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In a clinical trial involving Japanese patients with osteoporosis, post hoc analyses were performed to evaluate the incidence of acute phase reactions (APRs) after infusion of zoledronic acid (ZOL). The results highlighted differences in baseline factors between patients with vs without APRs. Changes in efficacy indicators such as bone turnover markers (BTMs) also showed significant differences. We, therefore, investigated the factors involved in the development of APRs in Japanese patients treated with a once-yearly intravenous infusion of ZOL 5 mg for 2 years by assessing the relation between APRs and efficacy. APRs reported in patients with primary osteoporosis from the ZONE study were analyzed post hoc. Baseline factors were compared in patients with vs without APRs, and changes in BTMs and bone mineral density (BMD) were also investigated. In the ZOL group, 51.2% (169/330) of patients developed APRs after the first infusion and 12.3% (33/268) after the second infusion. Comparison of baseline factors showed that patients without APRs in the ZOL group had a significantly higher neutrophil/lymphocyte ratio, lower serum levels of procollagen type I N-terminal propeptide, older age, and higher likelihood of prior bisphosphonate use vs patients with APRs. Patients with APRs showed significantly higher increases in total hip BMD at 6 and 12 months and larger reductions in BTMs vs patients without APRs. Patient profiles differed significantly between patients with vs without APRs, with APRs after the first infusion of ZOL being related to increases in total hip BMD and suppression of BTMs.This study is registered with ClinicalTrials.gov (identifier: NCT01522521; January 31, 2012).

To identify predictors for incident fractures in patients on pharmaceutical treatment for osteoporosis by a secondary analysis of the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04), which was a 2-year, randomized, parallel-group, controlled trial of minodronate and raloxifene in women with primary osteoporosis. This was a prospective, observational study using JOINT-04 data, in which biomarkers, such as undercarboxylated osteocalcin (ucOC), N-telopeptide of type 1 collagen, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase, homocysteine, and pentosidine in blood, and physical functions, such as the timed up and go test and one-leg standing test with eyes open (OLST), and the fall risk index, were measured. The relationships of incident morphometric vertebral fractures during the treatment period, as well as prevalent vertebral fractures, and baseline data were analyzed. The full analysis set of the JOINT-04 included 3247 patients (1623 in the minodronate group and 1624 in the raloxifene group). The hazard ratio (95% confidence interval) for incident vertebral fractures over 2 years of pharmacotherapy, adjusted for confounders, was 0.93 (0.90–0.96) for ucOC, 1.15 (1.08–1.23) for TRACP-5b, 1.02 (1.01–1.03) for pentosidine, 0.91 (0.88–0.94) for the OLST, and 1.27 (1.01–1.60) for the fall risk index, which were all independent predictors. Evaluating fracture risk for patients with osteoporosis considering these potential risk factors for fracture in addition to the established risk factors may be useful when starting pharmaceutical treatment.

BACKGROUND: Surgical manipulation of a tumor can lead to shedding of tumor cells that can enter the circulation and lead to metastasis. The present study evaluated the clinical relevance of circulating tumor cells (CTCs) that were identified immediately after non-small cell lung cancer resection in patients without preoperative CTCs, and whether postoperative CTC detection was associated with recurrence. METHODS: Immediate preoperative testing for CTCs was performed for 147 patients with pulmonary nodules. This study included 81 lung cancer patients (55.1%) with negative preoperative results for CTCs and who completed postoperative testing for CTCs. The clinical relevance of postoperative CTC detection was evaluated based on the clinicopathological characteristics and recurrence patterns. RESULTS: Among the eligible patients, the postoperative CTC results were none detected in 58 patients (71.6%, “Group N”), only a single CTC detected in 6 patients (7.4%, “Group S”), and CTC clusters detected in 17 patients (21.0%, “Group C”). The presence of postoperative CTCs was associated with tumor vessel invasion, lymph duct invasion, and pleural invasion. Distant metastasis was very common in cases with postoperatively detected CTC clusters. The 2-year recurrence-free survival rates were 94.6% for Group N, 62.5% for Group S, and 52.9% for Group C (P

In this post hoc analysis of the Denosumab Fracture Intervention Randomized Placebo-Controlled Trial (DIRECT) in Japanese postmenopausal women and men with osteoporosis, we evaluated the relationship between vertebral fracture risk and both bone mineral density (BMD) T-score and percent change after 24 months of denosumab treatment at total hip, femoral neck, and lumbar spine. Logistic regression analysis was performed and the proportion of treatment effect explained by BMD in vertebral fracture risk was estimated. The results demonstrate that both total hip BMD T-score and change can be strong predictors of subsequent fracture risk, and that total hip BMD change explained 73%, while T-score explained 23%, of the treatment effect. In contrast, neither femoral neck BMD change nor T-score can predict the effect of denosumab on vertebral fracture risk. Furthermore, although lumbar spine BMD T-score was associated with vertebral fracture incidence, lumbar spine BMD change was inversely related to vertebral fracture risk. Because there was no relationship between lumbar spine BMD change and T-score at 24 months of denosumab treatment, and because there can be small undetectable vertebral deformities that may increase BMD values, these results suggest that lumbar spine BMD change is not a good surrogate for vertebral fracture risk assessment. It is suggested that both total hip BMD change and T-score can be good surrogates for predicting vertebral fracture risk in Japanese patients with osteoporosis under denosumab treatment. ClinicalTrials.gov identifier: NCT00680953.

Zoledronic acid (ZOL) as a yearly infusion is effective in reducing fracture risk. An acute-phase reaction (APR), consisting of flu-like symptoms within 3 days after infusion, is commonly seen. The objective of this analysis was to investigate whether APR occurrence influences drug efficacy. This analysis uses data from the 3-year randomized clinical trial, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). APRs were identified as adverse events within 3 days of first infusion with higher frequency in ZOL than placebo. To compare mean 3-year change in bone mineral density (BMD) in ZOL versus placebo, among women with and without APR, t tests were used. Logistic regression was used to examine the relationship between APR occurrence and odds of incident morphometric vertebral fracture. Cox regression was used to determine the risk of nonvertebral and hip fractures for women with versus without APR. Logistic and Cox models were used to determine the risk of incident fracture in ZOL versus placebo for women with and without an APR. The analysis included 3862 women in the ZOL group and 3852 in placebo, with 42.4% in ZOL versus 11.8% in placebo experiencing an APR. The difference in BMD mean change for ZOL versus placebo was similar for women with and without an APR (all p interaction >0.10). Among ZOL women, those with APR had 51% lower vertebral fracture risk than those without (odds ratio [OR] = 0.49, p

We prospectively assessed, with predefined criteria, the location and rates of all femur fractures (hip, subtrochanteric/femoral shaft [ST/FS], including atypical [AFF] and distal fractures) in women at increased fracture risk during treatment with the cathepsin K inhibitor, odanacatib (ODN), or placebo over 5 years in the Long-Term ODN Fracture Trial (LOFT and LOFT Extension [NCT00529373, EudraCT 2007-002693-66]). ODN was an investigational antiresorptive agent previously in development as an osteoporosis treatment that, unlike bisphosphonates, reduces bone formation only transiently. Women aged >= 65 years with a bone mineral density (BMD) T-score

