Summary
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.
Summary
Although previous studies indicated that serum insulin-like growth factor-I (IGF-I) was inversely associated with the presence of vertebral fractures (VFs), little is known whether serum ...IGF-I is associated with multiple VFs. We report that serum IGF-I could be clinically useful for assessing the severity of VFs in type 2 diabetic postmenopausal women.
Introduction
The number of VFs is associated with the mobility and mortality of the elderly people. Although serum IGF-I is inversely associated with the presence of VFs, little is known about the relationship between serum IGF-I and multiple VFs.
Methods
In this cross-sectional study, we recruited 479 men and 334 postmenopausal women with type 2 diabetes mellitus and measured serum IGF-I, bone mineral density, and bone turnover markers. Lateral X-ray films of the thoracic and lumbar spine were taken to diagnose the VF.
Results
In postmenopausal women, serum IGF-I level was decreased when the number of VFs was increased no VFs; 138 ± 51 ng/ml (mean ± SD) vs. one VF; 119 ± 42 (
p
= 0.006), two VFs; 103 ± 39 (
p
= 0.002), and three and more VFs; 91 ± 40 (
p
< 0.001). Multiple logistic regression analysis adjusted for age, duration of diabetes, body mass index, serum creatinine, and HbA
1c
showed that serum IGF-I level was inversely associated with the presence of one VF odds ratio (OR) = 0.67,
p
= 0.029, two VFs (OR = 0.40,
p
= 0.017), as well as three and more VFs (OR = 0.27,
p
= 0.005). These associations were still significant after the additional adjustment for BMD at the lumbar spine. In contrast, no significant association of serum IGF-I level with VFs was found in men.
Conclusions
Serum IGF-I level was inversely associated with the number of prevalent VFs in postmenopausal women with type 2 diabetes, suggesting that serum IGF-I could be clinically useful for assessing the severity of VFs in the population.
Summary
A 48-week, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial (the TWICE study) conducted in Japanese primary osteoporosis patients with a high risk ...of fractures demonstrated that a 28.2-μg twice-weekly regimen of teriparatide can provide comparable efficacy to a 56.5-μg once-weekly regimen of teriparatide, while also improving safety.
Introduction
While a 56.5-μg once-weekly regimen of teriparatide has high efficacy for osteoporosis, treatment continuation rates are low, with one of the major causes being adverse drug reactions such as nausea or vomiting. The TWICE study was therefore conducted to investigate whether a twice-weekly regimen with 28.2-μg teriparatide can provide comparable efficacy to the 56.5-μg once-weekly regimen while improving safety.
Methods
A 48-week, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial was conducted in Japan. Patients with primary osteoporosis aged ≥ 65 years at high risk of fractures (
n
= 553) were randomly allocated to the 28.2-μg twice-weekly group (
n
= 277) or the 56.5-μg once-weekly group (
n
= 276). The primary endpoint was the percentage change in lumbar spine (L2–L4) bone mineral density (BMD) at final follow-up.
Results
The percentage changes in lumbar spine (L2–L4) BMD at final follow-up in the 28.2-μg twice-weekly and 56.5-μg once-weekly groups were 7.3% and 5.9%, respectively; the difference (95% confidence interval CI) in percentage change was 1.3% (0.400–2.283%). Since the lower limit of the 95% CI was above the pre-specified non-inferiority margin (− 1.6%), non-inferiority of the 28.2-μg twice-weekly group was demonstrated. Adverse drug reactions were significantly less frequent in the 28.2-μg twice-weekly group (39.7% vs 56.2%;
p
< 0.01); the incidence of major adverse drug reactions was lower, and the number of subjects who discontinued due to adverse drug reactions was less in the 28.2-μg twice-weekly group.
Conclusions
A 28.2-μg twice-weekly regimen of teriparatide can provide comparable efficacy to a 56.5-μg once-weekly regimen while improving safety.
Clinical trial registration
JapicCTI-163477
.
Cyclosporine (CyA) and atorvastatin (AT) are often administered concomitantly to treat dyslipidemia in renal transplant recipients. However, CyA greatly increases the plasma concentration of AT; ...therefore, concomitant use might increase the frequency of statin-induced adverse effects. The aim of this study was to investigate whether concomitant use of CyA and AT increases intolerance of the latter agent in Japanese renal transplantation recipients. We performed a retrospective cohort analysis of renal transplant recipients aged 18 years and older who had concomitantly received AT and CyA, or tacrolimus (Tac) therapy. We defined statin intolerance as a decrease in dose or discontinuation of AT due to adverse effects. We evaluated the incidence of statin intolerance in concomitant therapy with CyA for 100 days after the initial administration of AT in comparison with Tac. A total of 144 renal transplant recipients who received AT and CyA, or Tac between January 2013 and December 2019 were included. There was no statistical difference in the incidence of statin intolerance in both the CyA (1.8%; 1/57 patients) and Tac (3.4%; 3/87 patients) groups. Concomitant use of CyA and AT might not increase the incidence of statin intolerance in Japanese renal transplant recipients.
