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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 | 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.

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.

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).

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