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Tributyltin (TBT) is known as an endocrine-disrupting chemical. This study investigated the effects and possible mechanisms of TBT exposure on inducing human articular chondrocyte senescence in vitro at the human-relevant concentrations of 0.01-0.5 μM and mouse articular cartilage aging in vivo at the doses of 5 and 25 μg/kg/day, which were 5 times lower than the established no observed adverse effect level (NOAEL) and equal to NOAEL, respectively. TBT significantly increased the senescence-associated β-galactosidase activity and the protein expression levels of senescence markers p16, p53, and p21 in chondrocytes. TBT induced the protein phosphorylation of both p38 and JNK mitogen-activated protein kinases in which the JNK signaling was a main pathway to be involved in TBT-induced chondrocyte senescence. The phosphorylation of both ataxia-telangiectasia mutated (ATM) and histone protein H2AX (termed γH2AX) was also significantly increased in TBT-treated chondrocytes. ATM inhibitor significantly inhibited the protein expression levels of γH2AX, phosphorylated p38, phosphorylated JNK, p16, p53, and p21. TBT significantly stimulated the mRNA expression of senescence-associated secretory phenotype (SASP)-related factors, including IL-1β, TGF-β, TNF-α, ICAM-1, CCL2, and MMP13, and the protein expression of GATA4 and phosphorylated NF-κB-p65 in chondrocytes. Furthermore, TBT by oral gavage for 4 weeks in mice significantly enhanced the articular cartilage aging and abrasion. The protein expression of phosphorylated p38, phosphorylated JNK, GATA4, and phosphorylated NF-κB-p65, and the mRNA expression of SASP-related factors were enhanced in the mouse cartilages. These results suggest that TBT exposure can trigger human chondrocyte senescence in vitro and accelerating mouse articular cartilage aging in vivo.

Well-performing survival prediction models (SPMs) help patients and healthcare professionals to choose treatment aligning with prognosis. This retrospective study aims to investigate the prognostic impacts of laboratory data and to compare the performances of Metastases location, Elderly, Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy (METSSS) model, New England Spinal Metastasis Score (NESMS), and Skeletal Oncology Research Group machine learning algorithm (SORG-MLA) for spinal metastases (SM).From 2010 to 2018, patients who received radiotherapy (RT) for SM at a tertiary center were enrolled and the data were retrospectively collected. Multivariate logistic and Cox-proportional-hazard regression analyses were used to assess the association between laboratory values and survival. The area under receiver-operating characteristics curve (AUROC), calibration analysis, Brier score, and decision curve analysis were used to evaluate the performance of SPMs.A total of 2786 patients were included for analysis. The 90-day and 1-year survival rates after RT were 70.4% and 35.7%, respectively. Higher albumin, hemoglobin, or lymphocyte count were associated with better survival, while higher alkaline phosphatase, white blood cell count, neutrophil count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, or international normalized ratio were associated with poor prognosis. SORG-MLA has the best discrimination (AUROC 90-day, 0.78; 1-year 0.76), best calibrations, and the lowest Brier score (90-day 0.16; 1-year 0.18). The decision curve of SORG-MLA is above the other two competing models with threshold probabilities from 0.1 to 0.8.Laboratory data are of prognostic significance in survival prediction after RT for SM. Machine learning-based model SORG-MLA outperforms statistical regression-based model METSSS model and NESMS in survival predictions.

Background and purpose: Predicted survival may influence the treatment decision for patients with skeletal extremity metastasis, and PATHFx was designed to predict the likelihood of a patient dying in the next 24 months. However, the performance of prediction models could have ethnogeographical variations. We asked if PATHFx generalized well to our Taiwanese cohort consisting of 356 surgically treated patients with extremity metastasis.Patients and methods: We included 356 patients who underwent surgery for skeletal extremity metastasis in a tertiary center in Taiwan between 2014 and 2019 to validate PATHFx’s survival predictions at 6 different time points. Model performance was assessed by concordance index (c-index), calibration analysis, decision curve analysis (DCA), Brier score, and model consistency (MC).Results: The c-indexes for the 1-, 3-, 6-, 12-, 18-, and 24-month survival estimations were 0.71, 0.66, 0.65, 0.69, 0.68, and 0.67, respectively. The calibration analysis demonstrated positive calibration intercepts for survival predictions at all 6 timepoints, indicating PATHFx tended to underestimate the actual survival. The Brier scores for the 6 models were all less than their respective null model’s. DCA demonstrated that only the 6-, 12-, 18-, and 24-month predictions appeared useful for clinical decision-making across a wide range of threshold probabilities. The MC was < 0.9 when the 6- and 12-month models were compared with the 12-month and 18-month models, respectively.Interpretation: In this Asian cohort, PATHFx’s performance was not as encouraging as those of prior validation studies. Clinicians should be cognizant of the potential decline in validity of any tools designed using data outside their particular patient population. Developers of survival prediction tools such as PATHFx might refine their algorithms using data from diverse, contemporary patients that is more reflective of the world’s population.

