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We conducted a retrospective cohort study using a de-identified hospital administrative claims database to assess the risk of non-vertebral fracture in Japanese women with osteoporosis treated with raloxifene compared with alendronate. The study included Japanese women ≥50 years of age with newly initiated alendronate or raloxifene treatment between July 2008 and March 2013 (index date was defined as the day of first prescription for alendronate or raloxifene), and had any claim with an osteoporosis definition during the study period. A total of 37,056 patients in the database initiated treatment, and there were 4802 and 1250 patients included in the alendronate and raloxifene analysis groups, respectively. The mean observation period in the alendronate group (529.2 days) was significantly longer than that for the raloxifene group (473.5 days, P < 0.001). Non-vertebral fractures accumulated linearly, at a similar rate, for both study drugs: incidence at 1 year was 2.83 and 2.64% for the alendronate and raloxifene groups, respectively. For the relative risk of non-vertebral fracture within 1 year, the adjusted hazard ratio was 0.933 for raloxifene versus alendronate, indicating that the relative risk of non-vertebral fracture was similar for the two drugs. The effectiveness of raloxifene in preventing non-vertebral fractures in Japanese women with osteoporosis was similar to that of alendronate. Therefore, raloxifene may be worthy of consideration as an alternative treatment.

Objective: There have been no previous studies regarding the relationship between the respiratory function and incident diabetes in East Asian women in whom obesity is not prevalent., Methods: Using Cox regression models, hazard ratios (HRs) for incident diabetes for each one SD increase in the percent vital capacity (%VC), a parameter of restrictive pulmonary dysfunction, forced expiratory volume in one second over forced vital capacity (FEV1/FVC), a parameter of obstructive pulmonary dysfunction, and log high-sensitivity C-reactive protein (hs-CRP) were calculated in 1,704 men and 1,016 women among a Japanese health screening population., Results: Over the four-year study period (mean of 3.4 years), 54 men (3.2%) and 19 women (1.9%) developed diabetes. The HRs [95% confidence intervals (CIs); p values] for incident diabetes for each one SD increase in %VC and log hs-CRP were 0.81 (0.61-1.06; 0.127) and 1.29 (0.97-1.73; 0.085), respectively in men, and 0.55 (0.35-0.88) 0.012 and 2.50 (1.37-4.57; 0.003), respectively in women adjusted for age, fasting glucose and body mass index. The FEV1/FVC was not found to be significantly associated with incident diabetes in any regression models. The Spearman's correlation coefficients between %VC and hs-CRP was -0.11 (p<0.001) in men and -0.08 (p=0.007) in women. The HRs (95% CIs; p values) for each one SD increase in %VC and hs-CRP were 0.86 (0.65-1.13; 0.278) and 1.26 (0.94-1.70; 0.125), respectively in men, and 0.56 (0.34-0.94; 0.028) and 2.95 (1.49-5.81; 0.002), respectively in women, further adjusted for each other, systolic blood pressure, triglycerides and HDL cholesterol., Conclusion: A low %VC was found to be associated with incident diabetes, independent of hs-CRP in women among a Japanese health screening population.

Controversies concerning the association between obesity and acute myocardial infarction (AMI) are still ongoing in Japan. We investigated the association between obesity defined by body mass index of 25 kg/m(2) or higher and AMI by a case-control study using data from 1199 AMI cases and 4056 apparently healthy controls. The analysis was performed in age- and sex-matched samples of 621 case-control pairs younger than 80 years and in crude samples aged 40-79 years divided into 10-year age groups. Prevalence of obesity, diabetes, current smoking, hypertension, and hypercholesterolemia were compared between cases and controls, and a multivariable odds ratio (OR) of AMI was calculated for each risk factor in various age groups. The OR (95 % confidence interval (CI)) of AMI for obesity was 1.63 (1.23-2.17), P = 0.0008 in men younger than 80 years; 2.65 (1.41-5.00), P = 0.0025 in women younger than 80 years; 2.23 (1.46-3.41), P = 0.0002 in men aged 59 years or younger; 1.34 (0.90-2.01), P = 0.1510 in men aged 60-79 years; and 2.98 (1.56-5.71), P = 0.0010 in women aged 60-79 years using paired samples. The OR (95 % CI) of AMI for obesity was 4.92 (2.53-9.58), P < 0.0001 in men aged 40-49 years; 1.54 (1.07-2.21), P = 0.0197 in men aged 50-59 years; 1.07 (0.69-1.66), P = 0.7717 in men aged 60-69 years; 2.24 (1.20-4.20), P = 0.0118 in men aged 70-79 years; 2.48 (1.12-5.48), P = 0.0245 in women aged 60-69 years; and 3.05 (1.46-6.37), P = 0.0029 in women aged 70-79 years using crude samples. The association between obesity and AMI was age- and gender-dependent in a Japanese population.

