Low Bone Mineral Density as a Risk Factor for Liver Cirrhosis: A Prospective Cohort Study.

CONTEXT: Bone metabolism interplays with liver metabolism, also known as the liver-bone axis. Osteoporosis is a common complication of cirrhosis, but whether bone mineral density (BMD) can predict cirrhosis development is unknown. OBJECTIVE: This study aims to investigate the relationship between BMD and the risk of incident cirrhosis in the Hong Kong Osteoporosis Study (HKOS). METHODS: BMD was measured at the lumbar spine, femoral neck, total hip, and trochanter of 7,752 participants by the dual-energy X-ray absorptiometer (DXA), and the incidence of cirrhosis and mortality were followed by linking to the territory-wide electronic health records database. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% CI. RESULTS: With a median follow-up of 18.43 years, 42 incident cirrhosis were identified. Higher BMD T-scores at the femoral neck, total hip and trochanter were significantly associated with a reduced risk of cirrhosis (femoral neck: HR 0.56, 95% CI 0.39 to 0.82; total hip: HR 0.60, 95% CI 0.44 to 0.82; trochanter: HR 0.63, 95% CI 0.46 to 0.88). Similar associations were observed in participants without risk factors of cirrhosis at the baseline and further adjusting for the baseline level of alkaline phosphatase, albumin, and alanine transaminase. Consistent relationships in multiple sensitivity analyses suggest the robustness of the results. CONCLUSION: Low BMD could be a novel risk factor and early predictor for cirrhosis, with consistent associations observed in multiple sensitivity analyses.

Levothyroxine Treatment Among Pregnant Women and Risk of Seizure in Children: A Population-Based Cohort Study.

INTRODUCTION AND OBJECTIVE: The risk of seizure in offspring following prenatal exposure to levothyroxine is not well investigated. This study aimed to evaluate the association between levothyroxine treatment among pregnant women and the risk of seizure in their offspring. METHODS: This population-based cohort study included all pregnant women who delivered a live birth between January 2001 to January 2018, with a follow-up to December 2020, using data from the Hong Kong Clinical Data Analysis and Reporting System. Propensity score fine-stratification weighted hazard ratios (wHR) with 95% confidence intervals (CIs) were presented to assess the association between maternal levothyroxine use during pregnancy and seizures in children. RESULTS: Among 528,343 included mother-child pairs, 3044 children were prenatally exposed to levothyroxine at any time during the pregnancy period. A significantly increased risk of seizure was observed in children of the prenatally exposed group compared with the prenatally unexposed group (wHR 1.12, 95% CI 1.02-1.22). An increased risk of seizure was observed when comparing the prenatally exposed group with euthyroid mothers who had no history of thyroid-related diagnosis or prescriptions (wHR 1.12, 95% CI 1.02-1.23). However, no significant difference was observed between the prenatally exposed group and those previously exposed to levothyroxine but had stopped during pregnancy (wHR 0.97, 95% CI 0.66-1.44). No significant difference was observed in the sibling-matched analysis either (wHR 1.23, 95% CI 0.76-2.01). CONCLUSION: The observed increased risk of seizure in children born from mothers exposed to levothyroxine during pregnancy might be due to residual confounding by maternal thyroid disease. The findings support the current guidelines on the safe use of levothyroxine treatment during pregnancy.

Association of maternal levothyroxine use during pregnancy with offspring birth and neurodevelopmental outcomes: a population-based cohort study.