Background This study was to perform an economic evaluation to understand clinical outcomes and health resource use between hip fracture patients receiving hospital-based postfracture fracture liaison service (FLS) care and those receiving usual care (UC) in Taiwan. Methods This cohort study included hospital-based data of 174 hip fracture patients who received FLS care (FLS group) from National Taiwan University Hospital, and 1697 propensity score-matched patients who received UC (UC group) of National Health Insurance claim-based data. Two groups had similar baseline characteristics but differed in hip fracture care after propensity score matching. Clinical outcomes included refracture-free survival (RFS), hip-refracture-free survival (HRFS), and overall survival (OS). Health resource use included inpatient, outpatient, and pharmacy costs within 2 years follow-up after the index of hip fracture. The economic evaluation of the FLS model was analyzed using the net monetary benefit regression framework based on the National Health Insurance perspective. Results The FLS group had longer RFS than the UC group, with an adjusted difference of 44.3 days (95% confidence interval: 7.2–81.4 days). Two groups did not differ in inpatient and outpatient costs during follow-up, but the FLS group had a higher expenditure than the UC group on osteoporosis-related medication. The probability of FLS being cost-effective was >80% and of increasing RFS, HRFS, and OS was 95%, 81%, and 80%, respectively, when the willingness-to-pay threshold was >USD 65/gross domestic product per day. Conclusion FLS care was cost-effective in reducing refracture occurrence days for patients initially diagnosed with hip fractures.

A fracture liaison services (FLSs) and its modified services reduce refractures and mortality and can be cost-effective. Limited studies have addressed whether urban-rural differences exist in vertebral fracture outcomes and management. Therefore, the aims of the study were to investigate any urban-rural differences in refracture, mortality, prescription pattern, and associated factors of vertebral fractures after receiving assistance from an FLSs.Baseline characteristics and osteoporosis medication prescription patterns of participants were collected. After 1-year follow-up, mortality, refracture rate, and osteoporosis medication switching and adherence were evaluated. Multivariate logistic regressions were performed to identify baseline correlates on one-year mortality.There was higher mortality rate in the rural group but no urban-rural difference in the 1-year refracture rate after implementation of FLSs and medication management services (MMSs). The types of osteoporosis medications prescribed for both groups were similar, but participants in the rural group were less likely to change their osteoporosis medications during the 1-year follow-up timeframe and with lower adherence rate. The likelihood of being older and having chronic kidney disease, osteoarthritis, and neurological disease was higher in the rural group.Our multicomponent services have similar effectiveness in osteoporosis treatment between urban and rural areas. The overall adherence rate was lower in the rural group with higher mortality but no difference in the refracture rate in one year.

BACKGROUND The Skeletal Oncology Research Group machine-learning algorithms (SORG-MLAs) estimate 90-day and 1-year survival in patients with long-bone metastases undergoing surgical treatment and have demonstrated good discriminatory ability on internal validation. However, the performance of a prediction model could potentially vary by race or region, and the SORG-MLA must be externally validated in an Asian cohort. Furthermore, the authors of the original developmental study did not consider the Eastern Cooperative Oncology Group (ECOG) performance status, a survival prognosticator repeatedly validated in other studies, in their algorithms because of missing data. QUESTIONS/PURPOSES (1) Is the SORG-MLA generalizable to Taiwanese patients for predicting 90-day and 1-year mortality? (2) Is the ECOG score an independent factor associated with 90-day and 1-year mortality while controlling for SORG-MLA predictions? METHODS All 356 patients who underwent surgery for long-bone metastases between 2014 and 2019 at one tertiary care center in Taiwan were included. Ninety-eight percent (349 of 356) of patients were of Han Chinese descent. The median (range) patient age was 61 years (25 to 95), 52% (184 of 356) were women, and the median BMI was 23 kg/m2 (13 to 39 kg/m2). The most common primary tumors were lung cancer (33% [116 of 356]) and breast cancer (16% [58 of 356]). Fifty-five percent (195 of 356) of patients presented with a complete pathologic fracture. Intramedullary nailing was the most commonly performed type of surgery (59% [210 of 356]), followed by plate screw fixation (23% [81 of 356]) and endoprosthetic reconstruction (18% [65 of 356]). Six patients were lost to follow-up within 90 days; 30 were lost to follow-up within 1 year. Eighty-five percent (301 of 356) of patients were followed until death or for at least 2 years. Survival was 82% (287 of 350) at 90 days and 49% (159 of 326) at 1 year. The model's performance metrics included discrimination (concordance index [c-index]), calibration (intercept and slope), and Brier score. In general, a c-index of 0.5 indicates random guess and a c-index of 0.8 denotes excellent discrimination. Calibration refers to the agreement between the predicted outcomes and the actual outcomes, with a perfect calibration having an intercept of 0 and a slope of 1. The Brier score of a prediction model must be compared with and ideally should be smaller than the score of the null model. A decision curve analysis was then performed for the 90-day and 1-year prediction models to evaluate their net benefit across a range of different threshold probabilities. A multivariate logistic regression analysis was used to evaluate whether the ECOG score was an independent prognosticator while controlling for the SORG-MLA's predictions. We did not perform retraining/recalibration because we were not trying to update the SORG-MLA algorithm in this study. RESULTS The SORG-MLA had good discriminatory ability at both timepoints, with a c-index of 0.80 (95% confidence interval 0.74 to 0.86) for 90-day survival prediction and a c-index of 0.84 (95% CI 0.80 to 0.89) for 1-year survival prediction. However, the calibration analysis showed that the SORG-MLAs tended to underestimate Taiwanese patients' survival (90-day survival prediction: calibration intercept 0.78 [95% CI 0.46 to 1.10], calibration slope 0.74 [95% CI 0.53 to 0.96]; 1-year survival prediction: calibration intercept 0.75 [95% CI 0.49 to 1.00], calibration slope 1.22 [95% CI 0.95 to 1.49]). The Brier score of the 90-day and 1-year SORG-MLA prediction models was lower than their respective null model (0.12 versus 0.16 for 90-day prediction; 0.16 versus 0.25 for 1-year prediction), indicating good overall performance of SORG-MLAs at these two timepoints. Decision curve analysis showed SORG-MLAs provided net benefits when threshold probabilities ranged from 0.40 to 0.95 for 90-day survival prediction and from 0.15 to 1.0 for 1-year prediction. The ECOG score was an independent factor associated with 90-day mortality (odds ratio 1.94 [95% CI 1.01 to 3.73]) but not 1-year mortality (OR 1.07 [95% CI 0.53 to 2.17]) after controlling for SORG-MLA predictions for 90-day and 1-year survival, respectively. CONCLUSION SORG-MLAs retained good discriminatory ability in Taiwanese patients with long-bone metastases, although their actual survival time was slightly underestimated. More international validation and incremental value studies that address factors such as the ECOG score are warranted to refine the algorithms, which can be freely accessed online at https://sorg-apps.shinyapps.io/extremitymetssurvival/. LEVEL OF EVIDENCE Level III, therapeutic study.

