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Shiraki M.,Research Institute and Practice for Involutional Diseases | Kuroda T.,Public Health Research Foundation | Tanaka S.,Kyoto University
Internal Medicine | Year: 2011

Objective Osteoporosis has been reported to increase the risk of mortality. However, these reports did not evaluate the effects of co-mobidities and the severity of osteoporosis on mortality. The aim of our study was to determine whether or not major osteoporotic fractures contribute to the increased mortality risk in Japanese women. Method We conducted a prospective observational study. Risk factors contributing to mortality were assessed by Cox's proportional hazard model. Subjects A total of 1,429 ambulatory postmenopausal female volunteers aged over 50 years old were enrolled in the study. Information was obtained from the subjects on baseline biochemical indices, bone mineral density (BMD), prevalent fractures, and co-morbidities. Mortality was assessed and confirmed by the certificates or hospital records. The subjects were classified into three categories in accordance with or without osteoporosis. The osteoporotic group was further categorized by the basis of the presence or absence of major osteoporotic fractures. Results Mean age and SD of the participants were 66.5±9.3 (50-90) years old. The participants were followed for a total of 4.5±3.5 years (mean ± SD) and a total of 141 participants (9.9%) died during the observation. In addition to the traditional risks for mortality, such as age (Hazard ratio, 2.817, 95% CI, 2.237- 3.560, p<0.0001), BMI (HR 0.504, 0.304-0.824, p=0.0061), prevalent malignancies (HR 2.885, 1.929-4.214, p<0.0001), dementia (HR 1.602, 1.027-2.450, p=0.038) and cardio-vascular disease (HR 1.878, 1.228-2.787, p=0.0043), the serum level of creatinine (HR 2.451, 1.107-5.284, p=0.027) and severity of osteoporosis (HR 1.390, 1.129-1.719, P=0.0018) were found to be significant independent risk factors for all-cause mortality. Conclusion These results emphasize the importance of osteoporotic fracture in terms of survival. © 2011 The Japanese Society of Internal Medicine.


Tanaka S.,Kyoto University | Kuroda T.,Public Health Research Foundation | Saito M.,Jikei University School of Medicine | Shiraki M.,Research Institute and Practice for Involutional Diseases
Osteoporosis International | Year: 2013

This cohort study of 1,614 postmenopausal Japanese women followed for 6.7 years showed that overweight/obesity and underweight are both risk factors for fractures at different sites. Fracture risk assessment may be improved if fracture sites are taken into account and BMI is categorized. Introduction: The effect of body mass index (BMI) on fracture at a given level of bone mineral density (BMD) is controversial, since varying associations between BMI and fracture sites have been reported. Methods: A total of 1,614 postmenopausal Japanese women were followed for 6.7 years in a hospital-based cohort study. Endpoints included incident vertebral, femoral neck, and long-bone fractures. Rate ratios were estimated by Poisson regression models adjusted for age, diabetes mellitus, BMD, prior fracture, back pain, and treatment by estrogen. Results: Over a mean follow-up period of 6.7 years, a total of 254 clinical and 335 morphometric vertebral fractures, 48 femoral neck fractures, and 159 long-bone fractures were observed. Incidence rates of vertebral fracture in underweight and normal weight women were significantly lower than overweight or obese women by 0.45 (95 % confidence interval: 0.32 to 0.63) and 0.61 (0.50 to 0.74), respectively, if BMD and other risk factors were adjusted, and by 0.66 (0.48 to 0.90) and 0.70 (0.58 to 0.84) if only BMD was not adjusted. Incidence rates of femoral neck and long-bone fractures in the underweight group were higher than the overweight/obese group by 2.15 (0.73 to 6.34) and 1.51 (0.82 to 2.77) and were similar between normal weight and overweight/obesity. Conclusions: Overweight/obesity and underweight are both risk factors for fractures at different sites. Fracture risk assessment may be improved if fracture sites are taken into account and BMI is categorized. © 2012 International Osteoporosis Foundation and National Osteoporosis Foundation.


