Disulfiram ameliorates bone loss in ovariectomized mice by suppressing osteoclastogenesis.

INTRODUCTION: Disulfiram (DSF), known as an anti-alcoholism drug, has been reported to suppress osteoclast differentiation in vitro; however, it remains uncertain whether DSF is effective in preventing osteoclastogenesis in vivo. This study aimed to investigate the effect of DSF administration in osteoporotic mice and its contribution to osteoclastogenesis in vivo. MATERIALS AND METHODS: The bone phenotype of ovariectomized mice, both treated and untreated with DSF, was examined using microcomputed tomography analysis. Osteoclastic and osteoblastic parameters were assessed through bone morphometric analysis. The direct effect of DSF on osteoblastogenesis in vitro was evaluated via a primary osteoblast culture experiment. The expression of genes related to DSF targets (Nup85, Ccr2, and Ccr5) in osteoclast-lineage cells was examined using scRNA-seq analysis and flow cytometry analysis using the bone marrow cells from ovariectomized mice. The impact of DSF on osteoclast-lineage cells was assessed using primary cultures of osteoclasts. RESULTS: DSF administration ameliorated ovariectomy-induced bone loss and mitigated the increase of osteoclasts without affecting osteoblastogenesis. The scRNA-seq data revealed that osteoclast precursor cells expressed Nup85, Ccr2, and Ccr5. CCR2 and CCR5-positive cells in osteoclast precursor cells within bone marrow increased following ovariectomy, and this increase was canceled by DSF administration. Finally, we found that DSF had a significant inhibitory effect on osteoclastogenesis in the early stage by suppressing Tnfrsf11a expression. CONCLUSION: This study demonstrates that DSF could be a candidate for osteoporosis therapies because it suppresses osteoclastogenesis from an early stage in vivo.

Automatic Hardy and Clapham's classification of hallux sesamoid position on foot radiographs using deep neural network.

BACKGROUND: There is currently no deep neural network (DNN) capable of automatically classifying tibial sesamoid position (TSP) on foot radiographs. METHODS: A DNN was developed to predict TSP according to the Hardy and Clapham's classification. A total of 1554 foot radiographs were used for model development. The validation of the model was conducted using radiographs obtained from 113 consecutive first-visit patients of our foot and ankle clinic. On these 113 radiographs, TSP was independently classified by three foot and ankle surgeons and the DNN, and their results were compared. The weighted kappa value of TSP between the DNN prediction and the median of the three surgeons (KAI) was calculated. RESULTS: The KAI was 0.95 (95 %CI: 0.85- 1.00), indicating sufficient consistency between the surgeons and the DNN. CONCLUSIONS: We have developed a DNN for automated TSP classification that demonstrates sufficient consistency with foot and ankle surgeons. LEVELS OF EVIDENCE: Level 3 - Retrospective Cohort Study.

In vivo kinematic comparison of bi-cruciate retaining total knee arthroplasty between mechanical alignment and functional alignment methods.

Background/objective: This study aimed to clarify the kinematics of bi-cruciate-retaining (BCR) total knee arthroplasty (TKA) by comparing the mechanical alignment (MA) and functional alignment (FA) methods and to evaluate differences between the two alignment methods. Methods: The in vivo kinematics of 20 MA TKA and 20 FA TKA knees were investigated under fluoroscopy during squatting using a two-to three-dimensional registration technique. Accordingly, knee flexion angle, axial rotational angle, varus-valgus angle, anteroposterior translation of the medial and lateral low contact points of the femoral component relative to the tibial component and kinematic pathway were evaluated. Results: No difference in the knee flexion angle was observed between the MA and FA TKA groups. Femoral external rotation was observed in both groups and no significant difference was observed. Significant varus alignment from extension to early flexion range was observed in the FA TKA group. The posterior translation of the medial side was smaller in the FA TKA group than in the MA TKA group. Conversely, no significant difference in the anteroposterior translation of the lateral side was observed. In the kinematic pathway, a medial pivot motion from 0° to 20° of flexion and a lateral pivot motion beyond 20° of flexion were observed in both groups. Conclusion: During squatting in BCR TKA, the FA TKA group significantly showed varus alignment and smaller posterior translation of the medial side than the MA TKA group from extension to early flexion range.

