BMD observed in Caucasians was not replicated in our samples. Comparative genomics analysis indicated that rs9828717 is located within a highly conserved region. The minor T allele at rs9828717 may lead to loss of binding site for nuclear factor of activated T cells which binds and triggers the transcriptional program of osteoblasts. CONCLUSIONS: Our data suggest that variants in FLNB and CRTAP at 3p are involved in BMD regulation in southern Chinese.


Subject(s)
Asian People/genetics , Chromosomes, Human, Pair 3/genetics , Contractile Proteins/genetics , Extracellular Matrix Proteins/genetics , Microfilament Proteins/genetics , Osteoporosis/genetics , Adult , Aged , Bone Density/genetics , Computational Biology/methods , Epidemiologic Methods , Female , Femur Neck/physiopathology , Filamins , Genetic Linkage/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Guanine Nucleotide Exchange Factors/genetics , Haplotypes , Hip Joint/physiopathology , Humans , Lumbar Vertebrae/physiopathology , Middle Aged , Molecular Chaperones , Osteoporosis/physiopathology , Polymorphism, Single Nucleotide , Rho Guanine Nucleotide Exchange Factors
14.
Osteoporos Int ; 20(11): 1939-45, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19326036

ABSTRACT

UNLABELLED: This study estimated the 10-year probability of osteoporotic fracture in Hong Kong Southern Chinese based on a simplified model of the recently developed WHO fracture risk prediction tool (FRAX). Thus, the data provides further insights into potential development of a population-specific FRAX model for Hong Kong in the future. INTRODUCTION: The purpose of this paper was to estimate the 10-year probability of osteoporotic fracture in Hong Kong (HK) Southern Chinese according to age and bone mineral density (BMD) T-score at the femoral neck based on the methodology of the FRAX risk assessment tool calibrated to the epidemiology of HK. METHODS: Hip fracture data was obtained from the Clinical Data Analysis Reporting System (CDAS) of the Hospital Authority of HK and population size and death rates were taken from the HK Government Census and Statistics Department. Fracture probability was calculated using the cut-off values for T-scores derived from the NHANES III data for Caucasian women aged 20-29 years for BMD at the femoral neck. RESULTS: In this study, the 10-year probability of osteoporotic fracture in HK Southern Chinese increased markedly with increasing age and decreasing femoral neck BMD T-scores in both women and men. Interestingly, at low T-scores, the increase in 10-year probability of osteoporotic fracture in women with age was greater than in men. Fracture probabilities were substantially higher than those from mainland China. CONCLUSIONS: Based on this evidence, and until we have HK Southern Chinese population-specific information, we recommend the application of the Caucasian risk profile to calculate the absolute fracture risk for HK Southern Chinese subjects.


Subject(s)
Bone Density/physiology , Femur Neck/physiopathology , Hip Fractures/ethnology , Osteoporotic Fractures/ethnology , Age Distribution , Aged , Aged, 80 and over , Female , Hip Fractures/physiopathology , Hong Kong/epidemiology , Humans , Male , Middle Aged , Osteoporotic Fractures/physiopathology , Risk Assessment/methods , Sex Distribution
15.
Bone ; 43(3): 567-73, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18555764

ABSTRACT

Aceaea racemosa (formerly Cimicifuga racemosa, black cohosh, AR) extracts have been widely used as an alternative to hormonal replacement therapy for menopausal symptoms. Recent evidences suggest AR extracts are also effective in protecting against postmenopausal bone loss. To determine whether AR has any direct anabolic effect on osteoblasts, we investigated the ethanolic extract of AR on bone nodule formation in mouse MC3T3-E1 preosteoblast cells. AR did not stimulate osteoblast proliferation. Rather, at high doses of 1000 ng/mL for 48 h, AR suppressed (7.2+/-0.9% vs. control) osteoblast proliferation. At 500 ng/mL, a significant increase in bone nodule formation was seen with Von Kossa staining. Using quantitative PCR analysis, AR was shown to enhance the gene expression of runx2 and osteocalcin. Co-treatment with ICI 182,780, the selective estrogen receptor antagonist, abolished the stimulatory effect of AR on runx2 and osteocalcin gene induction, as well as on bone nodule formation in MC3T3-E1 cells. This is a first report of the direct effect of AR on enhancement of bone nodule formation in osteoblasts, and this action was mediated via an estrogen receptor-dependent mechanism. The results provide a scientific rationale at the molecular level for the claim that AR can offer effective prevention of postmenopausal bone loss.