Abstract
The upgrade of the beam power of J-PARC Main Ring to 750 kW by reducing the cycle from 2.48 s to 1.3 s is underway, and the upgrade of the four high-field (HF) septa will be completed by ...summer of 2023. The operation test of one HF septum, SM31, was conducted in 2020. First trial was 1 Hz operation test, and we confirmed the joule heating at the magnetic coil was lower than limit. Second was magnetic field measurement. We obtained a good linearity between the applied current and the gap field without saturation. The field integral of the gap field was measured to estimate the optimal current for beam extraction, and we found it is 3,400 A. We compared the gap field between in the neutrino line and that in the beam abort line, then we found the longitudinal distributions have a small discrepancy but it was acceptable. The large leakage field was observed around the end-fringes, therefore, in order to reduce the leakage field, we produced an additional duct shield for mounting in the circulating duct in 2022. We verified that the additional duct shield reduced the leakage field to ≈2% of unshielded leakage field. The new SM31 and other two HF septa have been installed in MR by end of May 2022. The beam operation with the new HF septa will be started in June 2022.
Abstract
As part of the goal of increasing the beam power of the Main Ring for Fast eXtraction (FX) in J-PARC to 750 kW, we have been evaluating new FX low-field septa of induced eddy current type ...(Eddy-septum) since 2014. To reduce the leakage field in the circulating line of the eddy-septa, new pure iron duct-type magnetic shields were produced in July 2021, and in March 2022 we verified that the leakage field was greatly reduced. The construction of the two eddy-septa and their power supplies was completed in May 2022. Beam operation with a new 1.3-s cycle will be started in June 2022.
Advanced glycation end-products (AGEs) play important roles in the progression of diabetic complications. Although sarcopenia is recently recognized as another complication associated with diabetes ...mellitus, its mechanism still remains unclear. In this study, we investigated the relationship between serum levels of pentosidine, which is one of AGEs, and insulin-like growth factor-I (IGF-I) vs. skeletal muscle mass by whole body dual-energy x-ray absorptiometry in 133 postmenopausal women with type 2 diabetes. Relative skeletal muscle mass index (RSMI) was calculated by following formula; appendicular skeletal muscle mass divided by height in meters squared. Simple correlation analyses showed that serum pentosidine levels were significantly and negatively correlated with muscle mass of legs (r=-0.21, p=0.017) and RSMI (r=-0.18, p=0.022), and that IGF-I was significantly and positively correlated with muscle mass of arms and legs (r=0.23, p=0.008 and r=0.30, p=0.001, respectively) as well as RSMI (r=0.20, p=0.022). Moreover, after adjusting for age, duration of diabetes, serum creatinine, HbA1c, and IGF-I, pentosidine was significantly and negatively associated with RSMI (β=-0.27, p=0.018) and marginally with muscle mass of legs (β=-0.18, p=0.071). The associations between IGF-I and indices of muscle mass such as arms, legs and RSMI were still significant after additional adjustment for pentosidine (p=0.016, 0.019 and 0.021, respectively). These findings indicate that increased serum pentosidine and decreased IGF-I are independent risk factors for loss of muscle mass in postmenopausal women with type 2 diabetes.
Abstract
As part of the effort to increase the beam power of the Main Ring (MR) for fast extraction (FX) in J-PARC to 750 kW, five new septum magnets for FX (FX-septa) were installed in the MR in ...2022. The most significant goal for the magnets was to achieve an extremely low leakage field in the circulating line. To realize the low leakage field, new pure iron duct-type magnetic shields were mounted in the circulating ducts of the two high-field FX-septa in 2022. In July 2022, we verified that the impact of the leakage field of all of the FX-septa on the 3-GeV circulating beam was below 10% of that of the previous FX-septa. We also measured the leakage field in the circulating ducts of the two high-field FX-septa with new shields in October 2022, and confirmed that the quadrupole field component was reduced to ≈1% of that of the previous high-field FX-septa.
Summary
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.
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