BACKGROUND: The influence of maternal levothyroxine treatment during pregnancy remains unclear. This study aimed to evaluate the associations of maternal levothyroxine treatment during pregnancy with the birth and neurodevelopmental outcomes in offspring. METHODS: This population-based cohort study was conducted among pregnant women using the Hong Kong Clinical Data Analysis and Reporting System. Mother-child pairs in Hong Kong from 2001 to 2015 were included and children were followed up till 2020. We defined the exposure group as mothers who were exposed to levothyroxine during pregnancy. Preterm birth and small for gestational age (SGA) were included as birth outcomes. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) were included as neurodevelopmental outcomes. Odds ratios (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) were evaluated to assess the association of gestational levothyroxine use with offspring birth and neurodevelopmental outcomes respectively, using propensity score fine-stratification weighting and a Cox proportional hazards regression model. RESULTS: Among 422,156 mother-child pairs, 2125 children were born from mothers exposed to levothyroxine during pregnancy. A significantly increased risk of preterm birth was observed in children with maternal levothyroxine exposure during pregnancy, when compared to mothers who had no history of thyroid-related diagnoses or prescriptions (weighted OR [wOR]: 1.22, 95% CI: 1.07, 1.39). Similarly, an increased risk of preterm birth was found among children of gestational levothyroxine users, when compared to children of mothers who had used levothyroxine before but stopped during pregnancy (wOR: 2.16, 95% CI: 1.09, 4.25). Sensitivity analysis, by excluding mothers exposed to psychotropic or antiepileptic medications before or during pregnancy, also indicated a similar increased risk of preterm birth regarding the gestational use of levothyroxine (wOR: 1.26, 95% CI: 1.10, 1.45). No significant association was observed for the risk of SGA, ADHD, and ASD. CONCLUSIONS: There is no evidence that gestational use of levothyroxine is associated with SGA, ADHD, or ASD in offspring. Gestational levothyroxine treatment is associated with a higher risk of preterm birth. Such risk might be confounded by the underlying maternal thyroid disease itself, however, we cannot completely exclude the possible effect of gestational L-T4 treatment on offspring preterm birth. Our findings provided support to the current guidelines on the cautious use of levothyroxine treatment during pregnancy.

Low Bone Mineral Density With Risk of Dementia: A Prospective Cohort Study.

OBJECTIVES: Osteoporosis and dementia often coexist, but the association between the 2 diseases remains unclear. This study aimed to investigate the relationship between bone mineral density (BMD) and the risk of incident dementia. DESIGN: Prospective cohort study, the Hong Kong Osteoporosis Study (HKOS). SETTING AND PARTICIPANTS: Data were from the HKOS and the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. A total of 5803 participants aged ≥40 years and free of dementia were included in the HKOS. METHODS: The baseline BMD at the lumbar spine, femoral neck, trochanter, and total hip were measured using dual-energy x-ray absorptiometry (DXA). The incidence of dementia was identified using their International Classification of Diseases, Ninth Revision, codes. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: The median follow-up time of the HKOS was 16.8 years. Higher BMD T scores at the lumbar spine, trochanter, and total hip were significantly associated with the reduced risk of dementia with the respective HR of 0.85 (95% CI 0.76-0.95; P = .004), 0.78 (95% CI 0.68-0.90; P < .001), and 0.82 (95% CI 0.72-0.93; P = .003). The subgroup analyses showed that associations were significant in women but not in men, whereas the associations were unaltered after adjusting for serum estradiol. CONCLUSIONS AND IMPLICATIONS: Low BMD was associated with an increased risk of dementia, particularly in women. Future studies evaluating the clinical usefulness of BMD on dementia prediction and management are warranted.

Hip Fracture as a Predictive Marker for the Risk of Dementia: A Population-Based Cohort Study.

OBJECTIVES: This study aimed to investigate the association between hip fracture and the risk of dementia. DESIGN: A retrospective real-world propensity score-matched cohort study was conducted using the real-world hip fracture cohort (RHFC). SETTING AND PARTICIPANTS: Electronic health record data from the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong were used. A total of 52,848 patients aged ≥65 years and with at least an event of fall from 2006 to 2015 were included in the RHFC. METHODS: The incidence of fall, hip fracture, and dementia was determined using their International Classification of Diseases, Ninth Revision (ICD-9) codes. Competing risk regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Hip fracture was associated with an increased risk of dementia (HR 1.09, 95% CI 1.04-1.15, P < .001). The subgroup analysis showed that association was significant in women but not in men. CONCLUSIONS AND IMPLICATIONS: Hip fracture was associated with the increased risk of dementia among older adults. Further studies investigating the potential roles of hip fracture in the development of dementia could benefit the management of both conditions in older adults.

Maternal Thyroid Dysfunction During Pregnancy and the Risk of Adverse Outcomes in the Offspring: A Systematic Review and Meta-Analysis.