Background To compare the risks of major osteoporotic, vertebral, and non-vertebral fractures between patients who discontinued anti-osteoporosis medications. Methods We conducted a comparative effectiveness study with a nationwide population-based cohort study design. Patients aged ≥50 years admitted between 2012 and 2015 for incident hip fractures and receiving denosumab or bisphosphonates with sufficient compliance for at least one year were included. Patients were categorized into persistent or non-persistent denosumab or bisphosphonates users based on their subsequent use pattern. The main outcomes were subsequent hospitalizations for a major osteoporotic, vertebral or non-vertebral fracture. Multivariate, time-varying Cox proportional hazards model was used to evaluate the risk of major outcomes. Results Compared with persistent denosumab users, non-persistent denosumab users had a significantly higher risk of major osteoporotic fractures (Hazard ratio (HR) = 1.60; 95% confidence interval (CI), 1.20 to 2.14),vertebral fractures (HR = 2.18; 95% CI, 1.46 to 3.24) and death (HR = 3.57; 95%CI, 2.63-4.84). However, the increased risk of fracture was not found in both persistent and non-persistent bisphosphonates users. Noteworthy, the increased risk of vertebral fractures in non-persistent denosumab users was more pronounced within one-year post discontinuation (HR = 2.90, 95% CI, 1.77 to 4.74) and among patients who discontinued from 2-year denosumab therapy (HR = 3.58; 95% CI, 1.74 to7.40). Discussion Discontinuation of denosumab resulted in an increased risk of major osteoporotic fractures, especially vertebral fractures. The increased risk tends to reveal within one-year post discontinuation and be greater after a longer treatment duration. Notably, only fracture with hospitalization was identified as our research outcome, the real risk of osteoporotic fracture post discontinuation is believed to be higher, especially for vertebral fracture. This article is protected by copyright. All rights reserved.

Organotin pollutant tributyltin (TBT) is an environmental endocrine disrupting chemical and is a known obesogen and diabetogen. TBT can be detected in human following consumption of contaminated seafood or water. The decrease in muscle strength and quality has been shown to be associated with type 2 diabetes in older adults. However, the adverse effects of TBT on the muscle mass and function still remain unclear. Here, we investigated the effects and molecule mechanisms of low-dose TBT on skeletal muscle regeneration and atrophy/wasting using the cultured skeletal muscle cell and adult mouse models.The mouse myoblasts (C2C12) and differentiated myotubes were used to assess the in vitro effects of low-dose tributyltin (0.01-0.5 μM). The in vivo effects of TBT at the doses of 5 and 25 μg/kg/day (n = 6/group), which were five times lower than the established no observed adverse effect level (NOAEL) and equal to NOAEL, respectively, by oral administration for 4 weeks on muscle wasting and muscle regeneration were evaluated in a mouse model with or without glycerol-induced muscle injury/regeneration.TBT reduced myogenic differentiation in myoblasts (myotube with 6-10 nuclei: 53.9 and 35.8% control for 0.05 and 0.1 μM, respectively, n = 4, P 0.05). TBT also decreased myotube diameter, upregulated protein expression levels of muscle-specific ubiquitin ligases (Atrogin-1 and MuRF1), myostatin, phosphorylated AMPKα, and phosphorylated NFκB-p65, and downregulated protein expression levels of phosphorylated AKT and phosphorylated FoxO1 in myotubes (0.2 and 0.5 μM, n = 6, P 0.05). Exposure of TBT in mice elevated body weight, decreased muscle mass, and induced muscular dysfunction (5 and 25 μg/kg, P 0.05 and P 0.05, respectively, n = 6). TBT inhibited soleus muscle regeneration in mice with glycerol-induced muscle injury (5 and 25 μg/kg, P 0.05 and P 0.05, respectively, n = 6). TBT upregulated protein expression levels of Atrogin-1, MuRF1, myostatin, and phosphorylated AMPKα and downregulated protein expression level of phosphorylated FoxO1 in the mouse soleus muscles (5 and 25 μg/kg, P 0.05 and P 0.05, respectively, n = 6).This study demonstrates for the first time that low-dose TBT significantly inhibits myogenic differentiation and triggers myotube atrophy in a cell model and significantly decreases muscle regeneration and muscle mass and function in a mouse model. These findings suggest that low-dose TBT exposure may be an environmental risk factor for muscle regeneration inhibition, atrophy/wasting, and disease-related myopathy.