Subject(s)
Bone and Bones/metabolism , Cimicifuga/metabolism , Ethanol/pharmacology , Osteoblasts/metabolism , Osteogenesis/drug effects , Plant Extracts/pharmacology , Animals , Cell Proliferation , Core Binding Factor Alpha 1 Subunit/biosynthesis , Dose-Response Relationship, Drug , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Fulvestrant , Mice , Osteoblasts/cytology , Osteocalcin/biosynthesis , Receptors, Androgen/metabolism
16.
Curr Med Res Opin ; 24(1): 99-106, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18028585

ABSTRACT

OBJECTIVE: To review data on the prevalence of vitamin D inadequacy and its causes in postmenopausal women in Eastern Asia. RESEARCH DESIGN AND METHOD: Data were obtained from the published biomedical literature as well as abstracts and posters presented at scientific meetings. Using MEDLINE, EMBASE and BIOSIS databases (to July 2007), epidemiological studies were identified using the search terms: 'human', 'vitamin D', 'vitamin D deficiency', 'vitamin D inadequacy', 'vitamin D insufficiency' and 'hypovitaminosis D', 'osteomalacia' and 'osteoporosis'. Additional references were also identified from the bibliographies of published articles. RESULTS: The prevalence of vitamin D inadequacy in studies of postmenopausal women (ambulatory or with osteoporosis or related musculoskeletal disorders) in Eastern Asia ranged from 0 to 92%, depending on the cut-off level of serum 25-hydroxycholecalciferol [25(OH)D] that was applied (range < or =6-35 ng/mL [< or = 15-87 nmol/L]). One large international study found that 71% of postmenopausal women with osteoporosis in Eastern Asia had vitamin D inadequacy, defined as serum levels of 25(OH)D < 30 ng/mL (75 nmol/L). Prevalence rates using this cut-off level were 47% in Thailand, 49% in Malaysia, 90% in Japan and 92% in South Korea. High prevalences of vitamin D inadequacy were evident in two studies using a lower 25(OH)D level cut-off value of < 12 ng/mL (30 nmol/L) - 21% in China and 57% in South Korea. Dietary deficiency and inadequate exposure or reactivity to sunlight (due to lifestyle choices, cultural customs and/or aging) were identified as important risk factors for vitamin D inadequacy. CONCLUSIONS: Non-uniform, epidemiological studies indicate a high prevalence of vitamin D inadequacy in postmenopausal women in Eastern Asia. Recommended remedial approaches are education campaigns and broad-based provision of vitamin D supplementation.


Subject(s)
Postmenopause/blood , Vitamin D Deficiency/epidemiology , Asia, Eastern/epidemiology , Female , Humans , Malaysia/epidemiology , Musculoskeletal Diseases/epidemiology , Musculoskeletal Diseases/etiology , Osteoporosis, Postmenopausal/epidemiology , Osteoporosis, Postmenopausal/etiology , Prevalence , Thailand/epidemiology , Vitamin D Deficiency/complications
17.
Osteoporos Int ; 19(4): 571-9, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17896124

ABSTRACT

UNLABELLED: The association between a newly identified CA repeat polymorphism of the estrogen receptor alpha gene (ESR1) with osteoporosis was investigated. Postmenopausal women with <18 CA repeats had low BMD, increased rate of bone loss and increased fracture risk. INTRODUCTION: Studies have shown that intronic dinucleotide repeat polymorphisms in some genes are associated with disease risk by modulating mRNA splicing efficiency. D6S440 is a newly identified intronic CA repeat polymorphism located downstream of the 5'-splicing site of exon 5 of ESR1. METHODS: The associations of D6S440 with bone mineral density (BMD), rate of bone loss and fracture risk were evaluated in 452 pre-, 110 peri- and 622 postmenopausal southern Chinese women using regression models. RESULTS: Post- but not premenopausal women with less CA repeats had lower spine and hip BMD. The number of CA repeats was linearly related to hip BMD in postmenopausal women (beta=0.008; p=0.004). Postmenopausal women with CA repeats <18 had higher risks of having osteoporosis (BMD T-score< -2.5 at the spine: OR 2.46, 95% CI 1.30-4.65; at the hip: OR 3.79(1.64-8.74)) and low trauma fractures (OR 2.31(1.29-4.14)) than those with >or= 18 repeats. Perimenopausal women with <18 CA repeats had significantly greater bone loss in 18 months at the hip than those with >or= 18 repeats (-1.96% vs. -1.61%, p = 0.029). CONCLUSIONS: ESR1 CA repeat polymorphism is associated with BMD variation, rate of bone loss and fracture risk, and this may be a useful genetic marker for fracture risk assessment.