CONTEXT: Previous studies suggested a potential link of maternal thyroid dysfunction with adverse neurocognitive outcomes and impaired development of internal organs in offspring. OBJECTIVE: To review the association between maternal thyroid dysfunction and the risk of adverse outcomes in offspring. DATA SOURCES: PubMed, EMBASE, and Cochrane Library. STUDY SELECTIONS: Eligible studies reported the association between maternal thyroid hormone function and the risk of adverse outcomes in their children. DATA EXTRACTION: Reviewers extracted data on study characteristics and results independently. DATA SYNTHESIS: Estimates were pooled and reported as odds ratio (OR) with 95% confidence interval (CI). I2 tests were applied to assess the heterogeneity across studies. RESULTS: We identified 29 eligible articles and found an association between maternal hyperthyroidism and attention deficit hyperactivity disorder (ADHD) (OR: 1.18, 95% CI: 1.04-1.34, I2 = 0%) and epilepsy (OR: 1.19, 95% CI: 1.08-1.31, I2 = 0%) in offspring; as well as an association of maternal hypothyroidism with increased risk of ADHD (OR: 1.14, 95% CI: 1.03-1.26, I2 = 25%), autism spectrum disorder (OR: 1.41, 95% CI: 1.05-1.90, I2 = 63%), and epilepsy (OR: 1.21, 95% CI: 1.06-1.39, I2 = 0%) in offspring. CONCLUSION: Routine measurement and timely treatment on thyroid function should be considered for pregnant women.

Development and Validation of a Risk Score to Predict the First Hip Fracture in the Oldest Old: A Retrospective Cohort Study.

BACKGROUND: To evaluate whether the common risk factors and risk scores (FRAX, QFracture, and Garvan) can predict hip fracture in the oldest old (defined as people aged 80 and older) and to develop an oldest-old-specific 10-year hip fracture prediction risk algorithm. METHODS: Subjects aged 80 years and older without history of hip fracture were studied. For the derivation cohort (N = 251, mean age = 83), participants were enrolled with a median follow-up time of 8.9 years. For the validation cohort (N = 599, mean age = 85), outpatients were enrolled with a median follow-up of 2.6 years. A five-factor risk score (the Hong Kong Osteoporosis Study [HKOS] score) for incident hip fracture was derived and validated, and its predictive accuracy was evaluated and compared with other risk scores. RESULTS: In the derivation cohort, the C-statistics were .65, .61, .65, .76, and .78 for FRAX with bone mineral density (BMD), FRAX without BMD, QFracture, Garvan, and the HKOS score, respectively. The category-less net reclassification index and integrated discrimination improvement of the HKOS score showed a better reclassification of hip fracture than FRAX and QFracture (all p < .001) but not Garvan, while Garvan, but not HKOS score, showed a significant over-estimation in fracture risk (Hosmer-Lemeshow test p < .001). In the validation cohort, the HKOS score had a C-statistic of .81 and a considerable agreement between expected and observed fracture risk in calibration. CONCLUSION: The HKOS score can predict 10-year incident hip fracture among the oldest old in Hong Kong. The score may be useful in identifying the oldest old patients at risk of hip fracture in both community-dwelling and hospital settings.

Serum metabolomic profiling and its association with 25-hydroxyvitamin D.

INTRODUCTION: The beneficial effect of vitamin D on the risk of non-musculoskeletal diseases has been investigated in observational studies and randomized clinical trials, but the findings were inconsistent. Identification of the metabolomic profile associated with vitamin D helps to identify novel biomarkers and increase the understanding of the biochemical and physiological role of vitamin D in different health conditions. METHOD: Serum metabolomic profiling was performed using liquid chromatography/tandem mass spectrometry [LC/MS] and their association with serum 25(OH)D was evaluated using multivariable linear regression in the baseline cohort of 316 participants (aged 20 or above; 92 men, 224 women; mean age±SD: 48.1 ± 15.8 years) and in the follow-up cohort of 275 participants (aged 20 or above; 12 men, 263 women; mean age: 56.2 ± 9.6) of the Hong Kong Osteoporosis Study. We discovered and validated potential metabolites; and by meta-analysis of these associations in two cohorts, we identified metabolites that were significantly associated with serum 25(OH)D levels. RESULTS: Among 835 known metabolites, 102 metabolites showed significant correlation with 25(OH)D levels at baseline visit. Of these metabolites, 27 were validated in the follow-up visit. In meta-analysis of data from these two visits, 13 metabolites were highly correlated with 25(OH)D. The majority of metabolites identified were lipid in nature. Docosahexaenoylcarnitine and eicosapentaenoylcholine had the highest correlations, with effect estimates 0.2554 (p = 9.60 × 10-9) and 0.1682 (p = 4.94 × 10-7) respectively. CONCLUSION: In Hong Kong Chinese at least, serum vitamin D level is closely related to lipid metabolism. Our finding highlights an important new direction in the study of vitamin D in different health conditions.

