Association between Reduction of Muscle Mass and Faster Declines in Global Cognition among Older People: A 4-Year Prospective Cohort Study.

OBJECTIVES: A few studies reported that both decrease and increase in body mass index (BMI) were associated with the development of dementia in later life. However, it is unclear what changes in body composition are associated with cognitive decline. This study investigated the longitudinal influences of changes in body composition on cognitive function among community-dwelling adults. DESIGN, SETTING AND PARTICIPANTS: This longitudinal study included older adults aged ≥60 years without cognitive impairment who participated in National Institute for Longevity Sciences - Longitudinal Study of Aging. MEASUREMENTS: Cognitive function was assessed using the MMSE. Body composition was measured by a dual-energy X-ray absorptiometry system. Then, BMI, fat mass index (FMI), fat-free mass index (FFMI), and muscle mass index (MMI) were calculated. The changes in body composition over 6 years (second wave to fifth wave) were calculated, and three groups were created: decreased group, decrease of >5%; stable group, change within 5%, and increased group, increase of >5%. In statistical analysis, a linear mixed model was applied by sex to investigate the influences of body composition changes on cognitive function over 4 years (fifth wave to seventh wave). RESULTS: This study analyzed 515 participants (mean age, 67.05 years; 53.4% men). Men with decreased group in FFMI and MMI exhibited faster declines in MMSE scores than those with stable group (ß [95% CI]: FFMI, -0.293 [-0.719 to -0.020]; MMI, -0.472 [-0.884 to -0.059]). In women, there was no significant association between body composition changes and cognitive functions. CONCLUSIONS: Decrease in fat-free mass and muscle mass is associated with faster cognitive declines in men. These results suggest the importance of continuous monitoring of muscle mass to prevent cognitive decline in later life.

Safety Profile of the Concomitant Use of Atorvastatin and Cyclosporine in Renal Transplant Recipients.

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.

Cross-Sectional Associations of Sarcopenia and Its Components with Neuropsychological Performance among Memory Clinic Patients with Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: The association of sarcopenia with cognitive function in its specific domains remains poorly understood. OBJECTIVES: To investigate the association of sarcopenia and its components with neuropsychological performance among patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). DESIGN: Cross-sectional design. SETTING: A memory clinic in Japan. PARTICIPANTS: The study included 497 MCI/684 AD patients aged 65-89 years. MEASUREMENTS: Patients were assessed for muscle mass by bioelectrical impedance analysis, muscle strength by hand grip strength (HGS), and physical performance by timed up and go test (TUG). Sarcopenia was defined as presence of both low muscle strength and low muscle mass. The patients underwent neuropsychological tests, including logical memory, frontal lobe assessment battery, word fluency test, Raven's colored progressive matrices, digit span, and the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog). RESULTS: The prevalence of sarcopenia in men and women was 24.1% and 19.5%, respectively. In multiple regression analyses adjusting for confounders, unlike in men, sarcopenia was associated with memory function in women (ADAS-cog, memory domain, coefficient = 1.08, standard error (SE) = 0.36), which was thought likely due to the relationship between HGS and memory function (immediate recall of logical memory, coefficient = 0.07, SE = 0.03; ADAS-cog, memory domain, coefficient = -0.10, SE = 0.03). Of the components of sarcopenia in both sexes, HGS and TUG were associated with visuospatial function and frontal lobe function, respectively. CONCLUSIONS: The specific association of sarcopenia and its components with cognitive domains may provide the key to elucidating the muscle-brain interactions in AD.

Characteristics of gut microbiome, organic acid profiles and viral antibody indexes of healthy Japanese with live Lacticaseibacillus detected in stool.