Ten-Year Incidence of Sarcopenia in a Population-Based Cohort: Results from the Research on Osteoarthritis/Osteoporosis Against Disability Study.

OBJECTIVES: To investigate the prevalence and incidence rates of sarcopenia in Japanese community-dwelling people according to the criteria of the Asian Working Group for Sarcopenia 2019 recommendations, using a large-scale population-based cohort over a 10-year follow-up period. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: This study was conducted using data from the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study. In total, 1551 participants (521 men and 1030 women; mean age, 65.8 years) from the second ROAD survey (2008-2-10) were included in this study. METHODS: The participants from the second survey were followed-up at 4, 7, and 10 years. Skeletal muscle mass, handgrip strength, and walking speed were assessed. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019 criteria. The incidence of sarcopenia was calculated using the person-year method. Cox proportional hazard model was used to assess risk factors for incident sarcopenia. RESULTS: The prevalence of sarcopenia was 8.1% (8.8% in men and 7.7% in women), and the prevalence of severe sarcopenia was 2.9% (2.7% in men and 3.1% in women). The incidence rates of sarcopenia were 17.8 per 1000 and 14.5 per 1000 person-years in men and women, respectively. Additionally, the incidence rates of severe sarcopenia were 6.4 per 1000 and 4.2 per 1000 person-years in men and women, respectively. The significant risk factors for the incidence of sarcopenia were age [+1 year; hazard ratio (HR), 1.10; 95% CI, 1.08-1.12] and body mass index (-1 kg/m2; HR, 1.27; 95% CI, 1.20-1.35). The significant risk factors for the incidence of severe sarcopenia were age (+1 year; HR, 1.18; 95% CI, 1.14-1.22) and body mass index (-1 kg/m2; HR, 1.21; 95% CI, 1.10-1.33). CONCLUSIONS AND IMPLICATIONS: The prevalence and incidence rates of sarcopenia in Japan were clarified in this study.

Impact of incidental dural tears on postoperative outcomes in patients undergoing cervical spine surgery: a multicenter retrospective cohort study.

BACKGROUND CONTEXT: Incidental dural tear (DT) during cervical spine surgery is a feared complication. However, its impact on patient-reported outcomes (PROs) remains unclear. PURPOSE: To determine the influence of DTs on PROs 1 year after cervical spine surgery. STUDY DESIGN: Retrospective cohort. PATIENT SAMPLE: Patients undergoing elective cervical spine surgery for cervical spondylosis, ossification of the posterior longitudinal ligament (OPLL), and cervical disc herniation. OUTCOME MEASURES: Analysis included patients' characteristics, perioperative complications, and PROs both preoperatively and at 1 year postoperatively. METHODS: This study enrolled consecutive patients who underwent elective cervical spine surgery at 13 high-volume spine centers. All patients were required to complete questionnaires both preoperatively and 1 year postoperatively, which included PROs such as numerical rating scales of pain or dysesthesia for each part of the body, Neck Disability Index NDI, and Core Outcome Measures Index. Patients were divided into 2 groups based on the presence (DT+) or absence (DT-) of dural injury. Comparisons were made regarding patient background, perioperative complications, and pre and postoperative PROs. Propensity score matching was also utilized to adjust for patient background, and further comparisons were made regarding complication rates and PROs. RESULTS: Out of 2,704 patients, dural tears were identified in 97 (3.6%) cases. The DT+ group had a significantly higher proportion of fixation surgeries, upper cervical surgeries, OPLL, and revision surgeries. Perioperative complications were significantly higher in the DT+ group, including intraoperative nerve damage, postoperative paralysis, surgical site infections (SSI), and cerebrovascular complications. Outcomes collected from 2,163 patients (79.9%) revealed significantly more severe neck and upper limb pain in the DT+ group. After propensity score matching, significant differences persisted in postoperative paralysis and SSI in the DT+ group, but no significant differences were observed in PROs. CONCLUSIONS: Patients with dural tears showed nearly equivalent postoperative outcomes at 1 year following cervical spine surgery compared to those without dural tears. However, the incidence of perioperative complications was higher, emphasizing the need for careful management.

Intrinsic Risk Factors for Noncontact Anterior Cruciate Ligament Injury in Young Female Soccer Players: A Prospective Cohort Study.