Serum Metabolome of Coffee Consumption and its Association With Bone Mineral Density: The Hong Kong Osteoporosis Study.

BACKGROUND: Inconsistent associations between coffee consumption and bone mineral density (BMD) have been observed in epidemiological studies. Moreover, the relationship of bioactive components in coffee with BMD has not been studied. The aim of the current study is to identify coffee-associated metabolites and evaluate their association with BMD. METHODS: Two independent cohorts totaling 564 healthy community-dwelling adults from the Hong Kong Osteoporosis Study (HKOS) who visited in 2001-2010 (N = 329) and 2015-2016 (N = 235) were included. Coffee consumption was self-reported in an food frequency questionnaire. Untargeted metabolomic profiling on fasting serum samples was performed using liquid chromatography-mass spectrometry platforms. BMD at lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable linear regression and robust regression were used for the association analyses. RESULTS: 12 serum metabolites were positively correlated with coffee consumption after Bonferroni correction for multiple testing (P < 4.87 × 10-5), with quinate, 3-hydroxypyridine sulfate, and trigonelline (N'-methylnicotinate) showing the strongest association. Among these metabolites, 11 known metabolites were previously identified to be associated with coffee intake and 6 of them were related to caffeine metabolism. Habitual coffee intake was positively and significantly associated with BMD at the lumbar spine and femoral neck. The metabolite 5-acetylamino-6-formylamino-3-methyluracil (AFMU) (ß = 0.012, SE = 0.005; P = 0.013) was significantly associated with BMD at the lumbar spine, whereas 3-hydroxyhippurate (ß = 0.007, SE = 0.003, P = 0.027) and trigonelline (ß = 0.007, SE = 0.004; P = 0.043) were significantly associated with BMD at the femoral neck. CONCLUSIONS: 12 metabolites were significantly associated with coffee intake, including 6 caffeine metabolites. Three of them (AFMU, 3-hydroxyhippurate, and trigonelline) were further associated with BMD. These metabolites could be potential biomarkers of coffee consumption and affect bone health.

Serum follicle stimulating hormone is associated with reduced risk of diabetes in postmenopausal women: The Hong Kong osteoporosis study.

Menopause is an important transition of reproductive stage in a woman's life. It is associated with diabetes, but the role of follicle stimulating hormone (FSH), a menopause-related hormone, in the risk of diabetes is largely unknown. We evaluated the relationship between serum FSH and diabetes in 1274 participants from the Hong Kong Osteoporosis Study aged≥55 at baseline. We also searched relevant databases for studies on serum FSH and incident diabetes and conducted a meta-analysis using fixed-effect modeling. Cases of incident diabetes (N = 60) were ascertained during a median follow-up of 10.7 years. Serum FSH was significantly associated with reduced risk of diabetes in both a crude model (hazard ratio [HR] per SD increase: 0.66; 95% CI: 0.48-0.89; P = 0.007) and a full model with adjustment for age, sex, body mass index, factors related to risk of diabetes, and reproductive health (HR per SD increase: 0.70; 95% CI: 0.51-0.97; P = 0.030); a similar result was observed when FSH was analysed in quintiles. In a fixed-effect meta-analysis of two studies, including the current study, serum FSH > 50 IU/L was associated with reduced risk of diabetes (HR = 0.56; 95% CI: 0.36-0.85; P = 0.006; I2 = 0). In conclusion, serum FSH levels were independently associated with diabetes.

