Denosumab vs. bisphosphonates in primary osteoporosis: a meta-analysis of comparative safety in randomized controlled trials.

Denosumab and bisphosphonates for primary osteoporosis are generally well-tolerated, but their comparative safety remains unclear. We aimed to explore the comparative safety of denosumab and bisphosphonates in primary osteoporosis. Databases such as PubMed and Google Scholar were searched for relevant peer-reviewed randomized controlled trials published in English (as of December 2023). Trials comparing adverse events (AE) between denosumab and bisphosphonates in patients with primary osteoporosis were investigated. Data were pooled using a fixed- or random-effects model to determine the risk ratios (RR) and 95% confidence intervals (CIs) for various AEs in patients treated with denosumab in comparison to patients treated with bisphosphonates. Eleven trials (5,545 patients; follow-up period: 12-24 months) were included in this meta-analysis. All trials had a risk of bias (e.g., reporting bias linked to secondary endpoints and selection bias linked to random allocation). In comparison to bisphosphonates, denosumab was significantly associated with less withdrawal due to AEs (RR = 0.49; 95% CI 0.34-0.71), more five-point major adverse cardiovascular events (RR = 2.05; 95% CI 1.03-4.09), more cardiovascular AEs (RR = 1.61; 95% CI 1.07-2.41), more infections (RR = 1.14; 95% CI 1.02-1.27), more upper respiratory tract infections (RR = 1.56; 95% CI 1.08-2.25), less vertebral fractures (RR = 0.54; 95% CI 0.31-0.93), and less abdominal pain (RR = 0.44;95% CI 0.22-0.87). We explored the comparative safety of denosumab and bisphosphonates for primary osteoporosis, some of which could be attributed to their beneficial effects. However, all trials had a risk of bias. Further investigations are required to confirm our results.

The diagnostic and prognostic value of tartrate-resistant acid phosphatase isoform 5b for giant cell tumor of bone.

BACKGROUND: Serum level of tartrate-resistant acid phosphatase 5b (TRACP5b) is an excellent serum marker of bone resorption. In patients with giant cell tumor of bone (GCTB), TRACP5b levels are reportedly elevated. This study investigated whether TRACP5b could be a diagnostic serum marker and be useful for detecting postoperative disease progression for GCTB. METHODS: Cohort 1: We abstracted data from 120 patients with TRACP5b measurements from our database: 49 patients with GCTB and 71 patients non-GCTB. We compared serum TRACP5b values between the GCTB and non-GCTB groups. Cohort 2 included 47 patients with GCTB who had more than 6 months of follow-up and multiple TRACP5b values. For patients with local recurrence, TRACP5b change rate was calculated by comparing the TRACP5b value just before progression (a) with the value at the time of progression (b): Change rate = [(b)-(a)]/(a). In the non-progression group, the change rate was calculated from the two consecutive TRACP5b values, (c) and (d): Change rate =[(c)-(d)]/(c). We compared TRACP5b change rates between the progression and non-progression groups. RESULTS: Cohort 1: The GCTB group had a significantly higher mean TRACP5b value (1756 ± 2021 mU/dL) than the non-GCTB group (415 ± 219 mU/dL) (p < 0.0001). Cohort 2: The mean TRACP5b change rate of the progression group was significantly higher than the non-progression group (8.53 ± 8.52 and 0.24 ± 0.27, respectively; p < 0.0001). CONCLUSION: TRACP5b is a useful diagnostic marker in GCTB. The rate of change in serum TRACP5b values is a highly sensitive marker for predicting local recurrence in GCTB.

Serum periostin levels correlate with severity of intervertebral disc degeneration.

PURPOSE: Periostin, an extracellular matrix protein closely related to mechanical stress, inflammation, and ageing, has been implicated in intervertebral disc degeneration (IVDD) in basic research. However, it has not been examined in clinical cases. This study aimed to evaluate the association between IVDD severity and serum periostin concentration as well as to analyse potential associations between IVDD and clinical and demographic factors. METHODS: This retrospective cohort study included 198 patients who underwent lumbar disc herniation and lumbar canal stenosis between January 2020 and December 2022. The severity of IVDD was evaluated using the Pfirrmann grading, whereas serum periostin levels were measured using ELISA kits. Clinical demographics, including age, sex, body mass index, comorbidities, psoas muscle index, and spinal disease, were also recorded. RESULTS: This study demonstrated a significant correlation between high serum periostin levels and IVDD severity, as indicated by a high cumulative Pfirrmann score. Serum periostin levels were identified as an independent risk factor for IVDD in a multivariate regression model. Correlation analysis showed a correlation between periostin levels and Pfirrmann grade at each lumbar level (ρ = 0.458-0.550, p < 0.001) and a strong correlation with cumulative Pfirrmann score (ρ = 0.690, p < 0.001). CONCLUSION: The higher the serum periostin level, the higher the cumulative Pfirrmann score. Multivariate analysis showed that serum periostin was an independent risk factor for IVDD. Periostin levels may be a clinically suitable and useful biomarker for diagnosing IVDD, estimating disease progression and activity, providing prognostic information, and evaluating treatment options.