To estimate the health-promoting effects of Lacticaseibacillus paracasei (previously Lactobacillus casei) strain Shirota (LcS) that reached the lower gastrointestinal tract alive, we investigated the characteristics of gut microbiome, organic acid profiles, defecatory symptoms and serum viral antibody indexes of healthy Japanese adults between the group in whom live LcS was detected or not from stool. The ß-diversity index of the gut microbiome constituted a significant difference between the live-LcS-detected-group (LLD) and the live-LcS-not-detected-group (LLnD). In the LLD, the Bifidobacteriaceae, Lactobacillaceae, and Coriobacteriaceae counts were significantly higher, and the succinate concentration was significantly lower than that in the LLnD. The serum herpes simplex virus (HSV) immunoglobulin (Ig)M antibody index in the LLD tended to be lower than that of the LLnD in HSV IgG-positive subjects. Of the LLD, those in the fermented milk products containing LcS (FML)-high-frequency-group (FML-HF) and those in the FML-low-frequency-group (FML-LF) had different gut microbiome and organic acid profiles. However, the pattern of differences between FML-HF and FML-LF was dissimilar those between LLD and LLnD. In contrast, among subjects with FML-LF, those in the group with LLD in stool (LF-LLD) and those in the LLnD in stool (LF-LLnD) showed a similar pattern of differences in their gut microbiome and organic acid profiles as those in the LLnD and LLD. The LLD and LF-LLD commonly had lower caloric and carbohydrate intakes from the diet than their respective control groups. In this study, we found that the presence of live LcS in stool is associated with a healthy gut environment and inhibition of the reactivation of latently infected viruses in the host. However, these health-promoting effects on the host were not related to the frequency of FML intake. Furthermore, dysbiosis of the gut microbiome and diet including caloric intake was related to the viability of ingested LcS in the gut.

The Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT): The Study Protocol for an 18-Month, Multicenter, Randomized, Controlled Trial.

BACKGROUND/OBJECTIVES: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. DESIGN/SETTING: Eighteen-month, multi-centered, randomized controlled trial. PARTICIPANTS: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. INTERVENTION: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. MEASUREMENTS: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. CONCLUSIONS: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.

Observation of nuclear-spin Seebeck effect.

Thermoelectric effects have been applied to power generators and temperature sensors that convert waste heat into electricity. The effects, however, have been limited to electrons to occur, and inevitably disappear at low temperatures due to electronic entropy quenching. Here, we report thermoelectric generation caused by nuclear spins in a solid: nuclear-spin Seebeck effect. The sample is a magnetically ordered material MnCO3 having a large nuclear spin (I = 5/2) of 55Mn nuclei and strong hyperfine coupling, with a Pt contact. In the system, we observe low-temperature thermoelectric signals down to 100 mK due to nuclear-spin excitation. Our theoretical calculation in which interfacial Korringa process is taken into consideration quantitatively reproduces the results. The nuclear thermoelectric effect demonstrated here offers a way for exploring thermoelectric science and technologies at ultralow temperatures.

A randomized, controlled trial of once-weekly teriparatide injection versus alendronate in patients at high risk of osteoporotic fracture: primary results of the Japanese Osteoporosis Intervention Trial-05.

In this randomized, controlled trial, treatment with once-weekly subcutaneous injection of teriparatide for 72 weeks was found to be associated with a significant reduction in the incidence of morphometric vertebral fractures compared with alendronate in women with primary osteoporosis who were at high risk of fracture. INTRODUCTION: To determine whether the anti-fracture efficacy of teriparatide is superior to that of alendronate, a prospective, randomized, open-label, blinded-endpoint trial was performed. METHODS: Japanese women aged at least 75 years were eligible for the study if they had primary osteoporosis and were at high risk of fracture. Patients were randomly assigned in a 1:1 ratio to receive sequential therapy (once-weekly subcutaneous injection of teriparatide 56.5 µg for 72 weeks followed by alendronate for 48 weeks) or monotherapy with alendronate for 120 weeks. The primary endpoint was the incidence of morphometric vertebral fractures at 72 weeks (at the end of teriparatide treatment). RESULTS: Between October 2014 and December 2017, 1011 patients (505 in the teriparatide group and 506 in the alendronate group) were enrolled. Of these, 778 patients (351 and 427, respectively) were included in the primary analysis. The incidence of morphometric vertebral fractures was significantly lower in the teriparatide group (56 per 419.9 person-years, annual incidence rate 0.1334) than in the alendronate group (96 per 553.6 person-years, annual incidence rate 0.1734), with a rate ratio of 0.78 (95% confidence interval 0.61 to 0.99, P = 0.04). In both groups, adverse events were most frequently reported in the following system organ classes: infections and infestations, gastrointestinal disorders, and musculoskeletal and connective tissue disorders. CONCLUSION: Once-weekly subcutaneous injection of teriparatide significantly reduced the incidence of morphometric vertebral fractures compared with alendronate in women with primary osteoporosis who were at high risk of fracture. TRIAL REGISTRATION: jRCTs031180235 and UMIN000015573, March 12, 2019.