Background: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on the risk of breast cancer recurrence. Methods: This prospective, randomised, multicentre open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients with stage I–IIIA hormone receptor-positive breast cancer who were disease-free after treatment with either 5 years of anastrozole alone or 2–3 years of tamoxifen followed by 2–3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole (1 mg/day orally) for an additional 5 years or stop anastrozole, using the central computer at the Comprehensive Support Project for Oncology Research Data Centre. Randomisation was stratified by type of postoperative endocrine therapy, nodal status, prior adjuvant chemotherapy, and facility. The primary endpoint was disease-free survival, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with UMIN clinical trials registry, number UMIN000000818. Findings: We enrolled 1697 patients from 117 facilities between November 2007 and November 2012. Patients were assigned randomly to the continue group (n=849) or the stop group (n=848). Follow-up information was available for 1593 patients (n=787 in the continue group, n=806 in the stop group) as the full analysis set. After a median follow-up of 5·1 years, there were 172 events involving disease recurrence or the occurrence of contralateral breast cancer (75 in the continue group and 97 in the stop group) and 40 deaths (21 in the continue group and 19 in the stop group). The 5-year disease-free survival rates were 91% (95% confidence interval [CI] 89–93) in the continue group and 86% (95% CI 83–88) in the stop group (hazard ratio [HR] for disease-free survival 0·61, 95% CI 0·46–0·82; p

As of 2015, the aging population in Japan was the largest in the world. Although the National Database of Health Insurance Claims (NDB) was developed in 2012, long‐term trends regarding hip fracture incidence in Japan remain unclear. In order to clarify the trend in hip fracture incidence from 1992 to 2017, we estimated the number of new hip fractures in 2017, the seventh in a series of nationwide hip fracture surveys performed every 5 years since 1987. We also investigated regional differences in hip fracture incidence. We collected data through a nationwide mail‐in survey of orthopedic institutions in Japan and calculated hip fracture incidence by sex and age, as well as standardized incidence ratio (SIR) across 12 districts. The total number (95% confidence interval) of hip fractures in 2017 was estimated at 193,400 (187,300–199,500), occurring in 44,100 (42,700–45,500) males and 149,300 (144,500–154,100) females. Of all the hip fracture surveys from 1992 to 2017, the 5‐year hip fracture increase rates from 2012 to 2017 was the lowest among female patients. In males, the 5‐year rates from 2012 to 2017 were lower than those from 2007 to 2012. The age‐adjusted incidence rates for patients in both sexes did not show significant change in the 25‐year period. The estimated incidence rates in 2017 for patients aged 70 to 79 years in both sexes were lowest from 1992 to 2017, and declined significantly over the 25‐year period. SIRs differed between northeast and southwest regions. Our findings were similar to those from a previous study in Japan using the NDB from 2012 to 2015. Progress in the development of osteoporosis medication may contribute to the continuous decline in the 70‐year to 79‐year age group. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Backgroud Changes in bone mineral density (BMD) are a potential surrogate marker for fracture endpoints in clinical trials. However little is known whether the increase in BMD in response to combination treatment with alendronate plus alfacalcidol is associated with fracture risk reduction. We aimed to evaluate the impact of BMD on fracture risk in osteoporosis patients, using the data from the randomized clinical trial comparing alendronate plus alfacalcidol with alendronate alone. Methods We selected 412 patients with two or more prevalent vertebral fractures and who had BMD measurements at baseline and after 6, 12, and/or 24 months out of 2022 patients from the database of the Japanese Osteoporosis Intervention Trial. Patients in this subset who received combination treatment with alendronate plus alfacalcidol had shown a lower risk of fracture than patients treated with alendronate alone. We used Poisson regression model analysis to calculate the proportion of treatment effect (PTE) that was attributable to BMD increases in patients receiving combination treatment. Results The highest PTE attributable to changes in BMD was 1.2% in patients with a BMD increase of 3% or more in the lumbar spine. For BMD measurements of the radius, the highest PTE was 2.8% with a BMD increase of 0% or more. For BMD measurements of the metacarpal bone, the highest PTE was 1.2% with a BMD increase of 3% or more. In patients with a BMD greater than or equal to 70% of the young adult mean in the lumbar spine, the PTE attributable to BMD was 0.2%. In patients with a BMD greater than or equal to 70% of the young adult mean in the radius, the PTE attributable to BMD was 0.3%. Conclusions The additional effects of alfacalcidol in reducing fracture risk do not likely result from increased BMD; other mechanisms remain a possibility.

Very few reports have described changes in bone mineral density (BMD) with long-term, once weekly administration of elcatonin, and its effects in reducing incident fractures remain unverified. Therefore, the efficacy and safety of once weekly elcatonin were examined over a 3 year period.This was a multicenter, double-blinded, randomized, placebo-controlled study. Postmenopausal women with primary osteoporosis received either 20 units of elcatonin (EL group, n = 433) or placebo (P group, n = 436) once a week for 144 weeks (3 years) intramuscularly. The primary endpoint was the incidence of new vertebral fractures at 24, 48, 72, 96, 120, and 144 weeks after the start. Secondary endpoints were the incidence of non-vertebral fractures, changes in lumbar, hip total and femoral neck BMD, and the incidence of adverse drug reactions (ADRs).No significant reduction in the incidence of new vertebral fractures was found in the EL group. The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration. Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD, no significant differences were observed between groups. The incidence of ADRs was significantly greater in the EL group, although these have all been previously reported and no new safety concerns were identified.Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems, but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated.

The effects of zoledronic acid on hip structural and biomechanical properties were evaluated in Japanese patients with osteoporosis by computed tomography (CT). The subjects included in this study were a subset of female subjects (zoledronic acid group, 49 subjects; placebo group, 53 subjects) in the phase 3 trial (ZONE study) who were available for multi-detector row CT (MDCT) scanning. Eligible subjects were those diagnosed with primary osteoporosis based on the Diagnostic Criteria for Primary Osteoporosis (2000) by the Japanese Society for Bone and Mineral Research and who had between one and four fractured vertebrae located between the fourth thoracic vertebra and the fourth lumbar vertebra. The subjects received a once-yearly intravenous infusion of zoledronic acid 5 mg or placebo for two years. CT data were obtained at baseline and at 12 and 24 months later and analyzed under blinded conditions. The results demonstrated that once-yearly intravenous infusion of zoledronic acid improved volumetric bone mineral density (vBMD), cortical bone geometry parameters, and CT-derived biomechanical parameters at the femoral neck, intertrochanteric region, and shaft; particularly at the intertrochanteric region, significant improvements in cortical bone geometry parameters and CT-derived biomechanical parameters, compared with those in the placebo group, were detectable early, at 12 months. The present data suggest that zoledronic acid has a possibility to reduce the risk of hip fractures in Japanese patients with osteoporosis., Bone, 106, pp.179-186; 2018

Denosumab, a human monoclonal antibody against RANK ligand, is shown to have strong anti-fracture effects in Japanese osteoporosis patients. However, there have been no data showing actions on Japanese bone architecture. Here we show that denosumab continuously improves several geometrical parameters calculated by hip structural analysis for 3 years. Compared to placebo, denosumab significantly increased bone mineral density, cortical thickness and cross sectional area in all of the three analyzed areas: the narrow neck, intertrochanter and femoral shaft. The subsequent derived mechanical parameters, cross-sectional moment of inertia, section modulus and buckling ratio, were also improved by denosumab. In addition, the improvement of these parameters was also observed in the patients that had switched from placebo to denosumab treatment. The present study suggests the structural evidence explaining the strong anti-fracture efficacy of denosumab and its significant effects on cortical bone in Japanese., Highlights • Denosumab improves several HSA parameters including BMD and cortical thickness. • The improvement of HSA parameters continues at least 3 years. • The improvement of HSA parameters was observed in the patients that had switched from placebo to denosumab.