Background: This study investigated the effects of endurance exercise training and zoledronic acid (Zol) treatment on ovariectomy-induced osteopenia. Methods: Middle-aged female Wistar rats were subjected to sham and ovariectomy surgeries and assigned to seven different groups according to Zol treatment doses and treadmill endurance exercise training; these were the Sham, Ovx, LowZ, HighZ, EXE, LowZ+EXE, HighZ+EXE groups. The subcutaneous (s.c.) doses of Zol for the LowZ and HighZ groups were 20 and 100 µg/kg, respectively. Total intervention period was 10 weeks. Results: Both Zol treatment and exercise training significantly blunted ovariectomy-induced osteopenia in spongy bone (pConclusions: Though exercise training did not demonstrate significantly synergistic or modifying effects to Zol-treated bone, results from energy, aging and bone related serum measurements indicate that exercise might reveal its benefits in later phases or at lower doses of bisphosphonate.

Due to the huge gap in the care of patients with osteoporosis and fragility fractures, we aimed to explore the effectiveness of the osteoporosis liaison service (OLS) in osteoporosis care. We found that OLS can improve osteoporosis care, including increasing medication compliance, increasing calcium/vitamin D/protein intake, and reducing fall rate. A significant gap exists in the care of patients with osteoporosis and fragility fractures. This study aimed to evaluate 1-year outcomes of an osteoporosis liaison service (OLS) program that includes two independent components: medication management services (MMS) to improve medication adherence and fracture liaison services (FLS) for secondary prevention. Patients with new hip fracture or untreated vertebral fractures enrolled in the FLS program (n = 600), and those with osteoporosis medication management issues but not necessarily fragility fractures enrolled in the MMS program (n = 499) were included. To evaluate outcomes, care coordinators assessed baseline items adapted from the 13 Best Practices Framework (BPF) standards of the International Osteoporosis Foundation, with telephone follow-up every 4 months for 1 year. Mean age of this cohort was 76.2 ± 10.3 years, 78.8% were female. After 1-year participation in the program, all patients had received bone mineral density tests, and medication adherence for the entire cohort at 12 months was 91.9 ± 19.6%, with significant improvement in fall rates (23.4% reduction), exercise rates (16.8% increase), calcium intake (26.5% increase), vitamin D intake (26.4% increase), and adequate protein intake (17.3% increase) (all p < 0.05). After 1-year OLS program, the overall rates of mortality, incident fracture, and falls were 6.6%, 4.0%, and 24.3%, respectively. The OLS program is associated with improved osteoporosis care, including increased medication adherence, calcium/vitamin D and protein intake, and reduced fall rate.

Objective To investigate the incidence and risk factors of bone cement implantation syndrome (BCIS) in bone tumor surgeries. Methods This was a retrospective observational study. We investigated patients who underwent bone tumor surgeries requiring cementation as part of the surgery between March 2016 and January 2018. We reviewed medical records, including formal anesthesia records and operation notes. Patients with complete data files were included. To investigate the general incidence of BCIS in tumor surgeries, patients of all ages, genders and tumor types were included. Vital signs, including oxygen saturation, blood pressure, heart rate, and respiratory rate, were checked and recorded once every 1–2 min after cementation. Accurate time points of cementation were recorded on formal anesthesia record sheets by the anesthesiologists. The definition and severity of BCIS were based on the classification system proposed in previous studies: grade I, moderate hypoxia (SpO2 20%); grade II, severe hypoxia (SpO2 40%) or unexpected loss of consciousness; and grade III, cardiovascular collapse requiring cardiopulmonary resuscitation. We also compared the incidence of BCIS between those patients with and without possible risk factors, including intraoperative blood loss, arthroplasty, use of an intramedullary device, patient age, gender, tumor location, and preexisting lung cancer or lung metastasis. Results A total of 88 patients were included. BCIS occurred in 23 patients, with an incidence of 26.1%. Among them, 19 had grade I and 4 had grade II BCIS. There was no patients with grade III BCIS. The lowest blood pressure occurred within 10 min in 21 (87.5%) patients and within 20 min for all patients. A total of 9 grade I BCIS were self‐limiting. The other 10 grade I hypotension cases and all grade II hypotension cases recovered after administration of a vasoconstrictor medication. Preexisting lung cancer or lung metastasis was the risk factor for BCIS; 40.0% of patients (16 in 40 patients) with preexisting lung cancer or metastasis had BCIS, whereas only 14.6% of patients (7 in 48 patients) without lung lesions had BCIS. There was no risk difference in terms of arthroplasty, old age, and increased blood loss. Apart from grades I and II bone cement implantation syndrome, there were no other major complications, including death, cardiovascular events, or cerebrovascular events. Conclusion Bone cement implantation syndrome is not unusual in bone tumor surgeries, and preexisting lung cancer or lung metastasis is a risk factor., The incidence of bone cement implantation syndrome (BCIS) in bone tumor surgeries was 26%. The incidence of grade I and grade II BCIS was 22% and 4%, respectively.