Study of twice-weekly injections of Teriparatide by comparing efficacy with once-weekly injections in osteoporosis patients: the TWICE study.

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 .

Assessment using serum insulin-like growth factor-I and bone mineral density is useful for detecting prevalent vertebral fractures in patients with type 2 diabetes mellitus.

Bone mineral density (BMD) is less useful for evaluating fracture risk in type 2 diabetes. This study showed for the first time that combined evaluation by serum insulin-like growth factor-I and BMD is useful to assess the risk of vertebral fracture in postmenopausal women and men with type 2 diabetes. INTRODUCTION: BMD is less useful for evaluating fracture risk in type 2 diabetes mellitus (T2DM). We aimed to examine the usefulness of combined evaluation by BMD and serum insulin-like growth factor-I (IGF-I) to assess the risk of vertebral fracture (VF) in T2DM. METHODS: In this cross-sectional study, 412 postmenopausal women and 582 men with T2DM, whose BMD, bone turnover markers, and serum IGF-I were measured, were enrolled. The association of BMD alone, serum IGF-I alone, and combined assessment by BMD and IGF-I with the presence of VF was examined. RESULTS: Multiple logistic regression analyses showed that IGF-I as well as BMD T-score at lumbar (L) and femoral neck (FN) were significantly associated with VF except for IGF-I in men, respectively. Receiver operating characteristic curves showed that the cutoff values of IGF-I, L T-score and FN T-score were 127 ng/mL, - 1.78, and - 2.02 in postmenopausal women and 127 ng/mL, - 1.67, and - 1.24 in men. Based on the cutoff vales, the subjects were divided into four categories. The category of lower IGF-I and lower T-scores had a significant increased risk of VF compared to higher IGF-I and higher T-scores both in postmenopausal women and in men. The sensitivity and specificity of the combined assessment to detect VF were better compared to using BMD alone or IGF-I alone. CONCLUSIONS: This is the first study to show that in addition to BMD measurement, the assessment using serum IGF-I is useful to estimate the prevalence of VF in patients with T2DM.

Cluster-Based Haldane State in an Edge-Shared Tetrahedral Spin-Cluster Chain: Fedotovite K_{2}Cu_{3}O(SO_{4})_{3}.

Fedotovite K_{2}Cu_{3}O(SO_{4})_{3} is a candidate of new quantum spin systems, in which the edge-shared tetrahedral (EST) spin clusters consisting of Cu^{2+} are connected by weak intercluster couplings forming a one-dimensional array. Comprehensive experimental studies by magnetic susceptibility, magnetization, heat capacity, and inelastic neutron scattering measurements reveal the presence of an effective S=1 Haldane state below T≅4 K. Rigorous theoretical studies provide an insight into the magnetic state of K_{2}Cu_{3}O(SO_{4})_{3}: an EST cluster makes a triplet in the ground state and a one-dimensional chain of the EST induces a cluster-based Haldane state. We predict that the cluster-based Haldane state emerges whenever the number of tetrahedra in the EST is even.

Metallic phase in stoichiometric CeOBiS2 revealed by space-resolved ARPES.

Recently CeOBiS2 system without any fluorine doping is found to show superconductivity posing question on its origin. Using space resolved ARPES we have found a metallic phase embedded in the morphological defects and at the sample edges of stoichiometric CeOBiS2. While bulk of the sample is semiconducting, the embedded metallic phase is characterized by the usual electron pocket at X point, similar to the Fermi surface of doped BiS2-based superconductors. Typical size of the observed metallic domain is larger than the superconducting correlation length of the system suggesting that the observed superconductivity in undoped CeOBiS2 might be due to this embedded metallic phase at the defects. The results also suggest a possible way to develop new systems by manipulation of the defects in these chalcogenides with structural instability.

Association between chronic musculoskeletal pain and executive function in community-dwelling older adults.