Serum 25-hydroxyvitamin D and the risk of stroke in Hong Kong Chinese.

Low vitamin D levels have been associated with various cardiovascular diseases; however, whether it is associated with stroke remains inconclusive. We aimed to evaluate the association between serum 25-hydroxyvitamin D and risk of stroke. We conducted a cohort study consisting of 3,458 participants from the Hong Kong Osteoporosis Study aged ≥45 at baseline, examined between 1995 and 2010 and followed up using electronic medical records. Ischaemic and haemorrhagic stroke were defined using the ICD-9 code. In multivariable Cox-proportional hazard regression, quintiles 1 and 4 were significantly associated with increased risk of stroke when compared to the highest quintile (Quintile 1: HR, 1.78; 95 % CI, 1.16-2.74 and quintile 4: HR, 1.61; 95 % CI, 1.07-2.43). A similar association was observed in both men and women. In subgroup analysis, the association was specifically observed for ischaemic stroke, but not haemorrhagic stroke. Using a penalized regression spline, the association between vitamin D and risk of stroke was in a reverse J-shape, with the lowest risk of stroke being observed at 25(OH)D levels between 70 and 80 nmol/l. In conclusion, a low vitamin D level is associated with increased risk of ischaemic stroke; however, whether high vitamin D level is also associated with increased risk of stroke requires further study.

Osteoporosis in East Asia: Current issues in assessment and management.

The greatest burden of hip fractures around the world is expected to occur in East Asia, especially China. However, there is a relative paucity of information on the epidemiology and burden of fractures in East Asia. Osteoporosis is greatly under-diagnosed and under-treated, even among the highest-risk subjects who have already suffered fractures. The accessibility to bone densitometry, the awareness of the disease by professionals and the public, and the use and reimbursement of drugs are some of the areas which need improvement especially. Cost-effective analysis on screening strategy and intervention thresholds based on local epidemiology data and economic status are available only in Japan. In addition, clinical risk factor models for the assessment of fracture probability may be ethnic specific. Further research is needed to develop a cost-effective risk assessment strategy to identify high-risk individuals for screening and treatment based on local data. Moreover, inadequate calcium and vitamin D intake is still an issue faced by this region.

Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels.

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.

A secular increase in BMD in Chinese women.

Population-based studies have revealed a decline in the incidence of age-adjusted hip fractures in southern Chinese women during the past decade. To determine whether there was a secular change in population characteristics that accounted for this decline, we compared the bone mineral density (BMD) and lifestyle habits of two cohorts of women who were more than 50 years of age and who were recruited from 1995 to 2000 and 2005 to 2010. The BMD levels in the 2005-2010 cohort were significantly higher at the spine and hip and ranged from 3.6 to 17.8% among the different age groups. Additionally, a significantly lower prevalence of subjects with osteoporosis and osteopenia was observed. Longer reproductive years, higher levels of physical activity, higher estradiol and 25(OH) vitamin D levels, and lower alkaline phosphatase levels were found in the 2005-2010 cohort. After adjusting for bone-determining factors, significant differences were detected in the BMD levels at the lumbar spine, femoral neck, and total hip (4.17, 9.02, and 9.34%, respectively) in women >50 years of age but not in women ≤50 years of age. The secular increase in BMD and healthier lifestyles most likely led to the decline in the incidence of age-adjusted fractures.

Outcomes of applying the NOF, NOGG and Taiwanese guidelines to a cohort of Chinese early postmenopausal women.