Older adults with hyperkyphosis might have a high risk of falls since their whole body center of mass may shift to the boundary of the base of support. Body composition changes, such as low bone mineral content (BMC), decreased muscle mass, high body mass index (BMI), and increased fat mass are common in older adults with hyperkyphosis. This study aimed to investigate the relationship between body composition and balance performance using a biomechanical analysis in older adults with hyperkyphosis. Thirty older adults with hyperkyphosis were recruited. BMC, muscle mass, BMI, and fat mass were measured for body composition. Balance performances were determined with walking, quiet standing, and forward reach. Gait speed, step length, center of mass–center of pressure inclination angle of heel strike (Inc-HS) and toe off (Inc-TO) during walking, center of mass–center of pressure inclination angle during quiet standing (Inc-QS), and reaching distance were calculated. BMC had a moderately positive correlation with gait speed (r = 0.48, p

Simple Summary CARMA3 is overexpressed in most cancers, and its expression is positively associated with poor prognosis. In this study, we evaluated the detailed mechanisms of CARMA3-mediated CRC metastasis. We found that overexpression of CARMA3 induced the expression of YAP and NF-κB activation, then elicited EMT induction to enhance cell migration and invasion. We demonstrate for the first time that YAP is a critical downstream regulator of CARMA3 in CRC. Our findings reveal a regulation axis between CARMA3 and Hippo oncoprotein YAP and further support the potential role of CARMA3 in the metastasis and cancer stemness of CRC. Abstract CARD-recruited membrane-associated protein 3 (CARMA3) is overexpressed in various cancers and is associated with cancer cell proliferation, metastasis, and tumor progression; however, the underlying mechanisms of CARMA3 in colorectal cancer (CRC) metastasis remain unclear. Here, we found that higher CARMA3 expression was correlated with poor overall survival and metastasis in CRC patients from the TNMplot database and Human Tissue Microarray staining. Elevating CARMA3 expression promoted cell proliferation, epithelial-mesenchymal transition (EMT) induction, migration/invasion abilities, sphere formation, and cancer stem cell markers expression. Knockdown of CARMA3 decreased these processes via the EMT-related transcription factor Slug. Moreover, CARMA3 depletion significantly reduced tumor growth in mice that were consistent with the in vitro results. CRC migration/invasion could be regulated by CARMA3/YAP/Slug signaling axis using genetic inhibition of Yes-associated protein (YAP). Interestingly, CARMA3 induced activation of nuclear factor (NF)-κB through YAP expression, contributing to upregulation of Slug. YAP expression positively correlated with CARMA3, NF-κB, and Slug gene expression and poor clinical outcomes in CRC patients. Our findings demonstrate for the first time that CARMA3 plays an important role in CRC progression, which may serve as a potential diagnostic biomarker and candidate therapeutic target for CRC treatment.

Summary: Background: Atypical lipomatous tumor (ALT) is a low-grade malignancy that frequently occurs at a subfascial anatomical location. While marginal excision is adequate for lipomas, excision with a surgical margin is suggested for ALTs. However, ALTs and lipomas are difficult to differentiate preoperatively, even with the help of imaging studies. In this study, we aimed to formulate a scoring system based on selected clinical and imaging characteristics to enhance the accuracy of pre-operative diagnosis of deep-seated ALTs. Methods: We enrolled 417 cases of deep-seated lipoma and 53 cases of ALTs from soft tissue treated between 2005 and 2016. Tumors arising from the bone, internal cavities, retroperitoneum, or nervous system were excluded. Clinical data were analyzed along with magnetic resonance image (MRI) features. We further developed a scoring formula to distinguish deep-seated ALTs from lipomas. Results: Older age, tumor location at lower limbs, and the presence of MRI features (larger size, thick septa > 2 mm, contrast enhancement>1 cm, fat component

Osteoporosis medication in fragility fracture patients is associated with better outcomes. However, limited studies have investigated whether fracture types affect outcomes among patients undergoing treatment. We performed a secondary data analysis on participants from a fracture liaison service and an osteoporosis medication management service. Participants (n = 974) were regrouped into hip fracture (HF), vertebral fracture (VF), HF + VF, and NO HF/VF groups at baseline. Bivariate and multivariate logistic regressions were performed to identify baseline correlates on one-year mortality, incident refractures, and falls. Baseline characteristics were different among fracture groups. The HF group was oldest, with the lowest body mass index (BMI), lowest FRAX® T-score and had the highest 10-year fracture risk. After intervention, the HF group still had the highest mortality, but the HF + VF group had the highest refracture and incident fall rates. In the multivariate regression analysis, prevalent HF and VF, lower BMI and albumin level, and having chronic kidney disease or cancer were associated with higher mortality rates. HF + VF patients had the highest refracture risk. Prevalent HF and VF, older age and higher BMI, and having cancer or osteoarthritis were associated with a greater fall risk. HF and VF are associated with adverse outcomes, even under an optimal fracture care.

Purpose The objective of this study was to investigate the association between the administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (cumulative duration, timing, and individual substance) and the risk of arthralgia by using a nationwide database with two methodological approaches including cohort and nested case-control study designs. Methods Using Taiwan's National Health Insurance Research Database, we identified patients who were newly prescribed with DPP-4 inhibitors, thiazolidinediones (TZDs), or acarbose between 1 March 2009 and 31 December 2012. The exposure of studied drugs was categorized into five exclusive categories: DPP-4 inhibitor, TZD, acarbose, combined use, or non-use, and assessed in a time-varying manner. Time-dependent Cox proportional hazard models were used to estimate the association between DPP-4 inhibitors and the risk of arthralgia. Particularly, we tested the impact of different cumulative duration, timing, and individual substance of DPP-4 inhibitors use on risk of arthralgia. A corresponding nested case-control study using conditional logistic regression was conducted to verify this association. Results An increased risk of arthralgia was observed during the first year after initiating DPP-4 inhibitors (adjusted Hazard Ratio = 1.35; 95% confidence interval [CI], 1.04-1.75) but the risk declined with cumulative use. This duration-response relation was not found in TZDs use and acarbose use. In the nested case-control study, there was a slightly increased risk of arthralgia (aOR = 1.08; 95% CI, 1.04-1.12) associated with current DPP-4 inhibitor use. Conclusion A relatively higher risk of arthralgia was associated with the initial administration of DPP-4 inhibitors, however, the risk declined among long-term users.