BACKGROUND: Previous studies have attempted to determine prognostic factors for predicting the occurrence of noncontact anterior cruciate ligament (ACL) injuries. However, studies on risk factors for noncontact ACL injuries in Asian female soccer players are limited. PURPOSE: To identify intrinsic risk factors for noncontact ACL injuries among young female Asian soccer players. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This study evaluated 145 female Japanese soccer players for potential risk factors for noncontact ACL injury during the preseason medical assessment. In total, 25 variables were examined-including anthropometric data, joint range of motion, muscle flexibility, muscle strength, and balance measurements. Participants were monitored throughout a single season for noncontact ACL injuries diagnosed by physicians. RESULTS: Noncontact ACL injuries occurred in 13 knees of 13 players (9%). Lower hamstring-to-quadriceps ratio (0.44 ± 0.07 vs 0.50 ± 0.10; P = .04), greater knee extension muscle strength (3.2 ± 0.5 vs 2.7 ± 0.5 N·m/kg; P < .01), and longer playing experience (10.8 ± 3 vs 8.1 ± 4.2 years; P = .02) were significantly associated with new-onset noncontact ACL injuries in young female soccer players. No statistically significant between-group differences were found for any other variables. CONCLUSION: New-onset noncontact ACL injury in young female soccer players was significantly associated with lower hamstring-to-quadriceps ratio, greater knee extension muscle strength, and longer soccer experience. These findings will help develop strategies for preventing noncontact ACL injuries among female soccer players.

Increased early complications after total hip arthroplasty compared with hemiarthroplasty in older adults with a femoral neck fracture.

Aims: The aim of this study was to compare the early postoperative mortality and morbidity in older patients with a fracture of the femoral neck, between those who underwent total hip arthroplasty (THA) and those who underwent hemiarthroplasty. Methods: This nationwide, retrospective cohort study used data from the Japanese Diagnosis Procedure Combination database. We included older patients (aged ≥ 60 years) who underwent THA or hemiarthroplasty after a femoral neck fracture, between July 2010 and March 2022. A total of 165,123 patients were included. The THA group was younger (mean age 72.6 (SD 8.0) vs 80.7 years (SD 8.1)) and had fewer comorbidities than the hemiarthroplasty group. Patients with dementia or malignancy were excluded because they seldom undergo THA. The primary outcome measures were mortality and complications while in hospital, and secondary outcomes were readmission and reoperation within one and two years after discharge, and the costs of hospitalization. We conducted an instrumental variable analysis (IVA) using differential distance as a variable. Results: The IVA analysis showed that the THA group had a significantly higher rate of complications while in hospital (risk difference 6.3% (95% CI 2.0 to 10.6); p = 0.004) than the hemiarthroplasty group, but there was no significant difference in the rate of mortality while in hospital (risk difference 0.3% (95% CI -1.7 to 2.2); p = 0.774). There was no significant difference in the rate of readmission (within one year: risk difference 1.3% (95% CI -1.9 to 4.5); p = 0.443; within two years: risk difference 0.1% (95% CI -3.2 to 3.4); p = 0.950) and reoperation (within one year: risk difference 0.3% (95% CI -0.6 to 1.1); p = 0.557; within two years: risk difference 0.1% (95% CI -0.4 to 0.7); p = 0.632) after discharge. The costs of hospitalization were significantly higher in the THA group than in the hemiarthroplasty group (difference $2,634 (95% CI $2,496 to $2,772); p < 0.001). Conclusion: Among older patients undergoing surgery for a femoral neck fracture, the risk of early complications was higher after THA than after hemiarthroplasty. Our findings should aid in clinical decision-making in these patients.

Impact of lumbar spine pathology on asymmetrical hallux valgus in a population-based cohort study.

This study aims to investigate the influence of lumbar spine disorders on the development of asymmetric hallux valgus (HV). Data from the fifth survey of the Osteoarthritis/Osteoporosis Against Disability (ROAD) study, a nationwide prospective study in Japan, were analyzed. HV severity was categorized into 4 grades based on the radiographic HV angle, and asymmetric HV was defined as having at least one HV on either side, with a difference of two or more severity grades between the left and right. Controls were matched from both the Normal group (without HV on both sides) and the Symmetric group (HV on at least one side with a difference of one or less severity grades). Univariate analysis assessed lumbar conditions, and multinomial logistic regression analysis explored the association between lumbar spine disorders and asymmetric HV. Among 1997 participants, 27 had asymmetric HV. Univariate analysis revealed a higher incidence of L5 spondylolisthesis and scoliosis in the Asymmetric group. Multinomial logistic regression analysis revealed that scoliosis independently increased the likelihood of asymmetrical HV (Odds ratio [OR] = 3.586, 95%Confidence interval [CI] 1.111-11.582), but showed no significant impact on symmetrical HV (OR 0.910, 95% CI 0.355-2.334). Asymmetric HV is rare but may be associated with lumbar spine disorders, particularly scoliosis.

