Emilin2 marks the target region for mesenchymal cell accumulation in bone regeneration.

BACKGROUND: Regeneration of injured tissue is dependent on stem/progenitor cells, which can undergo proliferation and maturation processes to replace the lost cells and extracellular matrix (ECM). Bone has a higher regenerative capacity than other tissues, with abundant mesenchymal progenitor cells in the bone marrow, periosteum, and surrounding muscle. However, the treatment of bone fractures is not always successful; a marked number of clinical case reports have described nonunion or delayed healing for various reasons. Supplementation of exogenous stem cells by stem cell therapy is anticipated to improve treatment outcomes; however, there are several drawbacks including the need for special devices for the expansion of stem cells outside the body, low rate of cell viability in the body after transplantation, and oncological complications. The use of endogenous stem/progenitor cells, instead of exogenous cells, would be a possible solution, but it is unclear how these cells migrate towards the injury site. METHODS: The chemoattractant capacity of the elastin microfibril interface located protein 2 (Emilin2), generated by macrophages, was identified by the migration assay and LC-MS/MS. The functions of Emilin2 in bone regeneration were further studied using Emilin2-/- mice. RESULTS: The results show that in response to bone injury, there was an increase in Emilin2, an ECM protein. Produced by macrophages, Emilin2 exhibited chemoattractant properties towards mesenchymal cells. Emilin2-/- mice underwent delayed bone regeneration, with a decrease in mesenchymal cells after injury. Local administration of recombinant Emilin2 protein enhanced bone regeneration. CONCLUSION: Emilin2 plays a crucial role in bone regeneration by increasing mesenchymal cells. Therefore, Emilin2 can be used for the treatment of bone fracture by recruiting endogenous progenitor cells.

Efficacy and safety of naldemedine treatment for opioid-induced constipation in gastrointestinal cancer: a retrospective analysis.

BACKGROUND: Gastrointestinal cancers are one of the most common cancer cases worldwide. Cancer treatment is multidisciplinary, which includes opioid pain management. Opioid analgesics cause opioid-induced constipation (OIC) with the onset of effect. Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in gastrointestinal cancers. METHODS: We retrospectively evaluated patients with gastrointestinal cancer treated with naldemedine at ten institutions in Japan from June 2017 to August 2019. Patients with gastrointestinal cancer who initiated treatment with opioids during hospitalization and were treated with naldemedine for the first time were included in the study. The gastrointestinal cancer types included were esophageal, gastric, small bowel, and colorectal cancers. We assessed the defecation frequency before and after the initiation of naldemedine use. Responders were defined as patients who defecated three or more times/week, with an increase from the baseline of one or more bowel movements/week over seven days after starting naldemedine. RESULTS: Thirty-three patients were observed for one week before and after starting naldemedine. Twenty-one patients had an increase in defecation frequency of at least three times per week or at least once per week above the baseline. The response rate was 63.6% [95% confidence interval (CI): 46.6-77.9%]. The median number of bowel movements for a week before and after the initiation of naldemedine treatment was 3 (range, 0-13) and 7 (range, 1-39), respectively, in the overall population (n=33), with a significant increase in defecation frequency following naldemedine administration (Wilcoxon signed rank test, P<0.005). Diarrhea was the predominant gastrointestinal symptom, with 13 (39.4%) patients experiencing grade 1 and none experiencing grade 3 or grade 4 adverse events. The frequency of other grade 1 adverse events was low abdominal pain in two patients, nausea in two patients, and anorexia in one patient, without any grade 2-4 adverse events. CONCLUSIONS: The results of the study suggest that naldemedine is effective and safe in clinical practice for gastrointestinal cancer treatment.

Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis.

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. METHODS: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. RESULTS: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. CONCLUSION: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.

Efficacy and Safety of Naldemedine for Patients with Cancer with Opioid-Induced Constipation in Clinical Practice: A Real-World Retrospective Study.