The non-inferiority of oral ibandronate 100 mg to intravenous (i.v.) ibandronate 1 mg in increasing lumbar spine (LS) bone mineral density (BMD) after 12 months of treatment was demonstrated in the randomized, phase III MOVEST study. We conducted subgroup analyses in the per-protocol set of the study (n = 183 oral ibandronate; n = 189 i.v. ibandronate). In patients with LS BMD T score ≥ –3.0 or < –3.0 at screening, LS BMD gains from baseline were 4.42 and 5.79%, respectively, with oral ibandronate, and 4.60 and 5.83%, respectively, with i.v. ibandronate. LS BMD gains in patients with or without prevalent vertebral fractures were 5.21 and 5.23%, respectively, with oral ibandronate, and 5.01 and 5.49%, respectively, with i.v. ibandronate. In patients aged

We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety. The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients’ quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433. A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78–1.13, p = .494), 0.86 (95% CI: 0.70–1.05, p = .147), and 1.22 (95% CI: 0.86–1.74, p = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p = .007, 12 months: p = .0003, 24 months: p Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

This randomized, clinical trial investigated whether zoledronic acid combined with oral health maintenance can improve periodontal disease associated with osteoporosis, thus reducing the risk of tooth loss.Participants were those of the ZONE (ZOledroNate treatment in efficacy to osteoporosis) study. None of the participants had symptomatic periodontal disease at baseline. Participants received either zoledronic acid (5 mg; n = 333 [male 21, female 312]) or placebo (n = 332 [male 19, female 313]) once yearly for 2 years, and their age was 74.0 ± 5.3 (65-88) and 74.3 ± 5.4 (65-87) years, respectively. Participants were instructed to maintain good oral hygiene at baseline and every 3 months. Participants with signs or symptoms involving their oral cavity at the monthly visit with their physician were referred to dentists for examination of oral disease. All cases were included to analyze adverse events in this study. Testing for significance was conducted using Fisher exact test (P 0.05).The incidence of oral adverse events was significantly higher in the control group (67 cases, 20.2%) than in the zoledronic acid group (47 cases, 14.1%; P = 0.04). The frequency of symptomatic periodontal disease observed during the study was significantly higher in the control group (40 cases, 12.0%) than in the zoledronic acid group (18 cases, 5.4%; P = 0.002). Loss of teeth was more frequent in the control group (36 cases, 10.8%) than in the zoledronic acid group (24 cases, 7.2%), although the difference was not significant.Zoledronic acid effectively prevented symptomatic periodontal disease in patients with osteoporosis who maintained good oral hygiene. : Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A438.

Although microsurgery is an established treatment modality for intracranial dural arteriovenous fistula (dAVF), data regarding the perioperative complication rate, cure rate, and long-term outcomes remain scarce. The aims of this study were to describe our original experience with microsurgery, including the surgical complications and pitfalls, and conduct a systematic review of the relevant literature. A multicenter cohort of patients with dAVF treated by microsurgery was retrospectively assessed. In addition, the PubMed database was searched for published studies involving microsurgery for dAVF, and the complication rate, cure rate, and long-term outcomes were estimated. The total number of patients in our multicenter series and published articles was 553 (593 surgeries). The overall rates of transient complications, permanent complications, death, and incomplete treatment were 11.4, 4.0, 1.2, and 6.5%, respectively. A favorable outcome was achieved for 90.1% patients, even though almost half of the patients presented with intracranial hemorrhage. Of note, the incidence of recurrence was only one per 8241 patient-months of postoperative follow-up. Surgeries for anterior cranial fossa dAVF were associated with a lower complication rate, whereas those for tentorial dAVF were associated with higher complication and incomplete treatment rates. The complication and incomplete treatment rates were lower with simple disconnection of cortical venous drainage than with radical occlusion/resection of dural shunts. Our findings suggest that the cure rate, complication rates, and outcomes of microsurgery for dAVF are acceptable; thus, it could be a feasible second-line treatment option for dAVF. However, surgeons should be aware of the specific adverse events of microsurgery.

Although once-yearly intravenous administration of zoledronic acid has been reported to inhibit bone resorption and increase bone mineral density, no studies have evaluated its effectiveness in treating osteoporosis in Japanese patients. Therefore, the purpose of this study was to investigate the pharmacokinetics and assess the safety of and changes in bone metabolism associated with zoledronic acid treatment in Japanese patients with primary osteoporosis. This was a single-administration study with a single-blind parallel-group design. The study participants were 24 Japanese patients with primary osteoporosis. The patients were divided into two groups, with each group receiving a single injection of zoledronic acid (4 or 5 mg). Pharmacokinetics and urinary excretion were then compared, and drug-related adverse events and changes in the levels of bone turnover markers were assessed at 12 months. Mean plasma concentrations of zoledronic acid peaked in both groups immediately after administration, and decreased to 1% or less of peak levels after 24 h. Noncompartmental analysis revealed that C max and the area under the curve from time zero to infinity increased in proportion to the dose. The levels of bone resorption and formation markers decreased from day 15 and from 3 months after administration respectively, and suppression of these markers remained constant for the entire study period. No serious adverse events were reported. There was no large difference between the 4- and 5-mg groups in terms of pharmacokinetics, changes in the levels of bone turnover markers, and safety profiles. This study demonstrated acceptable pharmacokinetics and changes in bone metabolism associated with zoledronic acid treatment in female Japanese osteoporosis patients. Both the 4-mg dose and the 5-mg dose demonstrated acceptable safety and sustained antiresorptive effects for the duration of the study.

Summary 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.