Functional Improvement and Patient Satisfaction Following Conversion of Fused Hip to Total Hip Arthroplasty.

BACKGROUND: This study aimed to determine the clinical outcomes, predictors of suboptimal functional improvement, and factors influencing patient satisfaction following conversion of a fused hip to total hip arthroplasty (THA). METHODS: A retrospective analysis of clinical and radiographic data was performed on 83 patients (83 hips) who underwent fused hip conversion to THA. Implant survival and predictors of poor functional outcome (Harris hip score < 70) were analyzed. In addition, factors associated with patient dissatisfaction (visual analog scale < 25th percentile) were analyzed in 63 patients (63 hips) who completed a patient-reported outcome measures questionnaire. RESULTS: The median Harris hip score improved from 55 (range, 18 to 77) to 78 (range, 36 to 100) at a mean follow-up of 10.2 ± 4.8 years (P < .001). Implant survival was 97.4% at 10 years and 91.3% at 20 years, with any revision as the endpoint. Multivariate analysis identified preoperative reliance on mobility aids as an independent predictor of poor functional outcome (P = .021). There were 48 of 63 patients (76%) satisfied (satisfaction visual analog scale ≥80) with the operated hip. Demographics and preoperative/postoperative clinical data did not differ between satisfied and unsatisfied patients. Among the patient-reported outcome measures, the Forgotten Joint Score-12 emerged as an independent discriminator of patient satisfaction. CONCLUSIONS: Conversion of a fused hip to THA provides functional improvement, favorable implant survival, and high patient satisfaction. However, patients dependent on mobility aids may experience suboptimal functional recovery, underscoring the need for careful preoperative counseling and patient selection.

Risk factors for progression of the severity of locomotive syndrome: A two-year longitudinal observational study.

BACKGROUND: The risk factors for progression of severity of locomotive syndrome (LS) remain unclear. METHODS: We conducted a longitudinal observational study of 1148 community-dwelling residents (median age, 68.0 years old; 548 males, 600 females) from 2016 to 2018. LS was assessed by the 25-question Geriatric Locomotive Function Scale (GLFS-25), and total scores of ≤6 points, 7-15 points, 16-23 points, and ≥24 points were diagnosed as non-LS, LS-1, LS-2, and LS-3, respectively. If the LS severity in 2018 was higher than in 2016, the case was defined as progression of LS severity; otherwise, it was defined as non-progressive LS. We compared the age, gender, body mass index, smoking status, alcohol consumption, living situation, car use, chronic musculoskeletal pain, comorbidities, metabolic syndrome, physical activity, and LS severity in 2016 between the progression and non-progression groups. Furthermore, a multivariate logistic regression analysis was performed to elucidate the risk factors for progression of LS severity. RESULTS: Participants in the progression group had a significantly older age, a lower rate of car use, a higher rate of low back pain, a higher rate of hip pain, a higher rate of knee pain, a higher GLFS-25 total score, and a higher rate of LS-2 than those in the non-progression group. The multivariate logistic regression analysis revealed that older age, female gender, higher body mass index (≥25.0 kg/m2), presence of low back pain, and presence of hip pain were risk factors for the progression of LS within two years. CONCLUSIONS: To prevent the progression of LS severity, related prophylaxis strategies should be implemented, especially for individuals with the above-mentioned characteristics. Further longitudinal studies with a longer observation period are necessary.

Capsular and fascial closure with barbed sutures reduces blood loss compared to traditional interrupted sutures in total hip arthroplasty.