Tanaka S.,Kyoto University | Kuroda T.,Public Health Research Foundation | Saito M.,Jikei University School of Medicine | Shiraki M.,Research Institute and Practice for Involutional Diseases
Journal of Bone and Mineral Research | Year: 2011

We investigated whether measurement of pentosidine, in addition to the conventional risk assessment tool, the Fracture and Immobilization Score (FRISC), improves early identification of fracture cases. A total of 765 postmenopausal Japanese women with baseline measurement of urinary pentosidine were followed in a hospital-based cohort study. Endpoints were incidence of vertebral fracture, incidence of long bone fracture, and incidence of long bone and vertebral fracture. To assess the effect of pentosidine on fracture risk, we fitted multivariate Cox regression models adjusted for age, body weight, diabetes mellitus, lumbar BMD, prior fracture, and presence of back pain. To explore potential nonlinear relationships, we fitted a multivariate generalized additive model. To assess the discriminatory power of pentosidine, we performed receiver operating characteristic analysis. The hazard ratios for a 1 SD increase in pentosidine were 1.18 (95% CI 1.05-1.33, p < 0.01) for vertebral fracture and 1.20 (95% CI 1.07-1.33, p < 0.01) for long bone and vertebral fractures. The relationship was approximately linear, and there was no indication of the presence of a threshold. The C statistics were 0.732 (95% CI 0.686-0.778) for the model with both pentosidine and the 10-year risk and 0.702 (95% CI 0.654-0.750) for the 10-year risk alone. Eighty-three subjects (11%) in the whole cohort were in the highest quartile of pentosidine, although their 10-year risks were less than 15% and included 17 incident vertebral fracture cases. Urinary pentosidine improves risk classification using conventional risk assessment tools. Optimal clinical strategies of diagnosis and treatment remain uncertain and in need of additional investigation. © 2011 American Society for Bone and Mineral Research.


Tanaka S.,Kyoto University | Yoshimura N.,Tokyo Medical University | Kuroda T.,Public Health Research Foundation | Hosoi T.,National Center for Geriatrics and Gerontology | And 2 more authors.
Bone | Year: 2010

Introduction: We aimed to (i) explore risk factors for major osteoporotic fracture or immobilization; (ii) develop a prediction model that can be used to assess the risk of fracture and immobilization; and (iii) assess external validity of the final model. Methods: A total of 1787 postmenopausal Japanese women were followed in a hospital-based cohort study. Endpoints included the annual incidence of major osteoporotic fracture and immobilization. For each endpoint, multivariate Poisson regression models were fitted separately and risk factors were screened through backward variable selection. The predictive accuracy of the final model (FRISC) was evaluated in two independent community-based cohorts. Results: Over a median follow-up of 5.3. years, a total of 383 major osteoporotic fractures (279 clinical vertebral, 44 hip, 60 distal forearm) and 83 immobilizations occurred in the developmental dataset. Backward variable selection confirmed that the following are risk factors for major osteoporotic fracture: age, weight, prior fracture, back pain, and lumbar bone mineral density (BMD). Age, prior fracture and dementia were significant risk factors for immobilization. Hosmer-Lemeshow tests did not indicate any significant deviation between the observed fracture frequency and prediction from the FRISC in the independent validation dataset. The C statistic for the FRISC was 0.727 (95% confidence interval: 0.660 to 0.794) and was higher than that for BMD alone significantly (p= 0.03). Conclusions: We developed a novel prediction model for fracture and immobilization, FRISC, and the clinical risk factors in the FRISC allows better identification of populations at high risk of fracture than BMD alone. A web application is available at http://www.biostatistics.jp/prediction/frisc. © 2010 Elsevier Inc.