Currently, the only available evidence for the efficacy of once-weekly 17.5 mg risedronate in preventing vertebral fractures was obtained in a 48-week study in Japan. We performed a 156-week prospective, longitudinal, observational study to determine the efficacy of the 17.5 mg risedronate in preventing vertebral fractures. We included Japanese patients with established osteoporosis who were older than 50 years and had radiographically confirmed vertebral fractures. The primary endpoint was the incidence of vertebral fractures every 24 weeks, with the final interval spanning 36 weeks. We also calculated the change in bone mineral density of the lumbar spine (L2-4 BMD) and urinary N-telopeptide of type I collagen (u-NTX), and assessed the incidence of adverse drug reactions and the drug adherence rate. Data from 241 patients were available for analysis of vertebral fracture prevention. The incidence rate of vertebral fractures decreased in a time-dependent manner (P = 0.0006; Poisson regression analysis). The risk ratio (fracture incidence per 100 person-years in the final 36 weeks versus that in the first 24 weeks) was 0.21 (95 % confidence interval 0.08-0.55). Compared to baseline values, L2-4 BMD increased by 6.41 % at 156 weeks, while u-NTX decreased by 36 % at 24 weeks and was maintained thereafter (P

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 ± 3.93 ng/mL to 2.59 ± 1.52 ng/mL at 6 months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96 ± 4.36 ng/mL to 4.05 ± 3.40 ng/mL at 6 months) (p

This study examined patients’ risk profiles and adherence to treatment in relation to the effect of risedronate and raloxifene on hip fracture incidence. Administrative billing data were used to follow two cohorts of women aged 65 and older after starting therapy with either risedronate (n = 86,735) or raloxifene (n = 37,726). The fracture risk profile was described using a 6-month history period before starting therapy. Effectiveness of each therapy was evaluated by comparing the incidence of hip fractures during the first 3 months with the subsequent 12 months among women adherent (medication possession ratio >80%) compared with those non-adherent to treatment. At the start of therapy, the raloxifene cohort was younger than the risedronate cohort (median age 73 vs. 76 years) and had fewer prior fractures (p

We planned to conduct multi-center, open-labeled, blinded-endpoints, head-to-head randomized trial of minodronate and raloxifene to compare incidences of vertebral and non-vertebral fractures. The study is the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-4). Here, we present the pre-fixed study design. The inclusion criteria are ambulatory older women with osteoporosis, aged > 60 years, and without pre-specified risk factors for secondary osteoporosis and dementia. The subjects who meet selection criteria will be randomly allocated to the raloxifene (60 mg/day) or minodronate (1 mg/day or 50 mg/4 weeks) groups using the central registry. The co-primary endpoints are osteoporotic (vertebral, humeral, femoral, and radial), vertebral, and major osteoporotic (clinical vertebral, humeral, femoral, and radial) fractures. Furthermore, we plan to use the Hochberg procedure to preserve an overall type 1 error rate. In addition, changes in bone mineral density (BMD), hip-structure analysis (HSA) variables, height, bone turnover markers, serum cholesterol and triglyceride concentrations, dental health questionnaire, fall frequency, fall risk index, nursing care level, physical function, quality of life (QOL), and safety profiles were assessed as secondary endpoints. To detect 24% reduction of major osteoporotic fractures with 80% power and a two-sided significance level of 5% with a 2-year observation period, 1734 patients/treatment arm would be required. Subgroup analysis stratified to the following factors age, body mass index, BMD, 25-hydroxyvitamin D concentration, estimated glomerular filtration rate (eGFR), prevalent vertebral fracture number, hypertension status, and diabetes mellitus is pre-specified. The protocol is registered in the trial registry system, and the trial identification number is UMIN000005433.

We examined response to bone mineral density (BMD) gains in the MOVER study following treatment with intravenous (IV) ibandronate 1 mg/month, and investigated the characteristics of a non-responder group. At 1 year, responder rates for patients with BMD increases >0 % were similar with IV ibandronate 0.5 or 1 mg/month and oral risedronate 2.5 mg/day. However, after 3 years, responder rates with BMD increases ≥3 % were highest with ibandronate 1 mg at all bone sites (>80 % at the lumbar spine [L2-L4] and >50 % at all femur sites, which was significantly higher than with risedronate). Non-responders were defined by BMD increases ≤3 % at L2-L4 or ≤0 % at total hip, and ≤50 % reduction in creatinine-corrected urinary collagen type 1 cross-linked C-telopeptide (uCTX) from baseline to 1 year. There were a small number of non-responders in the ibandronate 1 mg group: 3.3 % (10/299) with ≤0 % total hip BMD increase and ≤50 % uCTX reduction from baseline. These non-responders had lower 25-hydroxyvitamin D (25[OH]D) levels than responders, but no differences in kidney function, L2-L4 BMD or bone turnover marker baseline values. Throughout the study, non-responders failed to show any increases in BMD. Our analysis demonstrates significantly higher responder rates with IV ibandronate 1 mg/month than with risedronate at 3 years. A small number of non-responders in the ibandronate group had lower 25(OH)D baseline levels than responders, suggesting that 25(OH)D levels could be a useful indicator of BMD response to therapy.

The frequency of hip fractures associated with aging of the population is declining in many countries. Even in Japan, where this frequency has been increasing continually, a shift to decreasing frequency has been noted in recent reports. The objective of this study was to investigate the effects of this decrease and to estimate the number of hip fracture patients and the resulting reduction in national medical care expenditures. The differences in the number of patients were estimated by multiplying the population for each sex and each age group by the fracture rates before the decrease (2007) and after the decrease (2012). Total reduced cost was calculated by multiplying the treatment cost required for hip fracture and the annual medical cost of nursing care. The estimated number of hip fracture patients decreased by approximately 4000 in the elderly female population, and the resulting reduction in medical costs was approximately US$280 million. The number of patients with hip fractures has decreased in elderly Japanese women; as a result, the medical costs for treatment and nursing care might decrease.

Summary Combined treatment with alendronate and eldecalcitol was found to be more effective in reducing the bone turnover markers and increasing bone mineral density than alendronate treatment with vitamin D3 and calcium supplementation in the osteoporotic patients. Introduction We compared the clinical efficacy and safety of combined treatment with alendronate plus eldecalcitol (ALN + ELD) with those of treatment with ALN plus vitamin D and calcium (ALN + VitD). Methods Osteoporotic 219 patients were randomly assigned to the ALN + ELD, or the ALN + VitD group. Primary endpoint was the inter-group differences in lumbar spine BMD (L-BMD) at patient’s last visit. Secondary endpoints included the differences in BMD at other sites and the bone turnover marker (BTM) levels. Results L-BMD, total hip BMD and femoral neck (FN-BMD) increased from baseline by 7.30, 2.41, and 2.70 % in the ALN + ELD group, and by 6.52, 2.27, and 1.18 % in the ALN + VitD group, respectively. Inter-group differences of the L-BMD and total hip BMD values were not significant. The increase of the FN-BMD was larger in the ALN + ELD group than the ALN + VitD group. Reductions of the BTMs were greater in the ALN + ELD group than the ALN + VitD group. Interaction of the percent increase of the L-BMD with the baseline values of the BTMs was observed in the ALN + VitD group only. The increases of the FN-BMD in patients with lower baseline values of type-I-collagen C-telopeptide (sCTX) and serum 25(OH) D levels

We investigated changes in quality of life (QOL), including pain, in Japanese women aged ≥ 55 years who were diagnosed as having osteoporosis at 265 centers across Japan and treated continuously with once-weekly bisphosphonates for 24 months. In 2650 evaluable patients, a significant improvement in QOL was observed from 3 months after enrollment onward and maintained throughout the 2-year observation period. A significant improvement in scores was observed for all domains of the Euro QOL 5 Dimension (EQ-5D), and the “pain”, “health perception”, and “posture, figure” domains of the Japanese Osteoporosis QOL Questionnaire (JOQOL). Factors identified as significantly contributing to QOL change were “fractures within the year before enrollment”, “presence of spondylosis deformans”, “presence of osteoarthritis”, “use of activated vitamin D3”, and “age” based on the JOQOL, and “presence of spondylosis deformans”, “use of activated vitamin D3”, and “age” based on the EQ-5D. The results suggested that the patients’ perception of treatment effects, such as improvement in pain, contributes to treatment continuation. Osteoporosis patients should be informed that continuous treatment with once-weekly bisphosphonates can lead to a significant improvement in QOL regardless of concomitant locomotor diseases, to encourage them to remain on treatment. In conclusion, continuous bisphosphonate treatment improved the QOL even in patients with locomotor diseases, and the concomitant use of activated vitamin D3 may also facilitate further improvement in QOL.