Comparison of surgical outcomes for cervical radiculopathy by nerve root level.

Cervical radiculopathy might affect finger movement and dexterity. Postoperative features and clinical outcomes comparing C8 radiculopathies with other radiculopathies are unknown. This prospective multicenter study analyzed 359 patients undergoing single-level surgery for pure cervical radiculopathy (C5, 48; C6, 132; C7, 149; C8, 30). Background data and pre- and 1-year postoperative neck disability index (NDI) and numerical rating scale (NRS) scores were collected. The C5-7 and C8 radiculopathy groups were compared after propensity score matching, with clinical significance determined by minimal clinically important differences (MCID). Postoperative arm numbness was significantly higher than upper back or neck numbness, and arm pain was reduced the most (3.4 points) after surgery among the C5-8 radiculopathy groups. The C8 radiculopathy group had worse postoperative NDI scores (p = 0.026), upper back pain (p = 0.042), change in arm pain NRS scores (p = 0.021), and upper back numbness (p = 0.028) than the C5-7 group. NDI achieved MCID in both groups, but neck and arm pain NRS did not achieve MCID in the C8 group. In conclusion, although arm numbness persisted, arm pain was relieved after surgery for cervical radiculopathy. Patients with C8 radiculopathy exhibited worse NDI and change in NRS arm pain score than those with C5-7 radiculopathy.

Can magnetic resonance imaging distinguish clinical stages of frozen shoulder? A state-of-the-art review.

Background: Frozen shoulder (FS) is a common disorder causing shoulder pain and limited motion. Magnetic resonance imaging (MRI) is expected to help diagnose FS and realize the disease stage if stage-specific features are present. We aimed to survey stage-related MRI findings of FS in the literature. Methods: MEDLINE, SCOPUS, and Google Scholar databases were searched with search terms "frozen shoulder" or "adhesive capsulitis" combined with "magnetic resonance imaging." Studies that discussed MRI findings in relation to FS stages were retrieved. The course of FS was divided into stages 1 to 4 according to Hannafin and Chiaia. Results: Two of the noncontrast-enhanced MRI findings were stage-related. T2 signal hyperintensity of the joint capsule was more frequent in stages 1 and 2. The axillary capsule thickness was greater in stages 1 and 2. However, these findings were also seen in the later stages to a lesser degree. Effusion around the long head of biceps, subcoracoid fat obliteration, and coracohumeral ligament thickening were common in FS but their relation to the stages was not evident. Signal enhancement on contrast-enhanced MRI was not consistently linked to stages. Conclusion: T2 signal hyperintensity and axillary capsule thickening are characteristic of the early stages of FS, although MRI alone cannot completely define the disease stage.

Patient-Reported Outcomes and Patient Satisfaction Following Surgery for Thoracic Myelopathy.

Introduction: The association between postoperative patient-reported outcomes (PROs) and patient satisfaction remains poorly defined in patients undergoing surgery for thoracic myelopathy. This study aimed to investigate PROs and patient satisfaction following surgical intervention for thoracic myelopathy. Methods: A prospective cohort of 133 patients who underwent surgery for thoracic myelopathy at 13 hospitals between April 2017 and August 2021 was enrolled. Patient demographics and perioperative complications were recorded. PROs were assessed using questionnaires administered preoperatively and 1 year postoperatively, including the EuroQol-5 dimension, physical and mental component summaries of the 12-item Short-Form Health Survey, Oswestry Disability Index, and numerical rating scales for low back, lower extremity, and plantar pain. Patients were categorized into two groups: satisfied (very satisfied, satisfied, and slightly satisfied) and dissatisfied (neither satisfied nor dissatisfied, slightly dissatisfied, dissatisfied, and very dissatisfied). Results: The mean age of the patients was 66.5 years, comprising 87 men and 46 women. The most common diagnoses were ossification of the ligamentum flavum (48.8%) and thoracic spondylotic myelopathy (26.3%). Seventy-four (55.6%) and 59 (44.3%) patients underwent decompression surgery and underwent decompression with fusion, respectively. Eight patients required reoperation due to postoperative surgical site infection, hematoma, and insufficient decompression in four, three, and one patient. Ninety (67.7%) patients completed both the preoperative and postoperative PRO questionnaires, all of which demonstrated significant improvement. Among them, 58 (64.4%) and 32 (35.6%) reported satisfaction and dissatisfaction with their treatment, respectively. The satisfied group showed superior improvement in PROs than the dissatisfied group, although there were no significant differences in complication rates between the two groups. Conclusions: The 64.4% satisfaction rate observed in patients undergoing surgery for thoracic myelopathy was lower than that reported in previous studies on cervical or lumbar spine surgery. The dissatisfied group exhibited significantly poorer quality of life (QOL) and higher pain scores than the satisfied group.

