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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.


Nakamura T.,University of Occupational and Environmental Health Japan | Matsumoto T.,Tokushima University | Sugimoto T.,The University of Shimane | Shiraki M.,Research Institute and Practice for Involutional Diseases
Osteoporosis International | Year: 2012

The efficacy and safety of denosumab were evaluated in Japanese postmenopausal women with osteoporosis. Total hip and distal 1/3 radius bone mineral densities (BMDs) were increased, and lumbar spine BMD was increased in magnitude with increasing dose. Bone turnover markers significantly decreased compared with placebo. Denosumab was well tolerated in Japanese subjects. Introduction: The efficacy and safety of three doses of denosumab were compared with a placebo over 12 months in Japanese postmenopausal women with osteoporosis. Methods: In this phase 2 multicenter, randomized, placebo-controlled study, 226 subjects were randomized and 212 subjects received at least 1 dose of investigational product, subcutaneously. All subjects also received daily supplements of at least 600 mg elemental calcium and 400 IU vitamin D from the beginning of screening through 12 months of treatment. Results: Compared with placebo, denosumab (14, 60, and 100 mg) showed significant increases in percent BMD values of lumbar spine (5.25, 6.27, and 7.00) and total hip (3.90, 3.69, and 4.35) from baseline in 12 months. Distal 1/3 radius BMD was also significantly increased except at the 100-mg dose (1.82, 1.35, and 1.15). Denosumab significantly decreased the serum C-terminal crosslinking telopeptide of type 1 collagen and urinary N-terminal crosslinking telopeptide of type I collagen/urinary creatinine levels in 8 days, and bone alkaline phosphatase in 3 months. No new vertebral fracture was observed on spinal radiographs in either group. The overall incidences of adverse events were similar in the denosumab groups and the placebo group. No subject developed antibodies to denosumab. These results were similar to those obtained in the US phase 2 study. Conclusions: Denosumab 60 mg could be an effective dose for Japanese postmenopausal women with osteoporosis as was shown in the Caucasian population. © 2011 International Osteoporosis Foundation and National Osteoporosis Foundation.


Urano T.,University of Tokyo | Shiraki M.,Research Institute and Practice for Involutional Diseases | Sasaki N.,University of Tokyo | Ouchi Y.,University of Tokyo | And 2 more authors.
Aging Cell | Year: 2014

Genetic factors are important for the development of sarcopenia, a geriatric disorder characterized by low lean body mass. The aim of this study was to search for novel genes that regulate lean body mass in humans. We performed a large-scale search for 250K single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD) using SNP arrays in 1081 Japanese postmenopausal women. We focused on an SNP (rs12409277) located in the 5′-flanking region of the PRDM16 (PRD1-BF-1-RIZ1 homologous domain containing protein 16) gene that showed a significant P value in our screening. We demonstrated that PRDM16 gene polymorphisms were significantly associated with total body BMD in 1081 postmenopausal Japanese women. The rs12409277 SNP affected the transcriptional activity of PRDM16. The subjects with one or two minor allele(s) had a higher lean body mass than the subjects with two major alleles. Genetic analyses uncovered the importance of the PRDM16 gene in the regulation of lean body mass. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.


Shiraki M.,Research Institute and Practice for Involutional Diseases | Saito H.,Chugai Pharmaceutical Co. | Matsumoto T.,Tokushima University
Current Medical Research and Opinion | Year: 2012