Background Identification of vertebral fractures (VFs) is critical for effective secondary fracture prevention owing to their association with the increasing risks of future fractures. Plain abdominal frontal radiographs (PARs) are a common investigation method performed for a variety of clinical indications and provide an ideal platform for the opportunistic identification of VF. This study uses a deep convolutional neural network (DCNN) to identify the feasibility for the screening, detection, and localization of VFs using PARs. Methods A DCNN was pretrained using ImageNet and retrained with 1306 images from the PARs database obtained between August 2015 and December 2018. The accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were evaluated. The visualization algorithm gradient-weighted class activation mapping (Grad-CAM) was used for model interpretation. Results Only 46.6% (204/438) of the VFs were diagnosed in the original PARs reports. The algorithm achieved 73.59% accuracy, 73.81% sensitivity, 73.02% specificity, and an AUC of 0.72 in the VF identification. Conclusion Computer driven solutions integrated with the DCNN have the potential to identify VFs with good accuracy when used opportunistically on PARs taken for a variety of clinical purposes. The proposed model can help clinicians become more efficient and economical in the current clinical pathway of fragile fracture treatment.

Objectives Emerging evidence has indicated a role for pharmacologic agents in the primary prevention of osteoporotic fracture, but have not yet been systematically reviewed for meta-analysis. We conducted a meta-analysis to evaluate the efficacy of pharmacologic interventions in reducing fracture risk and increasing bone mineral density (BMD) in postmenopausal women with osteopenia or osteoporosis but without prevalent fragility fracture. Method The Medline, EMBASE, and CENTRAL databases were searched from inception to September 30, 2019. Only randomized placebo-controlled trials evaluating postmenopausal women with −1.0 > bone mineral density (BMD) T-score > −2.5 (low bone mass) and those with BMD T-score ≤ −2.5 (osteoporosis) but without baseline fractures, who were receiving anti-osteoporotic agents, providing quantitative outcomes data and evaluating risk of vertebral and/or non-vertebral fragility fracture at follow-up. The PRISMA guidelines were followed, applying a random-effects model. The primary endpoint was the effect of anti-osteoporotic regimens in reducing the incidence of vertebral fractures. Secondary endpoints were percentage changes in baseline BMD at the lumbar spine and total hip at 1 and 2 years follow up. Results Full-text review of 144 articles yielded, 20 for meta-analysis. Bisphosphonates reduced the risk of vertebral fracture (pooled OR = 0.50, 95%CIs = 0.36–0.71) and significantly increased lumbar spine BMD after 1 year, by 4.42% vs placebo (95%CIs = 3.70%–5.14%). At the hip, this value was 2.94% (95%CIs = 2.13%–3.75%). Overall results of limited studies for non-bisphosphonate drugs showed increased BMD and raloxifene significantly decreases the risk of subsequent clinical vertebral fractures. Conclusion The bisphosphonates are efficacious and most evident for the primary prevention of osteoporotic vertebral fractures, reducing their incidence and improving BMD in postmenopausal women with osteopenia or osteoporosis., Highlights • Bisphosphonates reduced the risk of vertebral fracture in postmenopausal women with osteopenia or osteoporosis but without fracture. • Bisphosphonates increased BMD in postmenopausal women with osteopenia or osteoporosis but without fracture. • Limited studies for non-bisphosphonate drugs showed increased BMD in postmenopausal women with osteopenia or osteoporosis but without fracture. • Raloxifene decreased the risk of clinical vertebral fractures in postmenopausal women with osteopenia or osteoporosis but without fracture.

Background: Since 2011, Taiwan’s National Health Insurance Administration (NHIA) issued a regulation on the reimbursement to anti-osteoporosis medications (AOMs). This study aimed to evaluate the impact of this regulation in reimbursement on the utilization of AOMs, clinical outcomes and associated medical expenditures of patients with incident hip fractures. Methods: By using the National Health Insurance Research Database (NHIRD), patients with incident hip fracture from 2006 to 2015 were identified as our study cohort. Patients younger than 50 years old or prescribed with AOMs within one year prior to incident fracture were excluded. Outcomes of interest were quarterly estimates of the proportion of patients who received bone mineral density (BMD) examination, who were prescribed AOMs, as well as who encountered subsequent osteoporotic fracture-related visits and associated medical expenditures. Particularly, age- and gender specific estimates were reported. An interrupted time series study design with segmented regression model was used to quantitatively explore the impact of the changes of the reimbursement criteria on the level (immediate) and trend (long-term) changes of these outcomes. Results: Our study enrolled 118 493 patients with incident hip fracture with those patients aged older than 80 years old accounting for the largest proportion. A significantly decreased trend of AOMs prescription rates was observed immediately post regulation except for female aged between 65 and 80, while the long-term pattern showed no significant difference. However, the percentage of patients encountered subsequent osteoporotic fracture-related visit was not statistically different between pre- and post-regulation periods. Noteworthy, the policy regulation was associated with an increasing trend of osteoporotic fracture associated medical expenditures, especially for patients older than 80 years old. Conclusion: The regulation on the reimbursement for AOMs decreased the prescribing rate of AOMs immediately although the effect did not sustain thereafter. However, higher subsequent osteoporotic fracture-related medical expenditures were introduced, especially among those very old population.