To clarify the additional efficacy and safety benefits of 24 months’ treatment with the once-weekly formulation of teriparatide, which is currently used for 72 weeks. This was a multicenter, open-label, single-arm study conducted in Japan. Subjects who were 65 years or older with prevalent vertebral fractures received once-weekly subcutaneous injection of 56.5 μg teriparatide for 24 months. The main outcome measure was percentage change from baseline in lumbar (L2–L4) BMD measured by dual-energy X-ray absorptiometry. A total of 189 subjects received at least one dose of the once-weekly formulation of teriparatide. Lumbar, femoral neck, and total hip BMD increased significantly compared with baseline at Weeks 24, 48, 72, and 104. In addition, significant increases in lumbar (+1.5%) and femoral neck (+0.8%) BMD were noted at Week 104 compared with Week 72. Significant increases from baseline in BMD for radius 1/10 were noted at Weeks 24 and 104. No substantial increases were noted in the cumulative incidences of new vertebral fracture and other types of fracture after Week 72. The safety profile seen in the first 72 weeks remained unchanged until 104 weeks. The once-weekly formulation of teriparatide is effective and safe for the treatment of osteoporosis over 24 months. The limitation of this study is that this was an open-label, single-arm study. Funding: Asahi Kasei Pharma Corporation. Clinical Trial Registration: JapicCTI-132276.

Assessment of vertebral fracture is critically important for the diagnosis and treatment of osteoporosis. This study aimed to clarify the effectiveness of the semiquantitative (SQ) method in the assessment of vertebral fractures in Japanese clinical practice. Forty-four physicians (seven experts and 37 nonexperts) assessed the spinal radiographs of 40 patients participating in the Adequate Treatment of Osteoporosis (A-TOP) Japanese Osteoporosis Intervention Trial (JOINT)-02 at the baseline, 12 months, and 24 months using the SQ method. The proportion of diagnosed fracture cases per spine was higher in the nonexpert group than in the expert group at each time point, and was especially high in the upper thoracic spine (T4-T6). The least mean squares spinal fracture index was significantly higher in the nonexpert group than in the expert group for all time points. The kappa statistics were also higher in the expert group than in the nonexpert group for all vertebral levels at all time points. Assessment of vertebral fractures using the SQ method tended to be overestimated by nonexpert physicians compared with the experts, with poor nonexpert interobserver reliability and well-matched expert interobserver reliability. Conscious efforts to avoid overestimation and to obtain higher reliability with the SQ method should be made to achieve more precise diagnoses and treatment of osteoporosis in Japanese clinical practice.

Intra-articular distal radial fractures with partial bone loss at the wrist were reconstructed using osteochondral grafts in 2 patients who were followed up for at least 18 months. Both patients experienced posttraumatic arthrosis of the wrist joint. The materials of the intra-articular fixation were bioabsorbable plates and screws. Reconstruction of a partially destroyed articular surface using a costal osteochondral graft is reliable and allows filling and resurfacing an articular cartilage void.

Context: Denosumab 60 mg sc injection every 6 months for 36 months was well tolerated and effective in reducing the incidence of vertebral, nonvertebral, and hip fracture in predominantly Caucasian postmenopausal women with osteoporosis. Objective: The objective of this phase 3 fracture study was to examine the antifracture efficacy and safety of denosumab 60 mg in Japanese women and men with osteoporosis compared with placebo. Design and Setting: A randomized, double-blind, placebo-controlled trial with an open-label active comparator as a referential arm was conducted. Patients: Subjects were 1262 Japanese patients with osteoporosis aged 50 years or older, who had one to four prevalent vertebral fractures. Intervention: Subjects were randomly assigned to receive denosumab 60 mg sc every 6 months (n = 500), placebo for denosumab (n = 511), or oral alendronate 35 mg weekly (n = 251). All subjects received daily supplements of calcium and vitamin D. Main Outcome Measure: The primary endpoint was the 24-month incidence of new or worsening vertebral fracture for denosumab vs placebo. Results: Denosumab significantly reduced the risk of new or worsening vertebral fracture by 65.7%, with incidences of 3.6% in denosumab and 10.3% in placebo at 24 months (hazard ratio 0.343; 95% confidence interval 0.194–0.606, P = .0001). No apparent difference in adverse events was found between denosumab and placebo during the first 24 months of the study. Conclusion: These results provide evidence of the efficacy and safety of denosumab 60 mg sc every 6 months in Japanese subjects with osteoporosis.

Introduction Denosumab inhibits bone resorption by binding to and inactivating RANK ligand (RANKL), a key mediator of osteoclast formation, maturation and activation. As in the pivotal phase 3 study, FREEDOM, in predominantly postmenopausal Caucasian women with osteoporosis the efficacy of denosumab was evaluated by the phase 3 study, DIRECT, in Japanese osteoporosis patients. The study showed that 2-year treatment of denosumab significantly reduced risk of new vertebral fracture by 74.0% compared to placebo. However, there have been no data showing actions on Japanese bone architecture. Objectives Here we evaluate the effect of denosumab to hip geometry by hip structural analysis using dual-energy X-ray absorptiometry (DXA) data in Japanese. Methods The images for 687 patients derived from DIRECT study were evaluable for HSA. DIRECT study consisted of a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase, in which all subjects received denosumab. Hip geometry was analyzed using Hologic Apex DXA software version 13.5 (Madison, WI). Measurements include: BMD as average pixel value in the profile, bone outer diameter, endocortical diameter, mineralized bone cross-sectional area, average cortical thickness, cross-sectional moment of inertia (CSMI) as BMD times square of the distance from the center of mass, section modulus as CSMI divided by Dmax (maximum distance between the center of the mass and the outer cortex), buckling ratio as the ratio of bone diameter to average cortical thickness, and Dmax. Percent changes from baseline in HSA parameters at each time point were analyzed using one-sample t-test. Comparisons between the treatment groups for the percent changes in HSA parameters at each time point were performed using a two-sample t-test. Results The images for 687 patients applicable to HSA were used in the present study. The baseline characteristics were similar to those in the total 952 participants. Compared to placebo, denosumab significantly increased BMD, cortical thickness and cross sectional area in all of the three analyzed areas: the narrow neck, intertrochanter and femoral shaft. The subsequent derived mechanical parameters, cross-sectional moment of inertia, section modulus and buckling ratio, were also improved by denosumab. In addition, the improvement of these parameters was also observed in the patients that had switched from placebo to denosumab treatment. Conclusions The present study reveals 3-year effect of denosumab on the geometrical parameters of hip bone structure. The improving effects suggest underlying mechanism for anti-fracture effect of denosumab in Japanese.