Background: Three-year treatment with eldecalcitol has been shown to improve lumbar and total hip bone mineral density (BMD), decrease bone turnover markers, and lower the incidences of vertebral and wrist fractures in patients with osteoporosis more than with treatment with alfacalcidol under vitamin D repletion. The purpose of this study was to determine whether there was a risk of eldecalcitol causing severely suppressed bone turnover in osteoporosis patients with low pre-treatment levels of bone turnover markers. Methods and results: Post-hoc analysis was conducted on the data from a 3-year, randomized, double-blind, active-comparator, clinical trial of eldecalcitol versus alfacalcidol under vitamin D repletion conducted in Japan. Enrolled patients with baseline measurements of bone turnover markers were stratified into tertiles according to their pre-treatment levels of serum bone-specific alkaline phosphatase, serum procollagen type I N-terminal propeptide, or urinary collagen-N-telopeptide. Eldecalcitol treatment rapidly reduced bone turnover markers, and kept them within the normal range. However, in the patients whose baseline values for bone turnover were low, eldecalcitol treatment did not further reduce bone turnover markers during the 3-year treatment period. Further long-term observation may be required to reach the conclusion. ClinicalTrials.gov number: NCT00144456. Conclusions: Eldecalcitol normalizes, but does not overly suppress, bone turnover regardless of baseline levels of bone turnover markers. Thus, it is unlikely that eldecalcitol treatment will increase the risk of severely suppressed bone turnover and therefore deterioration of bone quality, at least for a treatment duration of 3 years. © 2012 Informa UK Ltd All rights reserved.


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.


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.


Sugimoto T.,The University of Shimane | Nakamura T.,National Center for Global Health and Medicine | Nakamura Y.,Asahi Kasei Corporation | Isogai Y.,Asahi Kasei Corporation | Shiraki M.,Research Institute and Practice for Involutional Diseases
Osteoporosis International | Year: 2014

Changes in bone turnover markers with weekly 56.5 μg teriparatide injections for 24 weeks were investigated in women with osteoporosis. Changes in bone turnover markers 24 h after each injection of teriparatide were constant. During the 24 week period, bone formation markers increased and baseline bone resorption marker levels were maintained. Introduction: This study aimed to clarify the changes in bone turnover markers during 24 weeks of once-weekly teriparatide injections in postmenopausal women with osteoporosis. Methods: The 24 h changes in pharmacokinetics (PK), calcium metabolism, and bone turnover markers (serum osteocalcin, procollagen type I N-terminal propeptide (P1NP), urinary cross-linked N-telopeptide of type I collagen (NTX), deoxypiridinoline (DPD)) after each injection of 56.5 μg teriparatide at the data collection weeks (0, 4, 12, and 24 weeks) were investigated. The changes were evaluated by comparison with the data at 0 h in each data collection week. Results: Similar 24 h changes in each parameter after injection of teriparatide were observed in each data collection week. Serum calcium increased transiently, and intact PTH decreased 4-8 h after injection; serum calcium subsequently returned to baseline levels. Calcium and intact PTH levels decreased for 24 weeks. Although serum osteocalcin decreased at 24 h, it was significantly increased at 4 weeks. P1NP decreased transiently and then increased significantly at 24 h. P1NP was significantly increased at 4 weeks. Urinary NTX and DPD were significantly increased transiently and then decreased at 24 h. The urinary DPD level decreased significantly at 4 weeks. Conclusions: Twenty-four hour changes in PK, calcium metabolism, and bone turnover markers showed the same direction and level after once-weekly teriparatide injections for 24 weeks, with no attenuation of the effect over time. After 24 weeks, the bone formation marker, serum osteocalcin, increased significantly, but the serum P1NP, did not. Bone resorption markers decreased or remained the same. © 2013 The Author(s).


Shiraki M.,Research Institute and Practice for Involutional Diseases | Sugimoto T.,The University of Shimane | Nakamura T.,University of Occupational and Environmental Health Japan
Osteoporosis International | Year: 2013