The efficacy and safety of naldemedine for opioid-induced constipation in patients with cancer has not been investigated in clinical practice. We conducted a multicenter, retrospective study to assess the effects of naldemedine among 10 Japanese institutions between June 2017 and August 2019. We evaluated the number of defecations 7 days before and after naldemedine administration. A total of 149 patients (89 male) with a median age of 72 years (range, 38−96) were included. The performance status was 0−1, 2, and ≥3 in 40, 38, and 71 patients, respectively. The median opioid dose in oral morphine equivalents was 30 mg/day (range: 7.5−800 mg). We observed 98 responders and 51 non-responders. The median number of defecations increased significantly in the 7 days following naldemedine administration from three to six (p < 0.0001). Multivariate analysis revealed that an opioid dose <30 mg/day [odds ratio, 2.08; 95% confidence interval, 1.01−4.32; p = 0.042] was significantly correlated with the effect of naldemedine. Diarrhea was the most common adverse event (38.2%) among all grades. The efficacy and safety of naldemedine in clinical practice are comparable to those of prospective studies, suggesting that it is effective in most patients.

Real-World Patient Characteristics and Treatment Patterns of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Cancer: A Multicenter Retrospective Chart Review Study.

Background and Objectives: Naldemedine is a peripherally acting µ-opioid receptor antagonist that improves opioid-induced constipation. Although clinical trials have excluded patients with poor performance status (PS) and those started on naldemedine early after opioid initiation, clinical practice has used naldemedine for the same patients. Therefore, we investigated the treatment patterns of naldemedine in a real-world setting. Materials and Methods: This was a multicenter, retrospective chart review study of opioid-treated patients with cancer receiving naldemedine. Adverse events that occurred within 7 days of naldemedine initiation were evaluated in those who received one or more doses of the same. Effectiveness was assessed in patients who used naldemedine for more than 7 days. Results: A total of 296 patients satisfied the eligibility criteria, among whom 129 (43.6%) had a PS of ≥3 and 176 (59.5%) started naldemedine within 2 weeks of opioid initiation. Moreover, 203 (79.6%) patients had ≥3 bowel movements per week. Incidences of all grades of diarrhea and abdominal pain were 87 (29.4%) and 12 (4.1%), respectively. No patient had grade 4 or higher adverse events. Conclusions: Although nearly half of the patients receiving naldemedine in clinical practice belonged to populations that were not included in the clinical trials, our results suggested that naldemedine in clinical practice had the same efficacy and safety as that in clinical trials.

Effects of monthly intravenous ibandronate on bone mineral density and microstructure in patients with primary osteoporosis after teriparatide treatment: The MONUMENT study.

PURPOSE: To investigate the effects of sequential therapy with monthly intravenous ibandronate on bone mineral density (BMD) and microstructure in patients with primary osteoporosis who received teriparatide treatment. METHODS: Sixty-six patients with primary osteoporosis who had undergone teriparatide treatment for more than 12 months (mean 18.6 months) received sequential therapy with 1 mg/month intravenous ibandronate for 12 months. The patients were evaluated using dual-energy X-ray absorptiometry (DXA), quantitative ultrasound, bone turnover markers, and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6 and 12 months after beginning administration. RESULTS: At 12 months after beginning sequential therapy, the bone resorption marker, tartrate-resistant acid phosphatase-5b, decreased by 39.5%, with 82.3% of the patients exhibiting levels within the normal limit. DXA revealed that the BMD of the lumbar spine increased by 3.2%, with 79.0% of the patients exhibiting a response, and 40.3% experiencing an increase in BMD over 5%. HR-pQCT revealed that the cortical thickness of the distal tibia was increased by 2.6%. The cortical area increased by 2.5%, and the buckling ratio (an index of cortical instability) decreased by 2.5%. Most parameters of the trabecular bone showed no significant changes. These changes in the cortical bone were observed in both the distal radius and tibia and appeared beginning 6 months after treatment initiation. CONCLUSIONS: Sequential therapy with monthly intravenous ibandronate increased the BMD and improved the cortical bone microstructure of osteoporotic patients who had undergone teriparatide treatment.

Low back pain is closely associated with frailty but not with sarcopenia: Cross-sectional study of rural Japanese community-dwelling older adults.