BACKGROUND: STRATAFIX, a recently introduced barbed suture device, incorporates self-anchoring, knotless sutures with higher tensile strength and enhanced tissue-holding capacity compared to traditional braided absorbable sutures. This study aimed to compare the efficacy of barbed sutures and interrupted sutures in capsular and fascial closure during total hip arthroplasty. METHODS: We retrospectively reviewed the records of patients who underwent total hip arthroplasty between April 2017 and March 2021. Overall, 547 patients were evaluated, comprising 77 men and 470 women (mean age: 64.5 years). Among them, 330 patients were in the interrupted suture (control) group, while 217 were in the barbed suture (BS) group. Data on surgical time, perioperative hemoglobin, length of hospital stay, complications such as transfusions and delayed wound healing, and dislocation rates were collected during the latest outpatient follow-up and compared between the two groups. RESULTS: No differences were observed in intraoperative blood loss between the groups. However, the BS group exhibited significantly longer operative time, as well as significantly lower postoperative blood loss, total blood loss, and postoperative hemoglobin drop compared to the control group. Dislocation was reported in two cases within the control group, whereas no instances were recorded in the BS group. CONCLUSION: The use of barbed sutures demonstrated effectiveness in reducing perioperative blood loss for capsular and fascial closure during total hip arthroplasty.

Nupr1 deficiency downregulates HtrA1, enhances SMAD1 signaling, and suppresses age-related bone loss in male mice.

Nuclear protein 1 (NUPR1) is a stress-induced protein activated by various stresses, such as inflammation and oxidative stress. We previously reported that Nupr1 deficiency increased bone volume by enhancing bone formation in 11-week-old mice. Analysis of differentially expressed genes between wild-type (WT) and Nupr1-knockout (Nupr1-KO) osteocytes revealed that high temperature requirement A 1 (HTRA1), a serine protease implicated in osteogenesis and transforming growth factor-ß signaling was markedly downregulated in Nupr1-KO osteocytes. Nupr1 deficiency also markedly reduced HtrA1 expression, but enhanced SMAD1 signaling in in vitro-cultured primary osteoblasts. In contrast, Nupr1 overexpression enhanced HtrA1 expression in osteoblasts, suggesting that Nupr1 regulates HtrA1 expression, thereby suppressing osteoblastogenesis. Since HtrA1 is also involved in cellular senescence and age-related diseases, we analyzed aging-related bone loss in Nupr1-KO mice. Significant spine trabecular bone loss was noted in WT male and female mice during 6-19 months of age, whereas aging-related trabecular bone loss was attenuated, especially in Nupr1-KO male mice. Moreover, cellular senescence-related markers were upregulated in the osteocytes of 6-19-month-old WT male mice but markedly downregulated in the osteocytes of 19-month-old Nupr1-KO male mice. Oxidative stress-induced cellular senescence stimulated Nupr1 and HtrA1 expression in in vitro-cultured primary osteoblasts, and Nupr1 overexpression enhanced p16ink4a expression in osteoblasts. Finally, NUPR1 expression in osteocytes isolated from the bones of patients with osteoarthritis was correlated with age. Collectively, these results indicate that Nupr1 regulates HtrA1-mediated osteoblast differentiation and senescence. Our findings unveil a novel Nupr1/HtrA1 axis, which may play pivotal roles in bone formation and age-related bone loss.

Oxford Hip Scores, Floor-Sitting Score Trajectories, and Postoperative Satisfaction Rates at 10 Years After Primary Total Hip Arthroplasty.

BACKGROUND: Available evidence on outcomes at 5 years and beyond for total hip arthroplasty (THA) is mainly limited to patient-reported outcome measures (PROMs). This study documented the trajectory of functional measurement using the Oxford hip score (OHS) and floor-sitting posture in Japan for up to 10 years post-THA and investigated predictors of dissatisfaction at 10 years with THA. METHODS: Patients scheduled for primary THA at a university hospital in Japan between 2003 and 2006 were enrolled in this prospective study. Overall, 826 preoperative participants were eligible for follow-up, with response rates ranging from 93.6% to 69.4% at each postoperative survey point. The OHS and floor-sitting scores were calculated using a self-administered questionnaire 6 times up to 10 years postoperatively. Patient satisfaction, including general surgery, walking ability, and activities of daily living (ADL), was assessed in the 10-year survey. RESULTS: The linear mixed-effects model demonstrated a postoperative improvement, peaking at 7 years for OHS and 5 years earlier for the floor-sitting score. The postoperative overall surgical dissatisfaction at 10 years with THA was very low (3.2%). No predictors of surgical dissatisfaction were identified in the logistic regression analyses. Predictors of walking ability dissatisfaction were older age, men, and worse OHS at 1 year postoperatively. Predictors of ADL dissatisfaction were poorer preoperative and 1-year postoperative floor-sitting scores and 1-year postoperative OHS. CONCLUSION: The floor-sitting score is a simple PROM suitable for the Japanese population; other populations would require a scale suitable for their lifestyles.