OBJECTIVE: We applied the NOF (National Osteoporosis Foundation, USA), NOGG (National Osteoporosis Guideline Group, UK) and Taiwanese guidelines to a cohort of postmenopausal women and compared the effectiveness in fracture prevention according to these guidelines. DESIGN: This study is part of the Hong Kong Osteoporosis Study in which postmenopausal women underwent regular assessment and followed up for fracture outcome. SUBJECTS: We studied 2266 treatment-naïve postmenopausal women with mean age of 62·1 years and mean follow-up of 4·5 years. MEASUREMENT: The treatment recommendations based on different guidelines were compared. The women were followed up to determine the rate of fracture occurrence. RESULTS: A total of 106 new major osteoporotic fractures (MOF) were reported, of which 21 were hip fractures (HF). Application of the NOF, NOGG and Taiwanese guidelines resulted in bone mineral density (BMD) screening of 40·7%, 1·3% and 31·8% and treatment of 26·8%, 15·5% and 25·4% of the cohort, respectively. 85·7%, 52·4% and 85·7% of the subjects who sustained HFs would be offered treatment according to the NOF, NOGG and Taiwanese guidelines, respectively. Likewise, 58·5%, 34% and 59·4% of the subjects who sustained MOF would be offered treatment according to the 3 guidelines, respectively. The clinical utility indexes for the 3 guidelines based on the occurrence of MOF during follow-up were 0·0597, 0·0345 and 0·0651, respectively. The corresponding numbers for HFs were even lower. CONCLUSION: The clinical utility for these three guidelines is low for this postmenopausal cohort. Specific guidelines should be needed to guide BMD screening and treatment in our society.

Genetic variant in vitamin D binding protein is associated with serum 25-hydroxyvitamin D and vitamin D insufficiency in southern Chinese.

Previous large-scale genome-wide meta-analysis identified four loci affecting 25-hydroxyvitamin D (25(OH)D) concentrations. However, whether these loci are associated with 25(OH)D concentration in southern Chinese remain unknown. Our primary aim was to examine whether the four top hits (rs2282679, rs10741657, rs12785878 and rs6013897) could be replicated in 712 southern Chinese women. The associations between these single-nucleotide polymorphisms (SNPs), serum 25(OH)D concentration (continuous variable) and vitamin D insufficiency (dichotomized variable) were examined using multivariable linear regression and logistic regression, respectively. Age, body mass index and season were adjusted in the model. Among these four SNPs, rs2282679 was associated with serum 25(OH)D levels (ß=-0.066; P=9 × 10(-5)) and vitamin D insufficiency (odds ratio (OR)=1.51, 95% confidence interval (CI) 1.19-1.93; P=8.6 × 10(-4)), whereas rs12785878 was nominally associated with vitamin D insufficiency only (OR=0.79, 95% CI 0.63-0.99; P=0.042). Genotype risk score (GRS), by summing risk variants of these two SNPs, had more significant association with vitamin D insufficiency (OR=1.38; 95% CI 1.17-1.64; P(trend)=1.76 × 10(-4)) than the model that included only either SNP. The areas under receiver operating characteristic curves of rs2282679 and GRS were 0.561 (P=0.005) and 0.576 (P=5 × 10(-4)), respectively. Our study provides an independent evidence of the associations of rs2282679 and probably rs12785878 with 25(OH)D and vitamin D insufficiency in southern Chinese.

Genetic variants in GREM2 are associated with bone mineral density in a southern Chinese population.

CONTEXT: Gremlin 2 (GREM2) is a regulator of osteoblast differentiation and osteogenesis. A recent genome-wide association study identified GREM2 as a novel susceptibility gene for trabecular volumetric bone mineral density (BMD). OBJECTIVE: We investigated whether GREM2 gene variants were associated with areal BMD in southern Chinese people. RESEARCH DESIGN AND METHODS: We genotyped 108 single-nucleotide polymorphisms (SNPs) in 417 cases (defined as BMD Z-score ≤-1.28) and 359 controls (defined as BMD Z-score ≥+1). Multivariable logistic regression using an additive model was used to evaluate the association. The most associated SNPs of BMD at the spine, femoral neck, and total hip was then replicated in an additional 454 cases and 401 controls. RESULTS: Twelve, 13, and 14 SNPs showed nominal association with BMD at the spine, femoral neck, and total hip, respectively. The minor alleles of rs9728351 (odds ratio [OR] = 2.56; 95% confidence interval [CI] = 1.33-4.92), rs11588607 (OR = 1.65; 95% CI = 1.14-2.4), and rs4454537 (OR = 1.87; 95% CI = 1.22-2.86) were associated with the low BMD at the spine, femoral neck, and total hip, respectively. Among these SNPs most associated with BMD, rs4454537 was successfully replicated in an independent cohort (OR = 1.59; 95% CI = 1.05-2.4). Meta-analysis showed that the minor allele of rs4454537 was associated with low total hip BMD with an OR of 1.72 (95% CI = 1.28-2.31) (P = 3.2 × 10(-4); P(corrected) = .043). CONCLUSIONS: The minor allele of rs4454537 is significantly associated with low BMD at the total hip of southern Chinese people. Our study further suggests GREM2 as a novel susceptibility gene for osteoporosis.