AIM: We speculated that low back pain, which is the most common ailment in older adults, is associated with frailty and/or sarcopenia and contributes to the progression of either condition. Our objective was to evaluate the relationship between low back pain, sarcopenia and frailty in rural Japanese community-dwelling older adults. METHODS: We recruited 730 participants aged ≥65 years who underwent a comprehensive health examination between November 2016 and December 2018. The Oswestry Disability Index (ODI) was used to assess low back pain quantitatively, and scores were compared for the frail groups determined by the Japanese version of Cardiovascular Health Study, and the sarcopenia groups as determined by the Asian Working Group for Sarcopenia 2019. RESULTS: Among 730 participants, the prevalence of low back pain was 57.8%. There were significant differences in the ODI scores between the robust, prefrail and frail groups (P < 0.001). In contrast, there were no significant differences in the ODI scores among the robust, low appendicular skeletal muscle and sarcopenia groups. Logistic regression analysis showed that the prevalence of low back pain and the ODI scores were significantly associated with frailty after adjustment for age, sex and body mass index (odds ratio 3.41, 95% confidence interval 1.39-8.39, P = 0.008, and odds ratio 1.06, 95% confidence interval 1.04-1.09, P < 0.001, respectively). CONCLUSIONS: To the best of our knowledge, this study is the first to show the close association between low back pain and frailty, and suggests that not only the decline in physical function but also neuropsychiatric factors, including chronic pain, constitute a vicious cycle of frailty in community-dwelling older adults. Geriatr Gerontol Int 2021; 21: 54-59.

Bile acid micelle disruption activity of short-chain peptides from tryptic hydrolyzate of edible proteins.

We have investigated the potential of bile acid (BA)-binding short-chain peptides for suppressing cholesterol absorption in the intestine. In our previous report, we have revealed the physicochemical characteristics of high binding peptides using principal component analysis. In this study, we investigated the characteristics of amino acid residues of BA-binding short-chain peptides. We found that short-chain peptides containing lysine (K) and arginine (R) had a higher BA-binding ability than peptides containing other amino acids. Since short-chain tryptic peptides contain K or R residues, we focused on 4-mer, 5-mer, and 6-mer peptides, which were expectedly released from the edible proteins by trypsin. Forty-four short-chain peptides from lactoproteins (Bos taurus) and glutelin (Oryza sativa subsp. Japonica) were synthesized, and their BA micelle disruption activity was evaluated. We could observe such activities in nearly all tested peptides. We found that CEVFR, NGLK, and NSVFR had particularly high disruption activities. We determined that the 50% cholesterol concentration decrease value (DC50) of the micellar solution upon peptide addition was almost the same in case of the aforementioned peptides as that of the VAWWMY as a positive control. In addition, 4-mer and 5-mer peptides had higher BA micelle disruption activity than 6-mer peptides. Our results confirmed that the BA binding and micelle disruption activities were significantly higher if the short-chain peptides contained K and R residues.

Promoting Healthy Eating Habits for College Students Through Creating Dietary Diaries via a Smartphone App and Social Media Interaction: Online Survey Study.

BACKGROUND: Youth in developed countries face the contradictory health problems of obesity and an excessive desire for weight loss. Developing a better health attitude for college students is essential as this period of life establishes future lifestyle and habits. Online interaction on social media can help to improve eating habits by creating dietary diaries through a smartphone app; however, the effects of such interactions for college students have not been examined to date. OBJECTIVE: The aim of this study was to evaluate the potential effectiveness of social media interactions with the use of dietary diaries on a smartphone app to motivate college students in raising self-awareness of their eating habits. METHODS: Forty-two college students in the greater Tokyo area of Japan participated in the study by creating dietary diaries online through a smartphone app and then followed/interacted with each other using social media for 7 consecutive days in September to November 2017. Online surveys were administered at baseline, immediately after creating the dietary diaries, and at 1-month follow up. Participants rated their degree of interest and self-evaluation of eating habits using 7-point scales, and answered multiple choice questions related to their thoughts in choosing meals/drinks among 10 topics. Free descriptions about their overall experience throughout the project were also collected in the follow-up survey. RESULTS: Data from 38 participants who completed all processes were analyzed. Over time, the mean score for degree of interest in eating habits increased from 4.6 to 6.2 (P<.001), while the self-evaluation score decreased from 4.5 to 3.6 (P<.001); these significant differences remained after 1 month (5.3, P=.002; 4.1, P=0.04, respectively). A weak negative correlation (P=.009) was observed between scores for degree of interest and self-evaluation. Participants with lower scores for degree of interest at baseline tended to increase their interest level by more than 2 points above the average (P<.001). Participants gradually thought more about their eating habits from various perspectives when choosing a meal/drink, particularly with respect to maintaining well-balanced diets and introducing diverse ingredients. Participants evaluated their experiences as interesting/fun and reported familiarity with using the smartphone app and social media as the preferred method to keep track of their eating. All participants welcomed communication with fellow participants on social media and motivated each other, in addition to monitoring their eating habits through online dietary diaries. Some participants experienced difficulty, especially when they were busy or faced a lack of internet access. CONCLUSIONS: Through interactions on social media, college students experienced encouragement and developed an interest and critical thinking with respect to their eating habits. This approach, which embraces peer education and peer support with social media, holds promise for the future of youth health promotion. Further examination will be needed to explore how to sustain this level of heightened awareness.