Serum total bilirubin (TB) is a potent antioxidant and inversely associated with metabolic syndrome (MetS) in Asian populations. However, there has been no study which is aimed to investigate whether TB is a risk factor for MetS or not. We investigated cross-sectional and longitudinal associations between TB and MetS in 2,435 Japanese men and 1,436 Japanese women. The odds ratios [95 % confidence interval (CI)] of coexisting MetS for each 1 SD increase in log TB were 0.850 (0.754-0.958) (p = 0.008) in men and 0.809 (0.656-0.998) (p = 0.047) in women adjusted for sex, age, smoking, and other confounding covariates. Those for the third and fourth quartiles of TB compared with the lowest quartile were 0.720 (0.537-0.965) (p = 0.028) and 0.737 (0.530-1.052) (p = 0.095), respectively, in men and 0.822 (0.473-1.427) (p = 0.486) and 0.704 (0.362-1.369) (p = 0.301), respectively, in women. There was a tendency that TB and MetS changed inversely to each other. The similarly adjusted hazard ratios of developing MetS for each 1 SD increase in log TB and for the higher quartiles of TB compared with the lowest quartile were not significant either in men or in women. TB is inversely associated with MetS but not a risk factor for MetS in Japanese men and women.

Objective: Both increased serum levels of low-density lipoprotein cholesterol (LDLC) and metabolic syndrome (MetS) are associated with obesity and have been established to be risk factors of cardiovascular disease. However, studies on the relationship between LDLC and MetS have been limited., Methods: Cross-sectional (n=3,871) and longitudinal (n=2,558) associations between LDLC and MetS were examined in a Japanese health screening population., Results: The odds ratio (OR) [95% confidence interval (CI)] of coexisting MetS for each one SD increase in the LDLC level was 1.25 [1.12-1.40] (p<0.001) adjusted for body mass index (BMI) and other confounding covariates and 1.12 [0.97-1.28] (p=0.119) adjusted for numerical values of the components of MetS and other confounding covariates. The similarly adjusted ORs [95% CIs] for the highest quartile of LDLC (Q4) compared with the lowest quartile (Q1) were 1.76 [1.22-2.54] (p=0.002) and 1.46 (0.93-2.30) (p=0.101), respectively. The hazard ratio (HR) [95% CI] for developing MetS for each one SD increase in the LDLC level was 1.24 [1.10-1.40] (p<0.001) adjusted for BMI and other confounding covariates and 1.19 [1.05-1.34] (p=0.006) adjusted for the pre-existing dichotomous five components of MetS and other confounding covariates. The similarly adjusted HRs [95% CIs] for developing MetS for Q4 compared with Q1 were 1.71 [1.17-2.51] (p=0.006) and 1.61 [1.08-2.40] (p=0.020), respectively., Conclusion: The LDLC level is associated with coexisting MetS and functions as a predictor of the development of MetS, independent of BMI or the pre-existing components of MetS, in a Japanese health screening population.