Background Acrolein is an extremely electrophilic aldehyde. Increased urinary acrolein adducts have been found in type 2 diabetic patients and people with a smoking habit. The increased blood acrolein was shown in patients who received the cancer drug cyclophosphamide. Both diabetes and smoking are risk factors for skeletal muscle wasting or atrophy. Acrolein has been found to induce myotube atrophy in vitro. The in vitro and in vivo effects and mechanisms of acrolein on myogenesis and the in vivo effect of acrolein on muscle wasting still remain unclear. Methods C2C12 myoblasts were used to assess the effects of low‐dose acrolein (0.125–1 μM) on myogenesis in vitro. Mice were exposed daily to acrolein in distilled water by oral administration (2.5 and 5 mg/kg) for 4 weeks with or without glycerol‐induced muscle injury to investigate the effects of acrolein on muscle wasting and regeneration. Results Non‐cytotoxic‐concentration acrolein dose dependently inhibited myogenic differentiation in myoblasts (myotube formation inhibition: 0.5 and 1 μM, 66.25% and 46.25% control, respectively, n = 4, P

Arsenic, a widely distributed toxic metalloid, has been found to be associated with the low-birth-weight infants and the impairment of muscle regenerative capacity in areas with high levels of arsenic in drinking water. The distal muscular atrophy is one of side effects of arsenic trioxide (As2O3) for acute promyelocytic leukemia therapy. We hypothesized that arsenic may be a potential risk factor for skeletal muscle atrophy. Here, we investigated the action and molecular mechanism of low-dose arsenic on the induction of skeletal muscle atrophy in a skeletal muscle cell model. The differentiated C2C12 myotubes were treated with As2O3 (0.25–1 μM) for 48 h without apparent effects on cell viability. The signaling molecules for myotube atrophy were assessed. Submicromolar-concentration As2O3 dose-dependently triggered C2C12 myotube atrophy and increased the protein expressions of atrogenes Atrogin1 and MuRF1 and inhibited the upstream phosphorylated proteins Akt and FoxO1, while As2O3 dose-dependently increased AMPK phosphorylation in myotubes. Akt activator SC79 could significantly reverse the As2O3-induced myotube atrophy. These results suggest that arsenic is capable of inducing myotube atrophy by inhibiting an Akt signaling pathway.

Background: The deterioration of the musculoskeletal system imposes significant impact on physical activity. Exercise is an important strategy which minimizes these changes. It is not clear which type of exercise provides better improvement on low physical performance, low muscle mass and low strength of sarcopenia. We aim to develop an integrated care (IC) model and compare its relative efficacy in limb fat free mass, muscle strength, and physical performance with low extremities exercise (LEE) in community dwelling older adults with high risk of fractures (Fracture Risk Assessment Tool (FRAX®)) ≧3% for hip fracture, ≧20% for major osteoporotic fracture or 1-min osteoporosis risk test (≧1 point) or fall (≧2 falls in previous year). Methods: Patients were assigned randomized to participate in either IC or LEE group (n = 55 each) for 3 months. All participants received education including home-based exercise. The IC group consisted of different modalities of exercise while the LEE group performed machine-based low extremities exercise. Fat free mass, muscle strength, and physical performance were measured at their baseline and 3-months follow-up. Results: Mean age was 73.8 ± 7 years with 69.1% women. Entire cohort demonstrated significant increment in fat free mass, muscle strength (4 indicators) and physical performance (3 indicators). However, between group differences were not significant. Conclusion: With regular supervise exercise; both groups are equally effective in decreasing fat mass and increasing physical performance, muscle mass and strength. However, the IC group required fewer resources and thus more financially feasible in a community setting. Keywords: Bone mineral density, Gender differences, Integrated care, Low extremities exercise, Muscle strength

Osteoporosis and its associated fragility fractures are becoming a severe burden in the healthcare system globally. In the Asian-Pacific (AP) region, the rapidly increasing in aging population is the main reason accounting for the burden. Moreover, the paucity of quality care for osteoporosis continues to be an ongoing challenge. The Fracture Liaison Service (FLS) is a program promoted by International Osteoporosis Foundation (IOF) with a goal to improve quality of postfracture care and prevention of secondary fractures. In this review article, we would like to introduce the Taiwan FLS network. The first 2 programs were initiated in 2014 at the National Taiwan University Hospital and its affiliated Bei-Hu branch. Since then, the Taiwan FLS program has continued to grow exponentially. Through FLS workshops promoted by the Taiwanese Osteoporosis Association (TOA), program mentors have been able to share their valuable knowledge and clinical experience in order to promote establishments of additional programs. With 22 FLS sites including 11 successfully accredited on the best practice map, Taiwan remains as one of the highest FLS coverage countries in the AP region, and was also granted the IOF Best Secondary Fracture Prevention Promotion award in 2017. Despite challenges faced by the TOA, we strive to promote more FLS sites in Taiwan with a main goal of ameliorating further health burden in managing osteoporotic patients. Keywords: Asia-Pacific region, Taiwan, Fracture Liaison Service, Best Practice Framework, Osteoporosis