Kuroda T.,Public Health Research Foundation | Tanaka S.,Kyoto University | Saito M.,Jikei University School of Medicine | Shiraki Y.,Research Institute and Practice for Involutional Diseases | Shiraki M.,Research Institute and Practice for Involutional Diseases
Calcified Tissue International | Year: 2013

The aim of this cross-sectional cohort study was to clarify risk factors for severe vertebral fractures in postmenopausal Japanese women. Subjects were ambulatory volunteers age over 50 years who were recruited from a population of outpatients at a primary care institute. At registration, age, body mass index (BMI), bone mineral density (BMD), and present illness were investigated. Biochemical parameters including urinary levels of type I collagen cross-linked N-telopeptides (NTXs), and pentosidine and plasma levels of homocysteine were measured. Values were compared with different fracture grades (grade 0-3). A total of 1,475 postmenopausal women (66.6 ± 9.0 years) were included in the present study. Distributions of vertebral fracture grades were grade 1, 137 cases (9.3 %); grade 2, 124 cases (8.4 %); and grade 3, 162 cases (11.0 %). Age, BMI, BMD, NTX, pentosidine, and homocysteine were significantly associated with vertebral fracture in unadjusted analysis. In addition, a higher prevalence of hypertension was observed in patients with severe fracture. When comparing vertebral fracture grade 0 versus grade 2-3 by multiple regression analysis, pentosidine and homocysteine levels were a significant risk for moderate/severe vertebral fracture (odds ratio [OR] = 1.17, 95 % confidence interval [CI] 1.00-1.38, p = 0.049; OR = 1.22, 95 % CI 1.03-1.46, p = 0.013). Homocysteine levels were also a significant risk when comparing vertebral fracture grade 0 versus grade 3 (OR = 1.27, 95 % CI 1.04-1.58, p = 0.021). Plasma level of homocysteine was an independent risk for severe vertebral fractures. © 2013 Springer Science+Business Media New York.


Tanaka S.,Kyoto University | Kuroda T.,Public Health Research Foundation | Yamazaki Y.,Research Institute and Practice for Involutional Diseases | Shiraki Y.,Research Institute and Practice for Involutional Diseases | And 2 more authors.
Journal of Bone and Mineral Metabolism | Year: 2013

There is emergent evidence for divergent associations between 25(OH)D levels and fractures by race and ethnicity, but data on Asian populations are sparse. We investigated this association in a primary care cohort of 1470 postmenopausal Japanese women followed for a mean period of 7.2 years and explored a potential threshold of 25(OH)D. Endpoints were incident vertebral, proximal femur, and long bone fractures. Rate ratios were estimated using multivariate Poisson regression adjusted for lumbar or femur bone mineral density (BMD) less than −2.5 SD of the young adult mean (YAM), age, weight, presence of diabetes mellitus, parathyroid hormone, estimated glomerular filtration rate, prior fracture, back pain, present medications and past medical history. Mean age was 63.7 ± 10.7 years and osteoporosis patients were 41.3 %. The background data of the present participants were almost identical to the subjects participating in the National Health and Nutrition Survey of 2003. Overall, 49.6 % of the subjects had a 25(OH)D value <20 ng/mL and 27.8 % had a 25(OH)D value from 20 to 24 ng/mL. The propensity score for exposure to 25(OH)D < 25 ng/mL in the present and independent community dwelling populations, namely the Miyama and Taiji cohorts, were not significantly different, suggesting no evidence for selection bias. The generalized additive models showed clear decreasing trends in incidence rates of proximal femur and long bone fractures at higher levels of 25(OH)D, and the annual incidence rate of proximal femur fracture was around 0.0005 in women with 25(OH)D > 25 ng/mL, probably leading to the decreasing trend in long bone fracture. Multivariate-adjusted rate ratios of 25(OH)D < 25 ng/mL were 1.01 (95 % confidence interval [CI], 0.84–1.22, p = 0.88) for vertebral fracture, 2.71 (95 % CI 0.94–7.83, p = 0.07) for proximal femur fracture, and 2.20 (95 % CI 1.37–3.53, p < 0.01) for long bone fracture. The respective rate ratios of a BMD level lower than −2.5 SD of the YAM were 1.61 (95 % CI 1.33–1.94, p < 0.01), 1.52 (95 % CI 0.67–3.45, p = 0.32), and 1.54 (95 % CI 1.02–2.33, p = 0.04). In conclusion, 25(OH)D is a leading risk factor for long bone fracture comparable to BMD in Japanese postmenopausal women. The contribution of 25(OH)D to fracture risks is substantial even below 25 ng/mL and is possibly site-specific. We recommend measuring the serum 25(OH)D level in primary care settings. © 2013, The Japanese Society for Bone and Mineral Research and Springer Japan.