Predictors of preoperative deep vein thrombosis in hip fractures: A systematic review and meta-analysis.

BACKGROUND: The predictors of preoperative deep vein thrombosis (DVT) in patients with hip fractures remain unclear. Therefore, this study describes the results of a systematic review and meta-analysis of relevant peer-reviewed literature on this topic. METHODS: We searched PubMed, Google Scholar, Cochrane Library, Web of Science, and MEDLINE for articles published in English on the predictors of preoperative DVT in hip fractures. We calculated pooled odds ratios (OR) or mean differences (MD) for the DVT groups as compared with the non-DVT groups for each variable, including gender, age, body mass index, injury side, current smoking status, time from injury to admission, time from injury to surgery, fracture type, hypertension, arrhythmia, coronary artery disease, diabetes, stroke, kidney disease, liver disease, lung disease, malignancy, rheumatoid arthritis, D-dimer, fibrinogen, activated partial thromboplastin time, prothrombin time, thrombin time, hemoglobin, albumin, total cholesterol, and triglycerides. RESULTS: We included 9 studies involving 3,123 Asian patients with hip fractures (DVT, n = 570; non-DVT, n = 2,553). Being female (OR = 1.27; 95% confidence interval [CI] 1.04-1.56; p = 0.02), being of advanced age (MD = 1.63; 95% CI 0.80-2.47; p = 0.0001), having a longer time from injury to admission (MD = 0.80; 95% CI 0.48-1.12; p < 0.00001), having a longer time from injury to surgery (MD = 2.20; 95% CI 1.53-2.88; p < 0.00001), and the presence of kidney disease (OR = 1.76; 95% CI 1.04-2.96; p = 0.03) were correlated with a high risk of DVT. However, we found no significant differences between the two groups in the other predictors. CONCLUSIONS: Evidence indicates that being female, being of advanced age, having a longer time from injury to admission, having a longer time from injury to surgery, and having kidney disease are significantly correlated with a high risk of preoperative DVT in Asian patients with hip fracture. Further investigations with patients of other ethnicities are required.

The association of comorbidities with the 25-question geriatric locomotive function scale and the diagnosis of locomotive syndrome.

BACKGROUND: No studies have provided statistical evidence of the relationship between comorbidities and locomotive syndrome (LS). We therefore investigated the association of comorbidities with the 25-question Geriatric Locomotive Function Scale (GLFS-25) and the diagnosis of LS in community-dwelling residents. METHODS: This cross-sectional study was conducted on 2612 community-dwelling residents (≥40 years old) who attended a 'basic health checkup'. There were 432 participants with comorbidities (45 with cerebrovascular diseases, 133 with cardiovascular diseases, 83 with pulmonary diseases, 108 with renal diseases, and 63 with multiple diseases) and 2180 participants without comorbidities. Subjects with a GLFS-25 total score of ≤6 points, 7-15 points, 16-23 points, and ≥24 points were diagnosed with non-LS, LS-1, LS-2, and LS-3, respectively. The domain scores covered body pain (items 1-4), movement-related difficulty (items 5-7), usual care (items 8-11 and 14), social activities (items 12, 13, and 15-23), and cognition (items 24 and 25). A multivariate regression analysis and multivariate logistic regression analysis were performed to assess the association between the GLFS-25 scores and comorbidities and between the diagnosis of LS and comorbidities after adjusting for age, sex, body mass index, and smoking status. RESULTS: A multivariate regression analysis showed that comorbidities were significantly related to the GLFS-25 total score and all domain scores. A multivariate logistic regression analysis revealed that comorbidities were significantly related to a diagnosis of LS-1 or more, LS-2 or more, and LS-3 or more. CONCLUSIONS: Comorbidities were associated with increased GLFS-25 domain scores and total score and consequent diagnosis of LS. Therefore, attention should also be paid to the presence of comorbidities when diagnosing LS. Nevertheless, the causal relationship between comorbidities and the GLFS-25 remains unclear, and further studies are therefore required.

Is grip strength useful in screening to predict the severity of locomotive syndrome?