Background A global consensus on the loss of skeletal muscle mass and function in humans refers as sarcopenia and cachexia including diabetes, obesity, renal failure, and osteoporosis. Despite a current improvement of sarcopenia or cachexia with exercise training and supportive therapies, alternative and specific managements are needed to discover for whom are unable or unwilling to embark on these treatments. Alendronate is a widely used drug for osteoporosis in the elderly and postmenopausal women. Osteopenic menopausal women with 6 months of alendronate therapy have been observed to improve not only lumbar bone mineral density but also handgrip strength. However, the effect and mechanism of alendronate on muscle strength still remain unclear. Here, we investigated the therapeutic potential and the molecular mechanism of alendronate on the loss of muscle mass and strength in vitro and in vivo. Methods Mouse myoblasts and primary human skeletal muscle‐derived progenitor cells were used to assess the effects of low‐dose alendronate (0.1–1 μM) combined with or without dexamethasone on myotube hypertrophy and myogenic differentiation. Moreover, we also evaluated the effects of low‐dose alendronate (0.5 and 1 mg/kg) by oral administration on the limb muscle function and morphology of mice with denervation‐induced muscle atrophy and glycerol‐induced muscle injury. Results Alendronate inhibited dexamethasone‐induced myotube atrophy and myogenic differentiation inhibition in mouse myoblasts and primary human skeletal muscle‐derived progenitor cells. Alendronate significantly abrogated dexamethasone‐up‐regulated sirtuin‐3 (SIRT3), but not SIRT1, protein expression in myotubes. Both SIRT3 inhibitor AKG7 and SIRT3‐siRNA transfection could also reverse dexamethasone‐up‐regulated atrogin‐1 and SIRT3 protein expressions. Animal studies showed that low‐dose alendronate by oral administration ameliorated the muscular malfunction in mouse models of denervation‐induced muscle atrophy and glycerol‐induced muscle injury with a negative regulation of SIRT3 expression. Conclusions The putative mechanism by which muscle atrophy was improved with alendronate might be through the SIRT3 down‐regulation. These findings suggest that alendronate can be a promising therapeutic strategy for management of muscle wasting‐related diseases and sarcopenia.

Background A global consensus on the loss of skeletal muscle mass and function in humans refers as sarcopenia and cachexia including diabetes, obesity, renal failure, and osteoporosis. Despite a current improvement of sarcopenia or cachexia with exercise training and supportive therapies, alternative and specific managements are needed to discover for whom are unable or unwilling to embark on these treatments. Alendronate is a widely used drug for osteoporosis in the elderly and postmenopausal women. Osteopenic menopausal women with 6 months of alendronate therapy have been observed to improve not only lumbar bone mineral density but also handgrip strength. However, the effect and mechanism of alendronate on muscle strength still remain unclear. Here, we investigated the therapeutic potential and the molecular mechanism of alendronate on the loss of muscle mass and strength in vitro and in vivo. Methods Mouse myoblasts and primary human skeletal muscle-derived progenitor cells were used to assess the effects of low-dose alendronate (0.1-1 μM) combined with or without dexamethasone on myotube hypertrophy and myogenic differentiation. Moreover, we also evaluated the effects of low-dose alendronate (0.5 and 1 mg/kg) by oral administration on the limb muscle function and morphology of mice with denervation-induced muscle atrophy and glycerol-induced muscle injury. Results Alendronate inhibited dexamethasone-induced myotube atrophy and myogenic differentiation inhibition in mouse myoblasts and primary human skeletal muscle-derived progenitor cells. Alendronate significantly abrogated dexamethasone-up-regulated sirtuin-3 (SIRT3), but not SIRT1, protein expression in myotubes. Both SIRT3 inhibitor AKG7 and SIRT3-siRNA transfection could also reverse dexamethasone-up-regulated atrogin-1 and SIRT3 protein expressions. Animal studies showed that low-dose alendronate by oral administration ameliorated the muscular malfunction in mouse models of denervation-induced muscle atrophy and glycerol-induced muscle injury with a negative regulation of SIRT3 expression. Conclusions The putative mechanism by which muscle atrophy was improved with alendronate might be through the SIRT3 down-regulation. These findings suggest that alendronate can be a promising therapeutic strategy for management of muscle wasting-related diseases and sarcopenia.

Fracture liaison services (FLS), implemented in different ways and countries, are reported to be a cost-effective or even a cost-saving secondary fracture prevention strategy. This presumed favorable cost-benefit relationship is encouraging and lends support to expanded implementation of FLS per International Osteoporosis Foundation Best Practice Standards. This study summarizes the economic impact and cost-effectiveness of FLS implemented to reduce subsequent fractures in individuals with osteoporosis. This systematic review identified studies reporting economic outcomes for FLS in osteoporotic patients aged 50 and older through a comprehensive search of MEDLINE, EMBASE, Cochrane Central, and PubMed of studies published January, 2000 to December, 2016. Grey literature (e.g., Google scholar, conference abstracts/posters) were also hand searched through February 2017. Two independent reviewers screened titles and abstracts and conducted full-text review on qualified articles. All disagreements were resolved by discussion between reviewers to reach consensus or by a third reviewer. In total, 23 qualified studies that evaluated the economic aspects of FLS were included: 16 cost-effectiveness studies, 2 cost-benefit analyses, and 5 studies of cost savings. Patient populations varied (prior fragility fracture, non-vertebral fracture, hip fracture, wrist fracture), and FLS strategies ranged from mail-based interventions to comprehensive nurse/physician-coordinated programs. Cost-effectiveness studies were conducted in Canada, Australia, USA, UK, Japan, Taiwan, and Sweden. FLS was cost-effective in comparisons with usual care or no treatment, regardless of the program intensity or the country in which the FLS was implemented (cost/QALY from $3023-$28,800 US dollars (USD) in Japan to $14,513-$112,877 USD in USA. Several studies documented cost savings. FLS, implemented in different ways and countries, are reported to be cost-effective or even cost-saving. This presumed favorable cost-benefit relationship is encouraging and lends support to expanded implementation of FLS per International Osteoporosis Foundation Best Practice Standards.