This study investigated the effects of a single administration of teriparatide on bone turnover markers in postmenopausal women. Teriparatide caused a transient increase in bone resorption and inhibition of bone formation followed by a subsequent increase in bone formation and a decrease in resorption that lasted at least 1 week. Introduction: This study aims to investigate the effects of a single subcutaneous administration of teriparatide on bone turnover markers to elucidate why once weekly intermittent administration of teriparatide is effective on osteoporosis. Methods: Pharmacokinetics and calcium metabolism and bone turnover parameters were measured in 30 postmenopausal women after two doses of teriparatide (28.2 or 56.5 μg injection) or placebo in a randomized, double-blind, placebo-controlled study. Results: Teriparatide plasma concentration increased in a dose-dependent manner, and the maximum concentration was achieved 1 h after injection. Serum levels of calcium and phosphorus were transiently increased and decreased after teriparatide injection, respectively. Calcium metabolism returned to baseline levels 24 h later. Two days after injection, the serum level of 1,25-dihydroxy vitamin D was increased by ~80 % from baseline for both doses of teriparatide. Serum levels of osteocalcin and procollagen type I N-terminal propeptide decreased during the first 24 h followed by a ~10 % increase for 14 days. The serum level of cross-linked N-telopeptide (NTX) of type I collagen increased during the first 24 h followed by a 10 to 12 % dose-dependent suppression from baseline for 14 days. Urinary cross-linked C-telopeptide of type I collagen changes occurred in the same direction as serum NTX, but not dose dependently. Conclusion: A single administration of teriparatide caused an immediate, transient increase in bone resorption and inhibited bone formation followed by an increase in bone formation and decrease in resorption for ≥1 week. These findings may provide proof for the effect of a once-weekly regimen of teriparatide on bone turnover. © 2012 The Author(s).


Ito M.,Nagasaki University | Nakamura T.,University of Occupational and Environmental Health Japan | Fukunaga M.,Kawasaki Medical School | Shiraki M.,Research Institute and Practice for Involutional Diseases | Matsumoto T.,Tokushima University
Bone | Year: 2011

The effects of an active vitamin D analog, eldecalcitol (ELD), on bone mineral density (BMD), bone geometry, and biomechanical properties of the proximal femur were investigated by using clinical CT. The subjects - a subgroup of a recent randomized, double-blind study comparing anti-fracture efficacy of ELD with alfacalcidol (ALF) - constituted 193 ambulatory patients with osteoporosis (189 postmenopausal women and 4 men aged 52-85. years, average. ± SD: 70.9. ± 6.92. years) enrolled at 11 institutions. Multidetector-row CT data was acquired at baseline and at completion of 144. weeks' treatment. Cross-sectional densitometric and geometric parameters of the femoral neck were derived from three-dimensional CT data. Biomechanical properties including cross-sectional moment of inertia (CSMI), section modulus (SM) and buckling ratio (BR) of the femoral neck, and CSMI of the femoral shaft were also calculated. We found that, 1) with respect to the femoral neck cross-sectional parameters (total bone), in the ALF group, volumetric BMD (vBMD) decreased but bone mass was maintained and cross-sectional area (CSA) increased. In contrast, ELD maintained vBMD with a significant increase in bone mass and a trend toward increased CSA. 2) With respect to the femoral neck cross-sectional parameters (cortex), cortical thickness decreased in the ALF group, but was maintained in the ELD group. In the ALF group, vBMD and bone mass increased, and CSA was maintained. In the ELD group, vBMD, CSA, and bone mass increased. 3) With respect to the biomechanical properties of the femoral neck, ELD improved CSMI and SM to a greater extent than did ALF. BR increased in both the ALF and ELD groups. 4) With respect to the femoral shaft parameters, overall the results of bone geometry and CSMI of the femoral shaft were very consistent with the results for the femoral neck; however, cortical vBMD of the femoral shaft decreased significantly in both the ELD and ALF groups. In conclusion, our longitudinal analysis of hip geometry by clinical CT revealed the unexpected potential of ELD to increase cortical CSA, vBMD, and bone mass, and to maintain cortical thickness, probably through the more potent effect of ELD in mitigating endocortical bone resorption than ALF. By improving the biomechanical properties of the proximal femur, ELD may have the potential to reduce the risk of hip fractures. © 2011 Elsevier Inc.

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