BACKGROUND: This study was conducted to investigate the relationship between grip strength and the 25-question Geriatric Locomotive Function Scale (GLFS-25) score and the diagnosis of locomotive syndrome (LS), and the usefulness of grip strength in screening for LS. METHODS: This cross-sectional study was conducted on 2251 community-dwelling residents (male, n = 1035; female, n = 1216). Subjects with GLFS-25 scores of 0-6 points, 7-15 points, 16-23 points, and 24-100 points were diagnosed with non-LS, LS-1, LS-2, and LS-3, respectively. Multivariate linear regression and multivariate logistic regression analyses were performed to assess the relationship between grip strength and the GLFS-25 score and LS after adjustment for age, sex, and body mass index. A conventional receiver operating characteristic (ROC) curve analysis was used to calculate the optimal cutoff value of grip strength for predicting the severity of LS. The discriminative ability of the model was assessed using the area under the ROC curve (AUC). RESULTS: The multivariate linear regression analysis showed that grip strength was significantly associated with the GLFS-25 score. The multivariate logistic regression analysis revealed that grip strength was significantly associated with the diagnosis of LS. The optimal cutoff values of grip strength for identifying LS-1 or more, LS-2 or more, and LS-3 or more were 36.0 kg (sensitivity 65.7%, specificity 57.1%, AUC 0.66), 35.0 kg (sensitivity 70.0%, specificity 57.5%, AUC 0.70), and 34.0 kg (sensitivity 67.2%, specificity 62.5%, AUC 0.70), respectively, in males, and 24.0 kg (sensitivity 69.1%, specificity 45.4%, AUC 0.61), 23.0 kg (sensitivity 69.5%, specificity 52.3%, AUC 0.67), and 22.0 kg (sensitivity 69.1%, specificity 61.0%, AUC 0.69) in females. CONCLUSIONS: The use of grip strength in screening to predict the severity of LS may not be clinically useful. However, the results will increase our understanding of the relationship between grip strength and the GLFS-25 scores and LS.

Long-term antibacterial activity of silver-containing hydroxyapatite coatings against Staphylococcus aureus in vitro and invivo.

BACKGROUND: The potential of silver-containing hydroxyapatite (Ag-HA) coatings to prevent orthopaedic implant-associated infection was explored previously; however, the resistance of Ag-HA coatings to late-onset orthopaedic infections is unknown. This study aimed to evaluate the long-term Ag+ elution and antibacterial properties of the Ag-HA coatings through in vitro and in vivo experiments. METHODS: Ag-HA-coated disc specimens were immersed in fetal bovine serum (FBS) for six months. Ag concentration was measured over time using inductively coupled plasma-mass spectrometry to evaluate Ag release. The hydroxyapatite (HA)- or Ag-HA-coated disc specimens were immersed in FBS for 3 months to elute Ag+ for in vitro experiments. Methicillin-resistant Staphylococcus aureus (MRSA) suspensions were inoculated onto each disc; after 48 h, the number of colonies and the biofilm volume were measured. HA- or Ag-HA-coated disc specimens were inserted under the skin of Sprague-Dawley rats for three months for in vivo experiments. In in vivo experiment 1, specimens were inoculated with MRSA and the number of colonies was counted after 48 h. In in vivo experiment 2, the specimens were inoculated with bioluminescent S. aureus Xen36 cells, and bioluminescence was measured using an in vivo imaging system. RESULTS: The Ag-HA-coated disc specimens continued to elute Ag+ after six months. The biofilm volume in the Ag-HA group was lower than in the HA group. In in vitro and in vivo experiment 1, the bacterial counts in the Ag-HA group were lower than those in the HA group. In in vivo experiment 2, the bioluminescence in the Ag-HA group was lower than that in the HA group on days 1-7 after inoculation. CONCLUSIONS: The Ag-HA-coated discs continued to elute Ag+ for a long period and exhibited antibacterial activity and inhibition of biofilm formation against S. aureus. The Ag-HA coatings have the potential to reduce late-onset orthopaedic implant-associated infections.

How long will it take to reach the gender diversity goal for orthopaedics in Japan?