BackgroundDeteriorated quality of life (QOL) is a major problem in osteoporotic women. However, little is known regarding the determinants of QOL in patients with osteoporosis.ObjectiveOur aim was to explore the role of vitamin D status on QOL score in osteoporosis with high fracture risk.MethodsPatients were osteoporotic women aged ≥70 years and with ≥1 risk factor for incident fracture, namely prevalent osteoporotic fracture, bone mineral density (BMD) >–3.0 SD of young adult mean, or high bone turnover marker. Health-related QOL was assessed using the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL). When patients were classified into quartiles by total QOL score). Serum 25-hydroxyvitamin D (25[OH]D) level was measured by immunoassay.ResultsA total of 1585 osteoporotic women were included in the study (age range, 70–95 years). Age, body mass index, serum 25(OH)D status (low, normal, or high), bone mineral density, number of prevalent vertebral fractures, presence of hypertension, presence of osteoarthritis, and history of falls were significantly correlated with QOL quartile. Multivariate liner regression analysis indicated that low serum 25(OH)D level (20 ng/mL may be required to maintain patients’ QOL in osteoporosis.

Concurrent treatments with bisphosphonates and vitamin K are promising given that bisphosphonates possibly interfere with vitamin K activation. This is a prospective, multi-center, open-labeled, randomized trial of the efficacy of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone and to explore subsets of patients for which concurrent treatment is particularly efficacious (trial identification number UMIN000000991). Inclusion criteria are women who meet the criteria for pharmacological therapy for osteoporosis, aged ≥65 years, have any of pre-specified risk factors, can walk unassisted, and are able to answer questionnaires. Exclusion criteria are prior warfarin use, secondary osteoporosis or non-osteoporotic metabolic bone diseases, contraindication for vitamin K2 and risedronate, hyper- or hypoparathyroidism, mental disorders, prevalent vertebral fracture at ≥6 sites, severe degenerative spinal deformation between T4 and L4, serious heart, liver, or kidney disease, or bisphosphonate use within the previous 6 months. Patients were recruited from 123 institutes between January 2008 and February 2010, and allocated to vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate alone (2.5 mg/day or 17.5 mg/week) groups. Primary endpoint is a vertebral or non-vertebral fracture. Secondary endpoints are bone mineral density, height, undercarboxylated osteocalcin, JOQOL, EQ-5D and safety. A sample size of 910 subjects per group and 2-year follow-up will provide 80 % power to detect 35 % risk reduction for fracture, with a two-sided significance level of 5 %. Subgroup analysis stratified to adjustment factors for random allocation, body mass index, 25-hydroxyvitamin D, estimated glomerular filtration rate, grade of vertebral fracture, JOQOL, EQ-5D, and co-morbidity is pre-specified.

This study examined and compared the effects of four-week intermittent and daily administrations of minodronic acid, a highly potent nitrogen-containing bisphosphonate, on bone mineral density (BMD), bone strength, bone turnover, and histomorphometry on established osteopenia in ovariectomized (OVX) rats. Fourteen-week-old female F344 rats were OVX or sham-operated. At 12 weeks post surgery, minodronic acid was orally administered once every 4 weeks at 0.2, 1, and 5 mg/kg and once daily at 0.006, 0.03, and 0.15 mg/kg for 12 months. The total dosing amount was comparable between the two dosing regimens. The levels of urinary deoxypyridinoline and serum osteocalcin were measured to assess bone turnover. BMD as assessed via dual-energy X-ray absorptiometry, bone structure and dynamical changes in vertebral trabecula and biomechanical properties were measured ex vivo at 12 months to assess bone content and material properties. Minodronic acid dose-dependently ameliorated the decrease in BMD of lumbar vertebrae and the femur in both treatment regimens similarly. Minodronic acid suppressed elevated urinary levels of deoxypyridinoline, a bone resorption marker, and reduced the serum levels of osteocalcin, a bone formation marker. In the mechanical test at 12 months of treatment, minodronic acid dose-dependently ameliorated the reduction in bone strength in femur and vertebral body. There is no significant difference in parameters between the two regimens except maximal load of lower doses in lumbar vertebral body and absorption energy of middle doses in femur. With these parameters with significant differences, values of the intermittent regimen were significantly lower than that of daily repeated regimen. Bone histomorphometric analysis of the lumbar vertebral body showed that minodronic acid significantly ameliorated the decrease in bone mass, trabecular thickness and number, and the increase in trabecular separation, bone resorption indices (Oc.S/BS and N.Oc/BS), and bone formation indices (BFR/BS, MAR and OV/BV) in both regimens. Minodronic acid suppressed OVX-induced increases in bone turnover at the tissue level and ameliorated all structural indices, thereby improving the deterioration of bone quality under osteoporotic disease conditions regardless of the regimen. In conclusion, a four-week intermittent treatment of minodronic acid suppressed increased bone resorption as daily treatment when considering the total administered dose in OVX rats with established osteopenia. The improvement of microarchitectural destruction in low dose of intermittent treatment was weaker than that observed in a daily repeated regimen; however the effects of high and middle doses of intermittent treatment were equivalent to that observed in daily repeated regimen accompanied by sufficient bone resorption inhibition in rats. These findings suggest that minodronic acid at an appropriate dose in an intermittent regimen may be as clinically useful in osteoporosis therapy as in daily treatment.

Eldecalcitol, a vitamin D3 analogue, significantly reduces the risk of new vertebral fractures and increases bone mineral density (BMD) more than does alfacalcidol. To determine the effect of eldecalcitol on the incidence of all fragility fractures caused by osteoporosis, we conducted post hoc analyses of the phase III clinical trial to evaluate the incidence of the osteoporotic fractures defined in the World Health Organization (WHO) Technical Report, and, also, the incidence of the major osteoporotic fractures utilized in the WHO Fracture Risk Assessment Tool (FRAX), and compared those in the eldecalcitol group with those in the alfacalcidol group. We also analyzed the incidence of osteoporotic fractures stratified by prespecified risk factors for fractures. Eldecalcitol treatment reduced the incidence of osteoporotic fractures defined by the WHO more than alfacalcidol treatment (18.6 % vs. 25.2 %; hazard ratio, 0.70; 95 % CI, 0.54-0.93). Prevalent vertebral fractures, two or more prevalent vertebral fractures, and total hip BMD T score less than -2.5 were the risk factors for new osteoporotic fractures with significant differences between the two treatments. Eldecalcitol also decreased the incidence of major osteoporotic fractures in the FRAX more than alfacalcidol (11.1 % vs. 16.3 %; hazard ratio, 0.66; 95 % CI, 0.46-0.94). In conclusion, treatment with eldecalcitol reduced the risk of fragility fractures caused by osteoporosis compared with alfacalcidol administration, which may result from a potent effect of eldecalcitol on BMD, bone structure, and bone turnover.