Goal-directed osteoporosis treatment: ASBMR/BHOF task force position statement 2024.

The overarching goal of osteoporosis management is to prevent fractures. A goal-directed approach to long-term management of fracture risk helps ensure that the most appropriate initial treatment and treatment sequence is selected for individual patients. Goal-directed treatment decisions require assessment of clinical fracture history, vertebral fracture identification (using vertebral imaging as appropriate), measurement of bone mineral density (BMD), and consideration of other major clinical risk factors. Treatment targets should be tailored to each patient's individual risk profile and based on the specific indication for beginning treatment, including recency, site, number and severity of prior fractures, and BMD levels at the total hip, femoral neck, and lumbar spine. Instead of first-line bisphosphonate treatment for all patients, selection of initial treatment should focus on reducing fracture risk rapidly for patients at very high and imminent risk, such as in those with recent fractures. Initial treatment selection should also consider the probability that a BMD treatment target can be attained within a reasonable period of time and the differential magnitude of fracture risk reduction and BMD impact with osteoanabolic versus antiresorptive therapy. This position statement of the ASBMR/BHOF Task Force on Goal-Directed Osteoporosis Treatment provides an overall summary of the major clinical recommendations about treatment targets and strategies to achieve those targets based on the best evidence available, derived primarily from studies in older postmenopausal women of European ancestry.

Goal-directed treatment can help healthcare providers recommend the best treatments for individual patients to prevent fractures. The goal-directed strategy considers the site, number, and recency of prior fractures. This may require imaging for spine fractures, which may not have caused pain. Treatment decisions also require bone mineral density (BMD) measurement and consideration of other major risk factors. In contrast to the standard approach, same first treatment for all, treatment selection is tailored to an individual's risk. In patients with recent fractures of the spine, hip, or pelvis, fracture risk is very high and treatment should rapidly reduce that risk. For others, the target is a specific BMD level and should consider the likelihood that the treatment target can be attained within a reasonable period of time, which differs for osteoporosis medications. After initial therapy, BMD should be assessed to determine if the target has been achieved. If so, strategies should focus on maintaining BMD. If the target is not yet achieved, treatment should be intensified, or continued if it is already the most potent option. This position statement represents a consensus of expert recommendations about treatment targets and strategies to achieve those targets based on the best available evidence.

Combined Anterolateral and Posterior Approach in Total Hip Arthroplasty for Chronic Post-traumatic Hip Dislocation: A Case Report.

Hip dislocation is rare, and it typically results from high-energy trauma such as traffic accidents. Its management involves prompt reduction of the dislocated hip to minimize the risk of subsequent femoral head necrosis. Consequently, cases of chronic hip dislocation are extremely rare. This report presents a case of a 33-year-old male with chronic posterior hip dislocation due to a traffic accident 13 years ago. The left femoral head was completely dislocated posteriorly from the acetabulum, forming a false acetabulum with an arthritic change. The patient experienced difficulty walking and performing daily activities due to pain. We performed a total hip arthroplasty (THA) using a combined anterolateral and posterior approach. The outcome was favorable, with no complications during the two-year follow-up period. THA using a combined anterolateral and posterior approach is a valuable option for patients with chronic post-traumatic hip dislocation because it offers the advantages of optical visibility and the management of the adhered soft tissues.

Osteoporosis, spinal degenerative disorders, and their association with low back pain, activities of daily living, and physical performance in a general population.