Eldecalcitol is superior to alfacalcidol in maintaining bone mineral density in glucocorticoid-induced osteoporosis patients (e-GLORIA).

INTRODUCTION: Eldecalcitol increases bone mineral density (BMD) and reduces vertebral fracture in patients with primary osteoporosis. However, the effect of eldecalcitol on BMD and fracture in glucocorticoid-induced osteoporosis (GIO) patients is unknown. This study was undertaken to compare the effect of eldecalcitol on BMD and fracture with that of alfacalcidol in GIO patients. MATERIALS AND METHODS: A randomized, open-label, parallel group study was conducted to identify the effectiveness and safety of monotherapy with 0.75 µg eldecalcitol compared with 1.0 µg alfacalcidol in GIO patients. RESULTS: Lumbar spine BMD increased with eldecalcitol, but decreased with alfacalcidol at 12 and 24 months (between group difference 1.29%, p < 0.01, and 1.10%, p < 0.05, respectively). Total hip and femoral neck BMD were maintained until 24 months by eldecalcitol, but decreased by alfacalcidol (between group difference 0.97%, p < 0.05 and 1.22%, p < 0.05, respectively). Both bone formation and resorption markers were more strongly suppressed by eldecalcitol than by alfacalcidol. Eldecalcitol showed better effect on BMD than alfacalcidol in patients with no prevalent fracture and BMD > 70% of the young adult mean, and with ≤ 3 months of previous glucocorticoid treatment. No significant difference in the incidence of vertebral fracture was found, and the incidence of adverse events was similar between the two groups. CONCLUSIONS: Eldecalcitol was more effective than alfacalcidol in maintaining BMD in GIO patients. Because eldecalcitol was effective in patients with no or short-term previous glucocorticoid treatment, as well as those without prevalent fracture or low BMD, eldecalcitol can be a good candidate for primary prevention of GIO. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000011700.

Minodronate combined with alfacalcidol versus alfacalcidol alone for glucocorticoid-induced osteoporosis: a multicenter, randomized, comparative study.

INTRODUCTION: This study compared the clinical usefulness of minodronate (50 mg/4 weeks) plus alfacalcidol (1 µg/day) (Group M) with that of alfacalcidol alone (1 µg/day) (Group A) for treating glucocorticoid-induced osteoporosis. MATERIALS AND METHODS: The primary endpoints were the changes from baseline in lumbar spine (LS) bone mineral density (BMD) and the cumulative incidence of vertebral fracture at 24 months; secondary endpoints included the changes from baseline in total hip (TH) BMD and bone turnover markers. RESULTS: Of 164 patients enrolled, 152 (Group M, n = 75; Group A, n = 77) were included in the analysis of efficacy. At each time point and at 24 months, LS BMD and TH BMD were significantly higher in Group M than in Group A. The 152 patients were divided into two subgroups that were previously treated with glucocorticoids for ≤ 3 months or > 3 months. In both subgroups, the changes from baseline in LS BMD and TH BMD from baseline at 24 months had increased more in Group M than in Group A. There were no differences found in the incidence of vertebral fracture between the groups, because the number of enrolled patients was lesser than that initially expected. In Group M, both bone formation and resorption markers significantly decreased from baseline at 3 months and maintained at 6, 12, and 24 months. CONCLUSIONS: Minodronate plus alfacalcidol was more effective than alfacalcidol alone in increasing BMD and was effective in increasing BMD for both prevention and treatment. Therefore, minodronate can be a good candidate drug for the treatment of glucocorticoid-induced osteoporosis.