Introduction Aldehyde dehydrogenase 2 (ALDH2) degrades acetaldehyde produced by the metabolism of alcohol. The inactive ALDH2 phenotype is prevalent in East Asians, and an association between this ALDH2 polymorphism and osteoporosis has been reported. In our previous study, we found that alcohol consumption results in decreased trabecular bone volume in aldh2 knockout (aldh2−/−) mice compared with the volume in wild-type (aldh2+/+) mice. However, the effect of aldh2 gene on the skeletal phenotype in the absence of alcohol consumption remains unknown. The aim of this study was to clarify the effect of aldh2 disruption on femoral bone structure and dynamics in aldh2-disrupted mice in the absence of alcohol consumption. Materials and methods We examined aldh2−/− and aldh2+/+ mice at the ages of 4, 8 and 12 weeks. The femoral bone length and bone mineral density (BMD) were measured using peripheral quantitative computed tomography. The mechanical strength was assessed by the three-point bending test at 12 weeks, and cortical bone histomorphometry at the femur diaphysis was performed at all three time points. Osteogenic activities in aldh2−/− and aldh2+/+ mice were assessed by osteoblast culture from calvariae of the neonatal mice. Bilateral femoral and tibial bones containing no bone marrow cells of 8-week-old mice were used for analysis of mRNA expression. In addition, mRNA expression in aldh2−/− and aldh2+/+ mice after tail suspension or climbing exercise for 7 days from 8 weeks was analyzed to clarify the response to mechanical loading. Results At 12 weeks, there were no significant differences in femoral bone length, trabecular BMD in the distal metaphyses of the femurs, or mechanical strength between aldh2−/− and aldh2+/ + mice, whereas cortical BMD and cortical thickness were significantly increased and cross-sectional area and bone marrow area were significantly decreased in the femoral diaphysis of aldh2−/− mice relative to the corresponding values in aldh2+/+ mice. At 8 weeks, bone formation rate and mineral apposition rate on the periosteal and endocortical surfaces were significantly increased in aldh2−/− mice relative to the rates in aldh+/+ mice. Calvarial osteoblast culture study revealed that the percentage of alkaline phosphatase stained cells was significantly higher in aldh2−/− mice compared to that in aldh+/+ mice. Quantitative real-time RT-PCR revealed a significant increase in the expressions of bmp2, osterix, runx2, and col1a1 mRNA in aldh2−/− mice, along with an increase in the expression of wnt5a mRNA and the lrp5/sost mRNA ratio. The mRNA expressions of bmp2, osterix, runx2 and pthr in aldh2−/− mice were significantly decreased after climbing exercise compared to those in the control, although the mRNA expressions of bmp2, osterix, runx2 were not significantly decreased and pthr mRNA expression was increased in aldh+/+ mice after climbing exercise. Conclusion Our results show that disruption of aldh2 gene resulted in altered cortical bone structure and dynamics in mice. Cross-sectional area was decreased. Cortical BMD was increased owing to the promotion of cortical bone formation on the periosteal and endocortical surfaces of the femoral diaphysis. The possible mechanisms underlying altered cortical bone structure in aldh2−/− mice were gene-related higher osteogenic activity of osteoblasts and weakened osteogenice response to mechanical loading in growth period.

Background: Recent studies report a relatively high failure rate for tendon-bone healing after rotator cuff repair. Several studies have investigated biologically augmented rotator cuff repair; however, none has shown the application of synovial mesenchymal stem cells for such repair. Purpose: To demonstrate whether cells derived from shoulder tissues have mesenchymal stem cell properties and to identify which tissue is the best source of the mesenchymal stem cells. Study Design: Controlled laboratory study. Methods: Forty-two patients with a diagnosed rotator cuff tear preoperatively were enrolled in this study. Human mesenchymal tissues were obtained during arthroscopic surgery for rotator cuff tears from 19 donors who met the inclusion criteria and had investigable amounts of tissue. Colony-forming units, yield obtained, expandability, differentiation potential, epitope profile, and gene expression were compared among the cells from 4 shoulder tissues: synovium of the glenohumeral joint, subacromial bursa, margin of the ruptured supraspinatus tendon, and residual tendon stump on the greater tuberosity (enthesis). Results: The number of live passage 0 cells from whole tissue was significantly higher in cells derived from the subacromial bursa ( P < .05). Subacromial bursa–derived cells retained their expandability even at passage 10. In adipogenesis experiments, the frequency of Oil Red O–positive colonies was significantly higher for synovium- and subacromial bursa–derived cells than for tendon- and enthesis-derived cells ( P < .0001). In studies of osteogenesis, the rate of von Kossa– and alkaline phosphatase–positive colonies was highest in subacromial bursa–derived cells ( P < .0001). The chondrogenic potential was highest in cells derived from the enthesis. For epitope profiling, 11 surface antigens were measured, and most had similar epitope profiles, irrespective of cell source. Conclusion: The findings indicate that the subacromial bursa is a good candidate for the source of mesenchymal stem cells in rotator cuff tears. Clinical Relevance: Synovial cells from the subacromial bursa in patients with rotator cuff tears are a superior cell source in vitro, suggesting that mesenchymal stem cells from this tissue could be good candidates for biological augmentation of rotator cuff repair.

Context: Weekly teriparatide injection at a dose of 56.5 μg has been shown to increase bone mineral density. Objective: A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis. Design and Setting: In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed. Patients: Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture. Intervention: Subjects were randomly assigned to receive once-weekly sc injections of teriparatide (56.5 μg) or placebo for 72 wk. Main Outcome Measure: The primary endpoint was the incidence of new vertebral fracture. Results: Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable. Conclusion: Weekly sc administration of teriparatide at a dose of 56.5 μg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk., The Journal of clinical endocrinology & metabolism, 97(9), pp.3097-3106; 2012

A prospective observational study to test the effects of risedronate 17.5 mg/week treatment on quality of life (QOL) of 1,363 Japanese female patients with osteoporosis showed QOL improvement after 12 weeks of administration. Comorbid factors such as ischemic heart disease, hip osteoarthritis, and higher values of FRAX blunted the effects of QOL of the treatment. Few studies have investigated the effect of osteoporosis treatment on QOL in relationship to comorbid factors other than osteoporosis and fracture. Efficacy was determined by changes over time in EQ-5D at baseline, at 12 and 24 weeks, and at the final assessment. Factors affecting changes in EQ-5D were evaluated with a multivariate analysis. Safety was determined by assessing the incident rate of adverse events. The improvement of EQ-5D compared to baseline was observed as significant after 12 weeks of treatment (p

The aim of this study was to evaluate the efficacy and safety of intravenous alendronate (ALN) 900 µg every 4 weeks compared to oral ALN 35 mg once weekly.A 52-week, multicenter, randomized, double-masked, active-controlled, parallel-group, non-inferiority study was conducted in a total of 325 Japanese patients aged 48-87 years with osteoporosis. Patients were randomly assigned to an intravenous ALN (iv, n = 162) group or oral ALN (po, n = 163) group. The efficacy of the both formulations was assessed primarily by bone mineral density (BMD) measurement.The percentage BMD change from baseline in lumbar spine (L2-L4) after 52 weeks of treatment was 6.4 ± 0.3% in the iv group and 6.0 ± 0.3% in the po group (least-squares mean ± SE). The inter-group difference in least-squares mean of percentage change from baseline in BMD was 0.37%, and its 95% confidence interval was -0.47% to 1.20%. The non-inferiority of the iv group was established against the po group with a prespecified non-inferiority margin (Δ) of 1.5%. In addition, the four bone turnover markers were reduced to a similar level by either treatment throughout the treatment period. The safety profile was also similar between the two treatment groups. Because of the limitations presented in this study, the results of the iv group may not apply to non-Japanese patients with osteoporosis.The efficacy and safety of the intravenous ALN 900 µg once every 4 weeks were similar to those of the oral ALN 35 mg once weekly, indicating that intravenous administration of ALN is an effective treatment for osteoporosis and will provide a useful alternative to oral dosing.