Objective: Although metabolic syndrome (MS) is considered to be a predictor of diabetes and cardiovascular disease, its value for predicting diabetes beyond the levels of fasting glucose (FG) and hemoglobin A1c (HbA1c) remains questionable. In this study, we evaluated the usefulness of MS and Japanese MS (JMS) as predictors of diabetes., Methods: This study is a longitudinal study using data for 2,034 subjects who visited our Medical Check-up Center in both 2008 and 2011 and were free from diabetes at baseline. The odds ratios (ORs) of developing diabetes in 2011 for MS and JMS were calculated after being adjusted for FG, age, sex and antihypertensive and antihyperlipidemic medication use, then further adjusted for HbA1c. The optimal cutoff points for FG, HbA1c and body mass index (BMI) to discriminate the development of diabetes and their sensitivities/specificities were obtained from receiver operating characteristic curves. These sensitivities/specificities were compared with the sensitivities/specificities of MS and JMS., Results: The ORs (95% confidence intervals (CIs)) of developing diabetes for MS and JMS were 1.36 (0.57-3.23) (p=0.484) and 3.23 (1.25-8.36) (p=0.016), respectively, after being adjusted for FG and 1.06 (0.39-2.86) (p=0.915) and 2.34 (0.79-6.95) (p=0.126), respectively, after being further adjusted for HbA1c. The sensitivities/specificities of FG, HbA1c, BMI, MS and JMS were 0.625/0.897, 0.828/0/919, 0.625/0.734, 0.375/0.911, and 0.375/0.941, respectively., Conclusion: MS and JMS were found to be poor predictors of diabetes in a Japanese health screening population.

The aim of this study was to investigate the association between leukocyte subtype counts and hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia. Logistic regressions using hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia as a dependent variable and total leukocyte, basophil, eosinophil, neutrophil, lymphocyte, and monocyte counts as an independent variable were calculated adjusting for age, body mass index (BMI), high-sensitivity C-reactive protein (hs-CRP), smoking, drinking, and physical activity in apparently healthy Japanese men (1,803) and women (1,150). The odds ratio (OR) of hyper-LDL cholesterolemia for total leukocyte, eosinophil, and lymphocyte counts, the OR of hypertriglyceridemia for total leukocyte, eosinophil, neutrophil, and lymphocyte counts, and the OR of hypo-HDL cholesterolemia for total leukocyte, neutrophil, and lymphocyte counts were significant in men, and the OR of hyper-LDL cholesterolemia, for lymphocyte count, and the OR of hypo-HDL cholesterolemia for eosinophil count were significant in women. Lymphocyte count was significantly associated with hyper-LDL cholesterolemia independently of hs-CRP in apparently healthy Japanese.

Bilirubin is a potent antioxidant, and serum total bilirubin (TB) is reported to be negatively associated with cardiovascular disease (CVD). There has been no report on the association between TB and CVD prevalence in Japanese. The aim of the study is to examine the association between TB and CVD prevalence in a Japanese health screening population. Prevalence of CVD was studied in 3,375 Japanese men and 2,069 Japanese women. Odds ratios (ORs) of each higher quintile of TB using the lowest quintile as the reference in men and of each higher tertile of TB using the lowest tertile as the reference in women were calculated for coronary heart disease (CHD) and stroke adjusting for age, liver function tests, smoking, physical activity, and alcohol consumption. The ORs [95% confidence intervals (CIs)] for CHD and stroke of the 2nd, 3rd, 4th, and 5th quintiles of TB were 0.63 (0.37-1.07) and 0.49 (0.24-1.00), 0.45 (0.22-0.90) and 0.65 (0.28-1.51), 0.69 (0.39-1.20) and 0.37 (0.15-0.87), and 0.61 (0.34-1.09) and 0.40 (0.18-0.92), respectively in men. The ORs (95% CIs) for CHD and stroke of the 2nd and 3rd tertiles of TB were 1.32 (0.49-3.54) and 0.35 (0.13-0.93), and 1.26 (0.44-3.62) and 0.34 (0.13-0.93), [corrected] respectively in women. Low TB was associated with the higher prevalence of CHD and stroke in men and with the higher prevalence of stroke in women among a Japanese health screening population.