Measurement of the leak rate of masks used for anticancer drug handling using a mask fitting tester.

BACKGROUND: Exposure to inhalation of anticancer drugs is frequent in anticancer drug handling. Using an activated carbon mask with the ability to remove particulates and vapors of anticancer drugs may be effective. Mask fitting performance is important, because low fitting performance leads to inhalation via bypassing the mask filter (leak). This study evaluated the leak rate of multiple-shaped masks. METHODS: Activated carbon and nonactivated carbon masks of the pleated-type (like surgical mask) and cup-type were used. Four pharmacists wore the masks and a fitting tester was employed. The particle reduction rate of particles in ambient air was calculated using: particle count (outside - inside)/outside × 100 (%). Leak rate was calculated as the difference in the particle reduction rate due to the presence or the absence of a seal in the mask surroundings. RESULTS: Reduction rates of the pleated-type nonactivated carbon mask and the pleated-type activated carbon mask were 14.8% and 34.8% (mean). These values significantly increased to 85.6% and 83.3% upon sealing the mask surroundings. Particle reduction rates of the cup-type nonactivated carbon mask and activated carbon mask were 99.3% and 33.6%. When mask surroundings were sealed, these values were 99.6% and 39.2%. Leak rates of pleated-type nonactivated carbon mask, pleated-type activated carbon mask, cup-type nonactivated carbon mask, and cup-type activated carbon mask were 70.8%, 48.5%, 0.3%, and 5.6%, respectively. CONCLUSION: A difference was found in the leak rate between masks used in anticancer drug handling. Based on the low leak rate, the cup-type activated carbon mask was thought to be effective.

A randomized, double-blind, placebo-controlled study of once weekly elcatonin in primary postmenopausal osteoporosis.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Searching for high-binding peptides to bile acid for inhibition of intestinal cholesterol absorption using principal component analysis.

We previously proposed a new method for exploring functional peptides using both spot-synthesis peptide libraries and principal component analysis (PCA). Here, we applied these methods to determine if high-binding 6-mer peptides can be used on bile acid for the inhibition of intestinal cholesterol absorption. We used a binding assay of 512 basal 4-mer peptides to bile acid, and from these selected high-binding and low-binding peptides. PCA was performed on data from both these binding groups and many physicochemical variables of the 512 peptides tested, and then through this, the variables were reduced to two principal components (PCs). The peptides were plotted on the PCA chart, and we identified distinct clusters of high- and low-binding regions. These PCA regions were applied to 6-mer random peptides, and we identified 6-mer peptides with high and low binding capacity to bile acid. We confirmed that the average fluorescence intensity of high-binding peptides was 3.0-fold higher than that of low-binding peptides. We succeeded in identifying 6-mer peptides with high and low-binding affinity based on the PCA analysis of 4-mer peptides. These results were compared and discussed with regard to those acquired by our previous computational analysis based on neural networks.

Isotemporal substitution of sedentary time with physical activity and its associations with frailty status.

OBJECTIVES: Recently, isotemporal substitution has been developed to substitute activity time for an equivalent amount of another activity. This study employed this method to demonstrate the effects of replacing sedentary behavior (SB) time with an equivalent amount of light-intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA) on the risk for different severities of frailty. METHODS: A total of 886 older adults (average age 73.6 years, female 70%) participated in this cross-sectional study. Frailty status was assessed according to the cardiovascular health study criteria. MAIN OUTCOME MEASURES: Wrist-worn accelerometers were used to measure SB, LPA, and MVPA. Isotemporal substitution models were applied to show the estimated effects of substituting 30 min of SB with an equal amount of time spent in LPA or MVPA on the risk for pre-frailty and frailty. RESULTS: The physical activity level and SB were not associated with the incidence of pre-frailty. However, a 16% (OR: 0.84; 95% CI: 0.78-0.90) and 42% (OR: 0.58; 95% CI: 0.37-0.92) decrease in frailty risk was noted when SB was substituted with LPA and MVPA, respectively, in the crude model. In the adjusted model, the significant effect was sustained for LPA (OR: 0.86; 95% CI: 0.80-0.92) but not for MVPA (OR: 0.74; 95% CI: 0.47-1.17). CONCLUSIONS: This study indicates that replacing 30 min of SB with an equivalent amount of LPA decreases the risk for frailty in older adults. Moreover, increasing LPA seems more feasible than increasing MVPA in older adults, with substantial benefit.