Giant intracranial aneurysm is a life-threatening lesion and treatment of the aneurysm could be hazardous and complex. This study describes direct surgical treatment of giant middle cerebral artery (MCA) aneurysms using microvascular reconstruction techniques in 13 patients treated between 2006 and 2009. In all 13 patients, superficial temporal artery (STA)-MCA (M(2)) anastomosis was performed as a precaution prior to attacking the aneurysm. During surgery, microvascular reconstruction of incorporative arteries was additionally performed if the aneurysm was removed. Direct neck clipping was performed in four patients, trapping and removal of the aneurysm in one, and removal of the aneurysm with vascular reconstruction of the MCA in eight patients. Minor ischemic complications due to perforator ischemia were recognized in 6 patients, and 10 patients achieved functionally favorable outcomes (modified Rankin scale score 0 or 1). In direct surgery for giant MCA aneurysm, precautionary STA-M(2) bypass could provide appropriate surgical strategies tailored to individual cases, including direct clipping and removal of the aneurysm with or without vascular reconstruction. Microvascular reconstruction techniques are essential for complete cure of giant MCA aneurysms.

Adjuvant arthritis was induced in rats in the growth stage (aged 6 weeks) and those in the mature stage (aged 4 months), and changes in the systemic bone turnover and the effects of methotrexate (MTX, CAS 133073-73-l) were compared. After induction of adjuvant arthritis, the paw edema ratio and the urinary deoxypyridinoline (u-Dpy) level increased in both age groups. No marked changes were observed in the serum osteocalcin (s-OC) level in either group. In the 6-week-old rats, arthritis completely inhibited the bone mass, and strength of the femur and lumbar vertebral body. The 4-month-old rats showed more marked changes than the 6-week-old rats in the bone mass and strength of the lumbar, vertebral body. MTX administration (0.05, 0.1 and 0.2 mg/kg/day) resulted in significant dose-dependent inhibition of arthritis-induced changes, and the effects of MTX were similar between the two age groups. MTX was useful at each age. These results suggest that 4-month-old rats with arthritis are more appropriate as a mode1 for evaluation of drugs for bone metabolic turnover in human chronic rheumatoid arthritis.

The purpose of this study was to determine the mortality risk among Japanese men and women with height loss starting in middle age, taking into account lifestyle and physical factors. A total of 2498 subjects (755 men and 1743 women) aged 47 to 91 years old underwent physical examinations during the period 1994 to 1995. Those individuals were followed for mortality status through 2003. Mortality risk was estimated using an age-stratified Cox proportional hazards model. In addition to sex, adjustment factors such as radiation dose, lifestyle, and physical factors measured at the baseline—including smoking status, alcohol intake, total cholesterol, blood pressure, and diagnosed diseases—were used for analysis of total mortality and mortality from each cause of death. There were a total of 302 all-cause deaths, 46 coronary heart disease and stroke deaths, 58 respiratory deaths including 45 pneumonia deaths, and 132 cancer deaths during the follow-up period. Participants were followed for 20,787 person-years after baseline. Prior history of vertebral deformity and hip fracture were not associated with mortality risk. However, more than 2 cm of height loss starting in middle age showed a significant association with all-cause mortality among the study participants (HR = 1.76, 95% CI 1.31 to 2.38, p = 0.0002), after adjustment was made for sex, attained age, atomic-bomb radiation exposure, and lifestyle and physical factors. Such height loss also was significantly associated with death due to coronary heart disease or stroke (HR = 3.35, 95% CI 1.63 to 6.86, p = 0.0010), as well as respiratory-disease death (HR = 2.52, 95% CI 1.25 to 5.22, p = 0.0130), but not cancer death. Continuous HL also was associated with all-cause mortality and CHD- or stroke-caused mortality. Association between height loss and mortality was still significant, even after excluding persons with vertebral deformity. Height loss of more than 2 cm starting in middle age was an independent risk factor for cardiovascular and respiratory-disease mortality among the elderly, even after adjusting for potential risk factors. © 2012 American Society for Bone and Mineral Research

The objective of this study was to determine the safety and efficacy of long-term minodronate treatment in women with postmenopausal osteoporosis based on re-analysis of a phase III 2-year clinical trial with a 1-year extension. Women aged 55–80 years old with fragility fractures were enrolled and randomized to take 1 mg minodronate or placebo once a day in the original 2-year study. The subjects who completed the 2-year study were invited to participate in an additional 1-year extension in which all subjects were to receive minodronate. Finally, a total 380 subjects completed the extension study (186 from the placebo group and 194 from the minodronate group). Fracture results observed in the extension study were consistent with those observed in the first 2 years in minodronate group. In contrast, the placebo/minodronate group showed a decreased incidence of new vertebral fractures during year 3 compared to that in year 2. In the patients who received minodronate in the original 2-year study, lumbar bone mineral density (BMD) increased consistently during year 3 and bone turnover markers decreased within the first 6 months and remained constant thereafter over 3 years. Similar positive effects of minodronate on BMD and bone turnover markers occurred when therapy was initiated in the placebo/minodronate group. No new safety concerns observed during the extension period compared to the safety observations made during the 2-year study. It was concluded that daily administration of 1 mg oral minodronate is safe and well tolerated, and that the efficacy of this dose in reducing vertebral fracture risk in postmenopausal women over 2 years is sustained with continuing treatment.

BackgroundEldecalcitol is an analog of 1,25-dihydroxyvitamin D3 that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456.Methods and resultsThis 3year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75μg eldecalcitol versus 1.0μg alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92years old were randomly assigned 1:1 to receive eldecalcitol (n=528) or alfacalcidol (n=526). Patients were stratified by study site and serum 25-hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (

Summary Monthly minodronate at 30 or 50 mg had similar efficacy as 1 mg daily in terms of change in bone mineral density (BMD) and bone turnover markers with similar safety profiles. This new regimen provides patients with a new option for taking minodronate. Introduction Minodronate at a daily oral dose of 1 mg has been proven to have antivertebral fracture efficacy. In the present study, the efficacy and safety of oral minodronate at monthly doses of either 30 mg or 50 mg were compared with a daily dose of 1 mg. Methods A total of 692 patients with involutional osteoporosis were randomized to receive minodronate at either 30 or 50 mg monthly or a daily dose of 1 mg. The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at 12 months. Total hip BMD, bone turnover markers, serum calcium (Ca), and parathyroid hormone (PTH) levels were also evaluated. Results Minodronate at monthly doses of 30 or 50 mg were noninferior to the 1 mg daily dose in terms of change in LS-BMD. Changes in total hip BMD were also comparable. Although a transient decrease in serum Ca and increase in PTH levels were observed in all three groups at slightly different magnitudes and time courses, changes in bone turnover markers were comparable among the differentdosage groups with a similar time course. Safety profiles were also comparable. Conclusion Minodronate at monthly doses of 30 or 50 mg has similar efficacy to the daily 1 mg dose in terms of BMD and bone turnover markers with similar tolerability., Osteoporosis International, 23(6), pp.1737-1745; 2012