Genetic analysis of recently identified osteoporosis susceptibility genes in southern Chinese.

CONTEXT: Fifty-six genomic loci recently were identified as associated with bone mineral density (BMD) in a large meta-analysis study of mainly European-descent subjects. Circulating factors related to calcium and phosphate metabolism, eg, serum levels of calcium, phosphate, vitamin D metabolites, PTH, and alkaline phosphatase (ALP), may affect bone turnover and metabolism. OBJECTIVE AND DESIGN: We aimed to investigate the effects of these reported variants, as well as their interactions with 5 studied circulating factors, on BMD in a southern Chinese prospective cohort (n = 2670). The identified interactions were further replicated in an independent cohort of 800 Chinese females. RESULTS: Approximately half (n = 27) of the reported variants were successfully replicated in our sample of southern Chinese individuals. We further demonstrated a significant interaction between MARK3 and serum ALP levels (Pmeta = 9.89 ×10(-6)); the effect of MARK3 rs11623869 on BMD was stronger in the presence of high serum levels of ALP. In addition, several interactions between other genes and circulating factors were suggested. CONCLUSIONS: Our study has provided an independent replication of associations between several reported loci and BMD in a large sample of southern Chinese individuals. These replicated loci may represent osteoporosis susceptibility genes in both Chinese and European-descent populations. Furthermore, we have shown that serum ALP levels modified the association of MARK3 with BMD. Understanding the mechanisms of the interactions between BMD-related loci and circulating factors may help to determine the pathogenesis of susceptibility to osteoporosis and could have implications for clinical care.

Factors influencing diagnosis and treatment of osteoporosis after a fragility fracture among postmenopausal women in Asian countries: a retrospective study.

BACKGROUND: A vast amount of literature describes the incidence of fracture as a risk for recurrent osteoporotic fractures in western and Asian countries. Osteoporosis evaluation and treatment after a low-trauma fracture, however, has not been well characterized in postmenopausal women in Asia. The purpose of this study was to characterize patient and health system characteristics associated with the diagnosis and management of osteoporosis among postmenopausal women hospitalized with a fragility fracture in Asia. METHODS: Patient surveys and medical charts of postmenopausal women (N=1,122) discharged after a fragility hip fracture from treatment centers in mainland China, Hong Kong, Singapore, South Korea, Malaysia, Taiwan, and Thailand between July 1, 2006 and June 30, 2007 were reviewed for bone mineral density (BMD) measurement, osteoporosis diagnosis, and osteoporosis treatment. RESULTS: The mean (SD) age was 72.9 (11.5) years. A BMD measurement was reported by 28.2% of patients, 51.5% were informed that they had osteoporosis, and 33.0% received prescription medications for osteoporosis in the 6 months after discharge. Using multivariate logistic regression analyses, prior history of fracture decreased the odds of a BMD measurement (OR 0.63, 95% CI 0.45-0.88). Having a BMD measurement increased the odds of osteoporosis diagnosis (OR 10.1, 95% CI 6.36-16.0), as did having health insurance (OR 4.95, 95% CI 1.51-16.21 for private insurance with partial self-payment relative to 100% self-payment). A history of fracture was not independently associated with an osteoporosis diagnosis (OR 0.80, 95% CI 0.56-1.15). Younger age reduced the odds of receiving medication for osteoporosis (OR 0.59, 95% CI 0.36-0.96 relative to age ≥65), while having a BMD measurement increased the odds (OR 1.79, 95% CI 1.23-2.61). CONCLUSIONS: Osteoporosis diagnosis and treatment in Asian countries were driven by BMD measurement but not by fracture history. Future efforts should emphasize education of general practitioners and patients about the importance of fracture.