BACKGROUND: In Japan, orthopaedics is one of the medical fields with the lowest proportion of women. This study analyses the change in gender diversity over the past decade and estimates the time required to achieve the 30% gender diversity goal, according to the critical mass in Japan in 2020. METHODS: We investigated the demographic composition of orthopaedic surgeons in 2020 by age group, the gender ratio of the main clinical fields from 2010 to 2020, and estimated the time required for the bottom 10 (i.e., least diverse) medical departments in Japan to reach the proportion of 30% women. We used simple linear regression analyses to clarify the number of years. RESULTS: In 2020, the population pyramid of orthopaedic surgeons showed that those in their 50s were the largest component with 24.1%, followed by those in their 40s and 30s with 22.3% and 19.4%, respectively. The percentage of women orthopaedic surgeons increased slightly from 4.1% in 2010 to 5.7% in 2020. This means that to achieve the proportion of 30% women at the current annual increase rate, orthopaedics would require up to 160 years, cardiovascular 149 years, and neurosurgery 135 years. CONCLUSION: Contrary to the recent increase in the number of women physicians, there has been only a slight increase in the number of women orthopaedic surgeons over the past decade. Moreover, the number of young male orthopaedic surgeons has decreased. As current orthopaedic surgeons age and retire, Japan will soon face an overall shortage of orthopaedic surgeons. Issues that must still be addressed in Japanese orthopaedics include educating men and women about gender diversity and bias, changing stereotypes about surgical lifestyles, improving work-life balance, and diligent and collaborative efforts at both the individual and community levels.

Cardiopulmonary Cement Embolism Following Cement-Augmented Pedicle Screw Fixation: A Narrative Review.

Fixation using cement-augmented pedicle screws (CAPS) is being increasingly performed. However, CAPS-associated cement leakage is a critical problem that can lead to cardiopulmonary cement embolism (CPCE). This narrative review aimed to explore the incidence of and risk factors and treatment strategies for CPCE and cement leakage-related complications after CAPS fixation. Data were extracted from each article, including characteristics of CPCE after CAPS fixation (incidence, location, diagnostic method and criteria, treatment, and outcome and prognosis). Overall, 28 case series and 14 case reports that met the inclusion criteria were included. Of the 1974 cases included in the review, CPCE was noted in 123, symptomatic CPCE in 35, and death in six, respectively. The frequencies of PCE and symptomatic PCE after CAPS fixation were 6% (range: 0-28.6%) and 1.3% (range: 0-26%), respectively. The range of frequencies of PCE and symptomatic PCE after CAPS fixation may have been wide because the definition of CPCE and data collection methods differed among the reports analyzed. Since PCE due to large cement emboli may be primarily related to the surgical technique, improved technique, such as minimizing the number of CAPSs by injecting low-volume high-viscosity cement at low velocity and pressure, and careful observation of cement leakage during CAPS insertion may reduce PCE associated with cement leakage. Spinal surgeons should pay more attention to the occurrence of CPCE during and after CAPS insertion, which can cause serious complications in some patients.

A novel role of helix-loop-helix transcriptional factor Bhlhe40 in osteoclast activation.

The basic helix-loop-helix transcriptional factor, Bhlhe40 has been shown as a crucial regulator of immune response, tumorigenesis, and circadian rhythms. We identified Bhlhe40 as a possible regulator of osteoclast differentiation and function by shRNA library screening and found that Bhlhe40 was required for osteoclast activation. Bhlhe40 expression was induced in bone marrow macrophages (BMMs) by RANKL, whereas the expression of its homolog Bhlhe41 was decreased in osteoclastogenesis. µCT analysis of tibias revealed that Bhlhe40 knockout (KO) mice exhibited increased bone volume phenotype. Bone morphometric analysis showed that osteoclast number and bone resorption were decreased in Bhlhe40 KO mice, whereas significant differences in the osteoblast parameters were not seen between wild-type (WT) and Bhlhe40 KO mice. In vitro culture of BMMs showed that Bhlhe40 deficiency did not cause difference in osteoclast formation. In contrast, bone resorption activity of Bhlhe40 KO osteoclasts was markedly reduced in comparison with that of WT osteoclasts. Analysis of potential target genes of Bhlhe40 using data-mining platform ChIP-Atlas (http://chip-atlas.org) revealed that predicted target genes of Bhlhe40 were related to proton transport and intracellular vesicle acidification. We then analyzed the expression of proton pump, the vacuolar (V)-ATPases which are responsible for bone resorption. The expression of V-ATPases V1c1 and V0a3 was suppressed in Bhlhe40 KO osteoclasts. In addition, Lysosensor yellow/blue DND 160 staining demonstrated that vesicular acidification was attenuated in vesicles of Bhlhe40 KO osteoclasts. Furthermore, analysis with pH-sensitive fluorescent probe showed that proton secretion was markedly suppressed in Bhlhe40 KO osteoclasts compared to that in WT osteoclasts. Our findings suggest that Bhlhe40 plays a novel important role in the regulation of acid production in osteoclastic bone resorption.