Background: Serum total bilirubin (TB) is a potent antioxidant and may be a negative risk factor of cardiovascular disease. In non-diabetic adults, hemoglobin A(1c) (HbA(1c)), but not fasting plasma glucose, is an independent risk factor of cardiovascular disease., Methods and Results: Linear regression using TB as a dependent variable and cardiovascular risk factors, including HbA(1c), as independent variables, linear regression using HbA(1c) as a dependent variable and other cardiovascular risk factors, including TB, as independent variables, and logistic regression using the highest decile (≥ 5.4%) of HbA(1c) as a dependent variable and TB and other cardiovascular risk factors as independent variables were performed for 893 apparently healthy male smokers, 1,607 male nonsmokers, and 1,680 women. The standardized regression coefficient of HbA(1c) for TB and that of TB for HbA(1c) was -0.12 (P = 0.007) and -0.06 (P = 0.02), respectively, in the smokers, -0.20 (P < 0.0001) and -0.07 (P < 0.0001), respectively, in the nonsmokers, and -0.21 (P < 0.0001) and -0.14 (P < 0.0001), respectively, in the women. The odds ratio of 1 SD increment in TB for HbA(1c) ≥ 5.4% was not significant in the smokers, 0.67 (P = 0.002) in the nonsmokers, and 0.55 (P<0.0001) in the women., Conclusions: Bilirubin was negatively associated with HbA(1c) independently of other cardiovascular risk factors in apparently healthy Japanese men and women. The association was weak in male smokers.

Obesity is associated with hypertension. However, it is controversial which obesity index, body mass index (BMI) or waist circumference (WC), is more strongly associated with hypertension. We compared the cross-sectional associations of BMI and WC with hypertension. Logistic regressions using hypertension as a dependent variable and age, BMI, WC, fasting plasma glucose, triglycerides, high-density lipoprotein cholesterol, smoking status, drinking status, and physical activity as independent variables were performed using data from apparently healthy 1,803 Japanese men aged 49.9 ± 9.0 and 1,150 women aged 49.5 ± 9.0 excluding subjects with a history of cardiovascular disease, or with antidiabetic, antihypertensive and/or antihyperlipidemic medications. The odds ratio [95% confidence interval] of 1 kg/m² increase in BMI and that of 1 cm increase in WC for diagnosing hypertension were 1.23 [1.11-1.36] (p < 0.0001) and 0.99 [0.95-1.02] (p = 0.4) in men and 1.35 [1.16-1.58] (p < 0.0001) and 0.97 [0.91-1.03] (p = 0.4) in women, respectively. Thus, BMI, but not WC, was independently associated with hypertension in apparently healthy Japanese men and women.

Objective: To compare two systemic inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) and white blood cell count (WBC), as a component of metabolic syndrome (MetS)., Methods: Data of hs-CRP and WBC from 2,185 Japanese men and 1,383 Japanese women were examined using receiver operating characteristic (ROC) curve for diagnosing MetS and Spearman's correlation coefficients., Results: The area under ROC curve (AUC) of hs-CRP was 0.71 in men and 0.74 in women. The AUC of WBC was 0.65 in men and 0.69 in women. The optimal cutoff point (sensitivity; specificity) of hs-CRP was 0.40 mg/L (0.69; 0.65) in men and 0.35 mg/L (0.67; 0.72) in women. The optimal cutoff point (sensitivity; specificity) of WBC was 5,600/L(-6) (0.61; 0.61) in men and 5,000/L(-6) (0.65; 0.63) in women. Correlations between obesity parameters, blood pressure, and liver function tests were stronger with hs-CRP than with WBC. But, no correlation between MetS-related risk factors was stronger with WBC than with hs-CRP., Conclusion: Hs-CRP is superior to WBC as an inflammatory component of MetS in Japanese. However, WBC may be useful when hs-CRP is not available because WBC is routinely measured in clinical practice.

Background: Low-density lipoprotein (LDL) cholesterol and chronic kidney disease (CKD) are both well-known risk factors for cardiovascular disease. However, few studies have examined the associations between LDL cholesterol and CKD., Methods: In the present study, we investigated the associations between LDL cholesterol and CKD using medical check-up data from 2,449 Japanese men and 1,448 Japanese women. Metabolic syndrome (MetS) was defined according to the revised National Cholesterol Education Program (NCEP) criteria for Japanese people. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and/or proteinuria., Results: Blood levels of LDL cholesterol were higher in CKD subjects than in non-CKD subjects only in men and the frequency of antihyperlipidemic medication and MetS was higher in CKD subjects than in non-CKD subjects, regardless of gender. The frequency of CKD was significantly higher in male subjects with the highest quartile of LDL cholesterol than in those with the lowest quartile of LDL cholesterol. LDL cholesterol levels were significantly higher in subjects with eGFR corresponding to CKD stages 2 and 3 than in those with eGFR corresponding to CKD stage 1 both in men and women. LDL cholesterol was independently associated with CKD, eGFR <60 mL/min/1.73 m(2), and proteinuria in Japanese men, but not in women., Conclusion: LDL cholesterol is cross-sectionally associated with preclinical CKD in Japanese men.