Subject(s)
Bone Density/genetics , Dinucleotide Repeats/genetics , Estrogen Receptor alpha/genetics , Osteoporosis, Postmenopausal/physiopathology , Polymorphism, Genetic/genetics , Adult , Estrogen Receptor alpha/deficiency , Female , Fractures, Bone/prevention & control , Genotype , Humans , Logistic Models , Menopause , Middle Aged , Risk Factors
18.
Kidney Int ; 71(11): 1085-6, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17522693

ABSTRACT

Mutations of the calcium-sensing receptor (CaR) gene give rise to disorders of renal calcium excretion. It is now demonstrated that even common variants of CaR can cause alteration in tissue sensitivity to extracellular calcium and are associated with primary hypercalciuria. Agents targeting these functional domains may well be an option for the management of hypercalciuria and renal stones.


Subject(s)
Genetic Variation , Genotype , Phenotype , Receptors, Calcium-Sensing/genetics , Humans , Hypercalciuria/genetics , Kidney Calculi/therapy , Models, Genetic , Mutation , Polymorphism, Single Nucleotide
19.
Ann Nutr Metab ; 51(1): 59-64, 2007.
Article in English | MEDLINE | ID: mdl-17356256

ABSTRACT

INTRODUCTION: Vitamin D is a vital element for bone health but the problem of vitamin D deficiency is underestimated in Hong Kong. METHODS: Serum 25(OH)D and parathyroid hormone (PTH) levels were evaluated in 382 community dwelling Chinese adults >50 years for their relation with bone mineral density (BMD) and risks of osteoporotic fractures and falls. RESULTS: The mean age of the subjects was 69 +/- 9 years. The mean 25(OH)D level was 28.3 +/- 10.8 ng/ml with 62.8% of the subjects having levels <30 ng/ml. 6.3% of the subjects had elevated PTH levels. A curvilinear relation between serum PTH and 25(OH)D was found, with PTH starting to increase when 25(OH)D level fell below 30 ng/ml (r = -0.233, p < 0.05). Although subjects with vitamin D <30 ng/ml had significantly lower BMD, only sex, age and PTH but not 25(OH)D were predictors of BMD at the spine and hip. Subjects with elevated PTH levels had a 2.92-fold increased risk of falls and 2.94-fold increased risk of fractures at the hip and spine. CONCLUSIONS: Vitamin D insufficiency and its complication of secondary hyperparathyroidism is common even in subtropical region and is an important risk factor for low bone mass, falls and fractures.


Subject(s)
Vitamin D Deficiency/blood , Vitamin D Deficiency/epidemiology , Aged , Bone Density , China , Female , Fractures, Bone/etiology , Fractures, Bone/physiopathology , Humans , Hyperparathyroidism, Secondary , Male , Middle Aged , Osteoporosis/complications , Osteoporosis/physiopathology , Parathyroid Hormone/blood , Prevalence , Sterols/blood
20.
Ann Hum Genet ; 70(Pt 4): 428-38, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16759177

ABSTRACT

Bone mineral density (BMD), a risk factor for osteoporosis, is believed to be under genetic control. The effect of environmental factors and gender on the heritability of BMD and bone size is ill-defined. In this study, heritability estimates (h2) were determined in 3,320 southern Chinese subjects from 1,019 families using the variance components model. The h2 for age, weight and height-adjusted BMD was 0.63-0.71 for females, and 0.74-0.79 for males; and for bone size, 0.44-0.64 for females and 0.32-0.86 for males. Adjustment for lifestyle factors including calcium and phytoestrogen intake, exercise, smoking and alcohol consumption altered the h2 differently in males and females. The proportion of variance in BMD and bone size explained by all covariates varied between skeletal sites, but was consistently greater in females than males. A significant gender difference was observed in the genetic variance of BMD and bone size at the hip but not the spine. In conclusion, a gender difference was observed in the degree of heritability of BMD and bone size at specific skeletal sites. Environmental influences contributed variably at different sites in the two sexes.


Subject(s)
Bone Density/genetics , Bone and Bones/anatomy & histology , Osteoporosis/genetics , Adult , Aged , Female , Genetic Linkage , Health Behavior , Humans , Inheritance Patterns , Male , Middle Aged , Osteoporosis/epidemiology , Sex Factors
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