Leukemia/lymphoma-related factor (LRF) or osteoclast zinc finger protein (OCZF) overexpression promotes osteoclast survival by increasing Bcl-xl mRNA: A novel regulatory mechanism mediated by the RNA binding protein SAM68.

RANKL induces NFATc1, a key transcriptional factor to induce osteoclast-specific genes such as cathepsin K, whereas transcriptional control of osteoclast survival is not fully understood. Leukemia/lymphoma-related factor (LRF) in mouse and osteoclast zinc finger protein (OCZF) in rat are zinc finger and BTB domain-containing protein (zBTB) family of transcriptional regulators, and are critical regulators of hematopoiesis. We have previously shown that differentiation and survival were enhanced in osteoclasts from OCZF-Transgenic (Tg) mice. In the present study, we show a possible mechanism of osteoclast survival regulated by LRF/OCZF and the role of OCZF overexpression in pathological bone loss. In the in vitro cultures, LRF was highly colocalized with NFATc1 in cells of early stage in osteoclastogenesis, but only LRF expression persisted after differentiation into mature osteoclasts. LRF expression was further enhanced in resorbing osteoclasts formed on dentin slices. Osteoclast survival inhibitor such as alendronate, a bisphosphonate reduced LRF expression. Micro CT evaluation revealed that femurs of OCZF-Tg mice showed significantly lower bone volume compared to that of WT mice. Furthermore, OCZF overexpression markedly promoted bone loss in ovariectomy-induced osteolytic mouse model. The expression of anti-apoptotic Bcl-xl mRNA, which is formed by alternative splicing, was enhanced in the cultures in which osteoclasts are formed from OCZF-Tg mice. In contrast, the expression of pro-apoptotic Bcl-xs mRNA was lost in the culture derived from OCZF-Tg mice. We found that the expression levels of RNA binding splicing regulator, Src substrate associated in mitosis of 68 kDa (Sam68) protein were markedly decreased in OCZF-Tg mice-derived osteoclasts. In addition, shRNA-mediated knockdown of Sam68 expression increased the expression of Bcl-xl mRNA, suggesting that SAM68 regulates the expression of Bcl-xl. These results indicate that OCZF overexpression reduces protein levels of Sam68, thereby promotes osteoclast survival, and suggest that LRF/OCZF is a promising target for regulating pathological bone loss.

PMEPA1 and NEDD4 control the proton production of osteoclasts by regulating vesicular trafficking.

Osteoclast bone resorption activity is critically regulated to maintain bone homeostasis. Osteoclasts resorb bone by producing protons and acid hydrolase via lysosomal secretion, however, a detailed mechanism remains elusive. PMEPA1 is a vesicular membrane protein, which binds to the NEDD4 family member of ubiquitin ligases. We have previously reported that Pmepa1 is highly expressed in bone resorbing osteoclasts, and regulates bone resorption. Here, we investigated the mechanism of bone resorption regulated by PMEPA1. Mutant mice lacking NEDD4-binding domains of PMEPA1 displayed enhanced bone volume, and reduced bone resorption activity in comparison with those of WT mice. Analysis with pH-sensitive fluorescence probe revealed that proton secretion from osteoclasts significantly decreased in Pmepa1 mutant osteoclasts. Immunofluorescence analysis revealed that PMEPA1 was colocalized with NEDD4, V0A3, and V0D2 subunits of vacuolar ATPase, which regulate the proton production of osteoclasts. In addition, Nedd4 knockdown reduced bone resorption and proton secretion of osteoclasts. Furthermore, Pmepa1 mutation and Nedd4 knockdown altered the cytoplasmic distribution of components of V-ATPase and expression of autophagy-related proteins, suggesting that lysosomal secretion is affected. Collectively, these findings indicate that PMEPA1 controls proton secretion from osteoclasts via NEDD4 by regulating vesicular trafficking, and NEDD4 is an important regulator of bone resorption.

Application of contralateral osteotomy for the en bloc resection of paraspinal and spinal tumours: a report of three cases.