Shiraki M.,Research Institute and Practice for Involutional Diseases | Kuroda T.,Public Health Research Foundation | Shiraki Y.,Research Institute and Practice for Involutional Diseases | Tanaka S.,Kyoto University | Higuchi T.,Hirosaki University
Journal of Bone and Mineral Metabolism | Year: 2011

To clarify what kind of risk factors predict incident fractures in patients treated with bisphosphonates, the authors investigated the relationship between baseline characteristics and incident vertebral fracture in Japanese osteoporosis patients undergoing bisphosphonate treatment. This was a multi-center follow-up study conducted at three centers, in which a total of 251 Japanese patients with osteoporosis (mean age 70.5 years) from the three centers were followed for 3.2 ± 2.0 years. Baseline data, including pre-existing fractures, bone mineral density in the lumbar spine (LBMD), bone metabolic markers, urinary pentosidine, and plasma homocysteine, were evaluated. Changes in LBMD, bone turnover markers, and incident fractures after the treatment were followed. Sixty-one patients developed incident vertebral fractures; this group of patients was older and had lower LBMD, a higher prevalent vertebral fracture number, and higher homocysteine and pentosidine levels than patients who did not develop incident vertebral fractures. Changes in LBMD, urinary N-terminal telopeptides of type I collagen (NTX), and bone-derived alkaline phosphatase showed no significant association with the occurrence of vertebral fractures. Cox's proportional hazard model demonstrated that age, prevalent fracture, pentosidine, and homocysteine were independent predictors of the incident vertebral fracture rate under bisphosphonate treatment. Higher baseline levels of pentosidine and homocysteine in osteoporosis patients are potential risk factors for incident vertebral fractures when these patients are treated with bisphosphonates. Further clarification is needed to explain why such patients have higher fracture susceptibility. © 2010 The Japanese Society for Bone and Mineral Research and Springer.


Wada H.,Wada Womens Clinic | Hirano F.,Asahikawa Medical College | Kuroda T.,Public health research foundation | Shiraki M.,Research Institute and Practice for Involutional Diseases
Geriatrics and Gerontology International | Year: 2012

Aim: Arterial calcification and osteoporosis commonly accompany one another in postmenopausal women. Hypertension is a known contributing factor to arterial calcification. Thus, we aimed to investigate any associations between hypertension, arterial calcification and vertebral fractures in a cross-sectional study in Japanese postmenopausal women. Methods: The medical histories of 421 postmenopausal Japanese women diagnosed with hypertension, diabetes mellitus or hyperlipidemia were investigated. Bodyweight, body height and ultradistal bone mineral density (BMD) were measured. The prevalent vertebral fractures were diagnosed by a semiquantitative method, and the number of breast arterial calcifications (BAC) was investigated by mammography screening. Results: Patients with vertebral fractures were of a significantly higher age, lower height, lower ultradistal BMD and had a higher number of BAC compared with those without vertebral fractures. Furthermore, a significantly higher prevalence of hypertension was observed in the patients with vertebral fractures as compared with those without. A multivariate stepwise regression analysis using these variables for vertebral fractures showed that the significant odds ratios (OR) of age (OR 1.76, 95% CI 1.11-2.77, P=0.016), the prevalence of BAC (OR 2.52, 95% CI 1.62-3.93, P<0.001) and the presence of hypertension (OR 1.76, 95% CI 1.11-2.80, P=0.017) were found as significant independent risk factors for vertebral fractures. Conclusion: This is the first report of the relevance of BAC or hypertension to vertebral fractures in Japanese women. The results suggest that hypertension, BAC and osteoporotic fractures share a common metabolic pathway in their pathogenesis. © 2011 Japan Geriatrics Society.