Objective: To compare body mass index (BMI), waist circumference (WC), and percent body fat (%BF) as markers for the clustering of metabolic risk factors in Japanese., Methods: Age-adjusted correlation coefficients (Rs) were calculated between the three anthropometric markers of obesity and metabolic risk factors in 2,444 men and 1,442 women among Japanese. Areas under receiver operating characteristic curves (AUCs) of BMI, WC, and %BF were calculated for diagnosing the clustering of 1 or more, 2 or more, 3 or more, and 4 risk factors among increased blood pressure, impaired fasting glucose, increased triglycerides, and decreased HDL cholesterol and for the clustering of 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, and 6 risk factors among the upper four risk factors as well as increased high-sensitivity C-reactive protein and increased LDL cholesterol., Results: The Rs were not significantly different among BMI, WC, and %BF except for the difference between the R of BMI (0.217) and that of %BF (0.283) with LDL cholesterol in men (p=0.014). The AUCs of BMI, WC, and %BF for diagnosing any of the risk factor clustering patterns defined above were not significantly different in both men and women., Conclusion: The AUCs for diagnosing the clustering of metabolic risk factors were not significantly different among BMI, WC, and %BF.

To investigate the feasibility of newborn screening for glycogen storage disease type II (GSDII; Pompe disease or acid maltase deficiency) in the Japanese population, we assayed the acid alpha-glucosidase activity in dried blood spots from 715 Japanese newborns and 18 previously diagnosed patients using a fluorometric procedure. The enzyme activity of apparently healthy newborns showed a bimodal distribution. The median activity of the minor group (31 individuals, 4.3% of the samples) was 6.5 times lower than that of the major group. Four of the 715 control samples (0.56%) fell in the patient range. We then analyzed genomic DNA, extracted from the same blood spots, for the occurrence of two sequence variants, c.1726G>A and c.2065G>A, known to cause "pseudodeficiency". This analysis revealed that 27 of 28 individuals homozygous for c.[1726A; 2065A] belonged to the minor group. One c.[1726A; 2065A] homozygote had just slightly higher activity. Twelve of the 18 patients with GSDII either had one (9 cases) or two (3 cases) c.[1726A; 2065A] alleles. The frequency of this allele was double in the patient compared to the control group (0.42 vs 0.19) at the expense of a lower frequency of the c.[1726G; 2065G] and c.[1726G; 2065A] alleles (0.58 vs 0.71 and 0 vs 0.1). These findings illustrate that c.[1726A; 2065A] homozygosity among apparently healthy individuals (3.9 per 100) complicates newborn screening for GSDII in Japan, and further that one or more pathogenic mutations are associated with the c.[1726A; 2065A] allele.

Background: Gamma glutamyltransferase (GGT) or alanine aminotransferase (ALT) is reported to be an independent risk factor of diabetes and cardiovascular disease and proposed as a component of metabolic syndrome (MS). However, there are few studies examining the direct association between MS and GGT or ALT in Japanese men and women., Methods: Direct associations between GGT or ALT and MS defined by revised NCEP criteria for Japanese and between GGT or ALT and Japanese MS (JMS) defined by the Examination Committee for the Criteria of Metabolic Syndrome were examined using medical check-up data from 1,880 men and 1,079 women., Results: The prevalence of MS and JMS was significantly higher in subjects with the highest quartile of GGT or ALT than the subjects with the lowest quartile of GGT or ALT (p<0.0001 in men and p<0.0001 for MS and p<0.001 for JMS in women). The optimal cutoff points of GGT and ALT for diagnosing MS or JMS were 42 U/L or 41 U/L, respectively for GGT and both 25 U/L for ALT in men and 21 U/L or 23 U/L, respectively for GGT and 20 U/L or 25 U/L, respectively for ALT in women., Conclusion: The prevalence of MS and JMS increases with the increase in blood levels of GGT or ALT even through the normal range of GGT or ALT in Japanese men and women.