BACKGROUND: We examined the association of chronic musculoskeletal pain with executive function in community-dwelling older adults. METHOD: This cross-sectional study recruited 234 community-dwelling older adults in Japan (mean age: 72.7, women: 62.8%). Chronic musculoskeletal pain was defined as having moderate or more severe pain lasting ≥ 3 months. Executive function was assessed using the Digit Symbol Substitution Test (DSST), Trail Making Test (TMT) parts A and B, Letter Verbal Fluency Test (LVFT) and Category Verbal Fluency Test (CVFT). RESULTS: Prevalence of chronic musculoskeletal pain was 19% (n = 44). In the univariate analysis, the DSST and CVFT scores were significantly lower in the chronic musculoskeletal pain group than in the control group (DSST: chronic musculoskeletal pain group vs. control group, 40.2 vs. 45.4, respectively, p < 0.05; CVFT: 13.7 vs. 15.6, respectively, p < 0.05), whereas the TMT parts A and B and LVFT scores were not. The multivariate linear regression models adjusted for covariates showed that the chronic musculoskeletal pain group had significantly lower DSST (adjusted ß = -0.13, p < 0.05) and CVFT scores (adjusted ß = -0.17, p < 0.05) than the control group. CONCLUSION: Chronic musculoskeletal pain may interfere with the elements of executive function, processing speed and semantic fluency, in community-dwelling older adults. The association of chronic musculoskeletal pain with executive function requires further investigation. SIGNIFICANCE: Our results suggest an association between moderate-severe chronic musculoskeletal pain and impairments of semantic fluency and processing speed in community-dwelling older adults.

Treatment responses with once-weekly teriparatide therapy for osteoporosis.

UNLABELLED: Monitoring bone mineral density is useful to assess treatment response for osteoporosis, but it does not always reflect fracture prevention. Two types of bone mineral density thresholds were used to analyze data from a once-weekly teriparatide trial, and they appear to be useful indicators of treatment success for osteoporosis. INTRODUCTION: This study aimed to clarify whether the criteria of treatment response could be used to evaluate treatment success with once-weekly teriparatide. METHODS: The data of subjects whose lumbar or femoral neck bone mineral density (BMD) was measured in the TOWER study were included. The least significant change (LSC) and the absolute change were used as the criteria for judgment of treatment success. The correlation between the incidence of fractures and the treatment response was also assessed. RESULTS: There was no significant difference in baseline characteristics between the placebo and teriparatide groups. Once-weekly teriparatide therapy for 72 weeks showed treatment success in 79.2 % of the subjects for lumbar BMD and 44.1 % for femoral neck BMD by LSC and in 50.5 and 39.6 % by absolute change, respectively. A lower incidence of vertebral fracture was observed in patients who achieved treatment success for lumbar BMD. With the LSC, some treatment success was observed in the early phase of treatment, and it increased with treatment duration. CONCLUSIONS: It appears that the LSC could be used as a surrogate efficacy indicator at an earlier stage of treatment, and the absolute criterion of -2.5SD was confirmed as a useful marker of long-term treatment success.

Elevated Serum Pentosidine and Decreased Serum IGF-I Levels are Associated with Loss of Muscle Mass in Postmenopausal Women with Type 2 Diabetes Mellitus.

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 (ß=-0.27, p=0.018) and marginally with muscle mass of legs (ß=-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.

The effect of RE substitution in layered REO(0.5)F(0.5)BiS2: chemical pressure, local disorder and superconductivity.

We have studied the effect of RE substitution on the structure and the local atomic disorder in REO0.5F0.5BiS2 (RE = rare-earth) to understand their correlation with the bulk superconductivity in these materials. The mean RE size, affecting the chemical pressure, has been varied in two series namely Ce1-xNdxO0.5F0.5BiS2 and Nd1-ySmyO0.5F0.5BiS2. The lattice parameters evolve anomalously, showing an anisotropic shrinkage (elongation) of the c-axis (a-axis) to an isotropic expansion of the lattice with increasing mean RE size. The Bi L3-edge extended X-ray absorption fine structure (EXAFS) measurements are performed to investigate local displacements in the BiS2 lattice, revealing a large disorder and a sharp boundary between the Ce-containing and Sm-containing series with a distinct local structure. The results suggest that the bulk superconductivity in REO0.5F0.5BiS2 is correlated with anomalous atomic displacements in the Bi-S1 network, likely to be a combined effect of active Bi 6s electronic states and a possible Jahn-Teller-like instability of the Bi 6px/6py electrons.

Efficacy of weekly teriparatide does not vary by baseline fracture probability calculated using FRAX.