We herein report the effectiveness of contralateral osteotomy of the pedicle and posterolateral elements for en bloc resection (COPPER) of paraspinal and spinal tumours. This surgical method allows for complete resection of the localized tumour in the lateral posterior lesion without removing the entire vertebral body, as in total en bloc spondylectomy. Complete resection of paraspinal and spinal tumours is challenging for spinal surgeons because of anatomical complexities. Although the COPPER method has been introduced as a less invasive surgical procedure for wide resection of spinal tumours, no studies have reported the usefulness of this technique. We identified three patients with paraspinal or spinal tumours who underwent wide resection using the COPPER method and reviewed their clinical, radiological, and pathological outcomes. In all cases, we resected the spinal and paraspinal tumours extending to the anterior column and extravertebral component using the modified COPPER method. All patients underwent en bloc resection with a negative margin. We report three cases of spinal and paraspinal tumours extending to the anterior column and extravertebral component.

Development of a simple screening tool based on the 5-question geriatric locomotive function scale for locomotive syndrome.

BACKGROUND: The optimal cut-off values of the 5-question Geriatric Locomotive Function Scale (GLFS-5) as a screening tool to identify Locomotive Syndrome (LS) diagnosed with the 25-question Geriatric Locomotive Function Scale (GLFS-25) has yet to be fully investigated. This study aimed to construct a simple screening tool, based on the GLFS-5, for the detection of LS-1, LS-2, and LS-3 diagnosed with the GLFS-25. METHODS: This research was approved by the institutional review board of Fukushima Medical University School of Medicine (No. 2907). A cross-sectional study of 1258 consecutive Japanese volunteers with a mean age of 76.0 ± 6.0 years who consecutively attended a basic health checkup was conducted. We excluded individuals of <65 years of age, individuals with comorbidities, and individuals who did not fully complete the GLFS-25. Subjects with a GLFS-25 total score of 0-6 points, 7-15 points, 16-23 points, and 24-100 points were diagnosed with non-LS, LS-1, LS-2, and LS-3, respectively. A conventional receiver-operating characteristic curve analysis was used to confirm the optimal cut-off values of the GLFS-5 total score and their sensitivity and specificity in the identification of LS-1, LS-2, and LS-3, with a preference for slightly higher sensitivity as the intended use of the tool is primarily for screening purposes. RESULTS: The diagnoses of the 1258 subjects were as follows: non-LS (n = 559), LS-1 (n = 396), LS-2 (n = 134), and LS-3 (n = 169). The mean GLFS-5 was 3.3 ± 3.5 points. The optimal cut-off values of the GLFS-5 total score for discriminating LS-1, LS-2, and LS-3 (as a screening tool) were 2 points (sensitivity 91.7% and specificity 77.8%), 4 points (sensitivity 95.7% and specificity 81.7%), and 6 points (sensitivity 92.9% and specificity 90.0%), respectively. CONCLUSIONS: This simple screening tool based on GLFS-5 could help physicians and surgeons to easily and practically predict the severity of LS.

Development of a tool for screening the severity of locomotive syndrome by the loco-check.

BACKGROUND: The loco-check has been widely used to raise awareness of locomotive syndrome (LS) not only in the general population but also among medical practitioners. However, a screening tool of the loco-check for LS-1, LS-2, and LS-3 has not yet been established. The present study developed a screening tool for use with the loco-check to detect LS-1, LS-2, and LS-3. METHODS: A cross-sectional study of 1659 community-dwelling older adults (730 males, 929 females) with a mean age of 73.8 ± 6.0 years old (range, 65-96 years old) was conducted, based on the Standards for Reporting Diagnostic Accuracy (STARD). All subjects underwent the loco-check as an index test and the 25-question Geriatric Locomotive Function Scale (GLFS-25) as a reference standard at the same time. Subjects with a GLFS-25 total score of ≤6 points, 7-15 points, 16-23 points, and ≥24 points were diagnosed with non-LS, LS-1, LS-2, and LS-3, respectively. A conventional receiver-operating characteristic curve analysis was used to confirm the optimal cut-off values of the loco-check score and their sensitivity and specificity to identify LS-1, LS-2, and LS-3, with a preference for a slightly higher sensitivity as the tool is intended primarily for screening purposes. RESULTS: The optimal cut-off values of the loco-check score to discriminate LS-1, LS-2, and LS-3 as a screening tool were 1 point (sensitivity 85.4% and specificity 64.9%), 2 points (sensitivity 88.8% and specificity 75.1%), and 3 points (sensitivity 87.6% and specificity 84.6%), respectively. CONCLUSIONS: Our findings may help both the general population and medical practitioners become roughly aware of and estimate the severity of LS, which will contribute to its use in community health activities and the dissemination of the concept of LS.