Shiraki M.,Research Institute and Practice for Involutional Diseases | Yamazaki Y.,Research Institute and Practice for Involutional Diseases | Kuroda T.,Public Health Research Foundation | Tanaka S.,Kyoto University | Miyata K.,Aizawa Hospital
Osteoporosis International | Year: 2011

Summary: To elucidate whether serum levels of pepsinogens are associated with the occurrence of gastrointestinal adverse events induced by amino-bisphosphonates (amino-BP), the serum levels of pepsinogen were measured in amino-BP users. Our results indicate that measurement of pepsinogen I is useful in predicting gastric distress induced by amino-BP in osteoporosis. Introduction: To elucidate whether serum levels of pepsinogens are associated with the occurrence of gastrointestinal adverse events induced by amino-BP, the serum levels of pepsinogen I and II were measured in amino-BP users. Methods: When the patients complained of gastric distress symptoms during the first 6 months after amino-BP use resulting in discontinuation of the drug, endoscopical examinations were performed to assess whether gastric lesions were present. A total of 223 amino-BP users were enrolled in the study, of which 47 patients refused to take the drug due to gastric distress symptoms. The remaining 176 patients did not complain of any gastric distress. Results: Among 47 patients, eight patients showed obvious gastric lesions such as gastric or duodenal ulcers and acute gastric mucosal lesions in the endoscopical examination. The remaining 39 patients did not show any gastric lesions. The possible confounding factors, such as a Helicobactor pylori infection or concurrent use of ulcerogenic agents, did cause not affect gastric distress in amino-BP users. The serum pepsinogen I level was significantly associated with severity of the gastric lesion 46.8±27.7, 60.8±32.4, and 103.4± 49.2 ng/ml for patients without any gastric distress, with gastric distress accompanied no gastric lesions, and with gastric distress accompanied gastric lesions, respectively. Conclusions: ROC analysis revealed that the cutoff value of pepsinogen I for expectation of gastric regions was 76.8 ng/ml. The results clearly indicate that measurement of pepsinogen I may be useful in predicting gastric distress induced by amino-BP in osteoporosis. © International Osteoporosis Foundation and National Osteoporosis Foundation 2010.


Kuroda T.,Public Health Research Foundation | Onoe Y.,Tokyo Women's Medical University | Yoshikata R.,Tokyo Women's Medical University | Ohta H.,International University of Health and Welfare
Asia Pacific Journal of Clinical Nutrition | Year: 2013

Back ground and aims: It is well known that insufficient nutrient intake leads to poor bone status. To find a simple evaluation method for prevention of nutrition intake disorder, a cross-sectional study with 275 healthy Japanese female students aged 19-25 was conducted. Methods: Anthropometric parameters, bone mineral density (BMD) at lumbar and total hip, bone metabolic markers and physical activity were measured in study participants and the frequency of skipping meals (breakfast, lunch, supper), and absolute values for nutrient intakes were assessed using a Diet History Questionnaire. Results: The frequency of skipping breakfast significantly correlate to total energy intake (ρ= -0.276, p<0.001). BMI, total intake of energy, intake of protein, intake of phosphate, and energy expenditure positively correlated significantly to BMD at lumbar and total hip (p<0.05) using simple linear regression. BMI (regression coefficient (b))=0.088, p<0.001), bone alkaline phosphatase (b= -0.050, p=0.012), total energy expenditure (b=0.019, p<0.001), and frequency of skipping breakfast (b= -0.018, p=0.048) were independent risk factors for lower total hip BMD by multiple regression analysis. The total hip BMD in participants who skipped breakfast three or more times was significantly lower than in those who did not skip breakfast (p=0.007). Conclusions: In conclusion, managing the frequency of skipping breakfast and reducing it to <3 times per week may be beneficial for the maintenance of bone health in younger women.

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