UNLABELLED: The aim of this study was to determine the efficacy of once-weekly teriparatide as a function of baseline fracture risk. Treatment with once-weekly teriparatide was associated with a statistically significant 79 % decrease in vertebral fractures, and in the cohort as a whole, efficacy was not related to baseline fracture risk. INTRODUCTION: Previous studies have suggested that the efficacy of some interventions may be greater in the segment of the population at highest fracture risk as assessed by the FRAX® algorithms. The aim of the present study was to determine whether the antifracture efficacy of weekly teriparatide was dependent on the magnitude of fracture risk. METHODS: Baseline fracture probabilities (using FRAX) were computed from the primary data of a phase 3 study (TOWER) of the effects of weekly teriparatide in 542 men and postmenopausal women with osteoporosis. The outcome variable comprised morphometric vertebral fractures. Interactions between fracture probability and efficacy were explored by Poisson regression. RESULTS: The 10-year probability of major osteoporotic fractures (without BMD) ranged from 7.2 to 42.2 %. FRAX-based hip fracture probabilities ranged from 0.9 to 29.3 %. Treatment with teriparatide was associated with a 79 % (95 % CI 52-91 %) decrease in vertebral fractures assessed by semiquantitative morphometry. Relative risk reductions for the effect of teriparatide on the fracture outcome did not change significantly across the range of fracture probabilities (p = 0.28). In a subgroup analysis of 346 (64 %) participants who had FRAX probabilities calculated with the inclusion of BMD, there was a small but significant interaction (p = 0.028) between efficacy and baseline fracture probability such that high fracture probabilities were associated with lower efficacy. CONCLUSION: Weekly teriparatide significantly decreased the risk of morphometric vertebral fractures in men and postmenopausal women with osteoporosis. Overall, the efficacy of teriparatide was not dependent on the level of fracture risk assessed by FRAX in the cohort as a whole.

Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT).

SUMMARY: A 12-month extension phase of DIRECT in Japanese subjects with osteoporosis showed that total 3 years of denosumab treatment in Japanese postmenopausal women and men with osteoporosis was associated with low fracture rates, persistent bone turnover marker (BTM) reductions, continuous bone mineral density (BMD) increases, and a favorable overall benefit/risk profile. INTRODUCTION: The DIRECT trial demonstrated that 2 years of treatment with denosumab 60 mg subcutaneously every 6 months significantly reduced the incidence of vertebral fracture compared to placebo in Japanese postmenopausal women and men with osteoporosis. The purpose of this study is to evaluate the efficacy and safety of denosumab treatment for up to 3 years. METHODS: This study includes a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase in which all subjects received denosumab. The data correspond to 3 years of denosumab treatment in subjects who received denosumab (long-term group) and 1 year of denosumab treatment in subjects who received placebo (cross-over group) in the double-blind phase. RESULTS: Eight hundred and ten subjects who completed the double-blind phase enrolled into the extension phase, and 775 subjects completed the study. All subjects received denosumab with daily supplements of calcium and vitamin D. The cumulative 36-month incidences of new or worsening vertebral fractures and new vertebral fractures were 3.8 and 2.5 %, respectively, in the long-term group. In this group, the BMD continued to increase, and the reduction in BTMs was maintained. In the cross-over group, comparable BMD increases and BTMs reductions to those of in their first year of the long-term group were confirmed. Adverse events did not show a notable increase with long-term denosumab administration. One event of osteonecrosis of the jaw occurred in the cross-over group. CONCLUSIONS: Three-year denosumab treatment in Japanese subjects with osteoporosis showed a favorable benefit/risk profile.

Determination of local atomic displacements in CeO(1-x)F(x)BiS2 system.

We have used Bi and Ce L3-edges extended x-ray absorption fine structure measurements to study local structure of CeO(1-x)F(x)BiS2 system as a function of F-substitution. The local structure of both BiS2 active layer and CeO1-xFx spacer layer changes systematically. The in-plane Bi-S1 distance decreases (ΔRmax ∼ 0.08 Å) and the out-of-plane Bi-S2 distance increases (ΔRmax ∼ 0.12 Å) with increasing F-content. On the other hand, the Ce-O/F distance increases (ΔRmax ∼ 0.2 Å) with a concomitant decrease of the Ce-S2 distance (ΔRmax ∼ 0.15 Å). Interestingly, the Bi-S1 distance is characterized by a large disorder that increases with F-content. The results provide useful information on the local atomic displacements in CeO(1-x)F(x)BiS2, that should be important for the understanding of the coexistence of superconductivity and low temperature ferromagnetism in this system.