CD109 deficiency induces osteopenia with an osteoporosis-like phenotype in vivo.

Osteoporosis is a global public health problem that is increasing along with an aging population. A major determinant of osteoporosis is high bone turnover, which results from osteoclast activation. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, a deficiency that leads to a psoriasis-like skin inflammation in mice. Although the expression of CD109 has been reported in mouse pre-osteoclast cells, its function in osteoclasts in vivo remains largely unknown. To investigate the physiological role of CD109 in bone metabolism, we analyzed bones from wild-type and CD109-deficient adult mice. Micro-computed tomography analysis of the femur (thigh bone) showed that bone volume was lower in CD109-deficient mice than in wild-type mice. Bone histomorphometric analysis showed not only a reduction in bone volume but also an increase in bone turnover in CD109-deficient mice as compared with wild-type mice. Additionally, we measured serum levels of several markers of bone turnover and found a significant increase in the N-terminal telopeptide of type I collagen, a bone resorption marker, as well as alkaline phosphatase, a bone formation marker, in CD109-deficient mice. These results indicate that CD109 deficiency induces a high-turnover, osteoporosis-like phenotype, which suggests that CD109 plays a role in bone metabolism in vivo.

WAIF1 Is a Cell-Surface CTHRC1 Binding Protein Coupling Bone Resorption and Formation.

The osteoclast-derived collagen triple helix repeat containing 1 (CTHRC1) protein stimulates osteoblast differentiation, but the underlying mechanism remains unclear. Here, we identified Wnt-activated inhibitory factor 1 (WAIF1)/5T4 as a cell-surface protein binding CTHRC1. The WAIF1-encoding Trophoblast glycoprotein (Tpbg) gene, which is abundantly expressed in the brain and bone but not in other tissues, showed the same expression pattern as Cthrc1. Tpbg downregulation in marrow stromal cells reduced CTHRC1 binding and CTHRC1-stimulated alkaline phosphatase activity through PKCδ activation of MEK/ERK, suggesting a novel WAIF1/PKCδ/ERK pathway triggered by CTHRC1. Unexpectedly, osteoblast lineage-specific deletion of Tpbg downregulated Rankl expression in mouse bones and reduced both bone formation and resorption; importantly, it impaired bone mass recovery following RANKL-induced resorption, reproducing the phenotype of osteoclast-specific Cthrc1 deficiency. Thus, the binding of osteoclast-derived CTHRC1 to WAIF1 in stromal cells activates PKCδ-ERK osteoblastogenic signaling and serves as a key molecular link between bone resorption and formation during bone remodeling. © 2018 American Society for Bone and Mineral Research.

The effect of once-yearly zoledronic acid on hip structural and biomechanical properties derived using computed tomography (CT) in Japanese women with osteoporosis.

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 5mg or placebo for two years. CT data were obtained at baseline and at 12 and 24months 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 12months. The present data suggest that zoledronic acid has a possibility to reduce the risk of hip fractures in Japanese patients with osteoporosis.

Monthly oral ibandronate 100 mg is as effective as monthly intravenous ibandronate 1 mg in patients with various pathologies in the MOVEST study.

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 <75 or ≥75 years, LS BMD gains were 5.46 and 4.51%, respectively, with oral ibandronate, and 5.25 and 5.77%, respectively, with i.v. ibandronate. LS BMD gains in patients with baseline 25-hydroxyvitamin D levels ≥20 or <20 ng/mL were 5.35 and 4.76%, respectively, with oral ibandronate, and 5.05 and 6.57%, respectively, with i.v. ibandronate. Similar results were obtained in patients with or without prior bisphosphonate (BP) treatment, and in those receiving osteoporosis drug treatment other than BPs. In conclusion, oral ibandronate 100 mg demonstrated comparable BMD gains with monthly i.v. ibandronate, and thus shows high utility in the lifestyle and disease conditions associated with osteoporosis in Japanese patients.