Osteoporosis, vertebral fractures, and spinal degenerative diseases are common conditions that often coexist in older adults. This study aimed to determine the factors influencing low back pain and its impact on activities of daily living (ADL) and physical performance in older individuals with multiple comorbidities. This cross-sectional study was part of a large-scale population-based cohort study in Japan, involving 1009 participants who underwent spinal magnetic resonance imaging (MRI) to assess cervical cord compression, radiographic lumbar spinal stenosis, and lumbar disc degeneration. Vertebral fractures in the thoracolumbar spine were evaluated using sagittal MRI with a semi-quantitative method. Bone mineral density was measured using dual-energy X-ray absorptiometry. Low back pain, Oswestry Disability Index (ODI), and physical performance tests, such as one-leg standing time, five times chair-stand time, maximum walking speed, and maximum step length, were assessed. Using clinical conditions as objective variables and image evaluation parameters as explanatory variables, multiple regression analysis showed that vertebral fractures were significantly associated with low back pain and ODI. Vertebral fractures and osteoporosis significantly impacted physical performance, whereas osteoporosis alone did not affect low back pain or ODI. Our findings contribute to new insights into low back pain and its impact on ADL and physical performance.

Outcomes after hip fracture surgery in patients receiving non-steroidal anti-inflammatory drugs alone, acetaminophen alone, or both.

Aims: The use of multimodal non-opioid analgesia in hip fractures, specifically acetaminophen combined with non-steroidal anti-inflammatory drugs (NSAIDs), has been increasing. However, the effectiveness and safety of this approach remain unclear. This study aimed to compare postoperative outcomes among patients with hip fractures who preoperatively received either acetaminophen combined with NSAIDs, NSAIDs alone, or acetaminophen alone. Methods: This nationwide retrospective cohort study used data from the Diagnosis Procedure Combination database. We included patients aged ≥ 18 years who underwent surgery for hip fractures and received acetaminophen combined with NSAIDs (combination group), NSAIDs alone (NSAIDs group), or acetaminophen alone (acetaminophen group) preoperatively, between April 2010 and March 2022. Primary outcomes were in-hospital mortality and complications. Secondary outcomes were opioid use postoperatively; readmission within 90 days, one year, and two years; and total hospitalization costs. We used propensity score overlap weighting models, with the acetaminophen group as the reference group. Results: We identified 93,018 eligible patients, including 13,068 in the combination group, 29,203 in the NSAIDs group, and 50,474 in the acetaminophen group. Propensity score overlap weighting successfully balanced patient characteristics among the three groups, with no significant difference in in-hospital mortality rates observed among the groups (combination group risk difference 0.0% (95% CI -0.5 to 0.4%); NSAIDs group risk difference -0.2% (95% CI -0.5 to 0.2%)). However, the combination group exhibited a significantly lower risk of in-hospital complications than the acetaminophen group (risk difference -1.9% (95% CI -3.2 to -0.6%)) as well as a significantly lower risk of deep vein thrombosis (risk difference -1.4% (95% CI -2.2 to -0.7%)). Furthermore, total hospitalization costs were higher in the NSAIDs group than in the acetaminophen group (difference USD $438 (95% CI 249 to 630); p < 0.001). No significant differences in other secondary outcomes were observed among the three groups. Conclusion: The combination of acetaminophen with NSAIDs appears to be safe and advantageous in terms of reducing in-hospital complications.

Oncostatin M-driven macrophage-fibroblast circuits as a drug target in autoimmune arthritis.

BACKGROUND: Recent single-cell RNA sequencing (scRNA-seq) analysis revealed the functional heterogeneity and pathogenic cell subsets in immune cells, synovial fibroblasts and bone cells in rheumatoid arthritis (RA). JAK inhibitors which ameliorate joint inflammation and bone destruction in RA, suppress the activation of various types of cells in vitro. However, the key cellular and molecular mechanisms underlying the potent clinical effects of JAK inhibitors on RA remain to be determined. Our aim is to identify a therapeutic target for JAK inhibitors in vivo. METHODS: We performed scRNA-seq analysis of the synovium of collagen-induced arthritis (CIA) mice treated with or without a JAK inhibitor, followed by a computational analysis to identify the drug target cells and signaling pathways. We utilized integrated human RA scRNA-seq datasets and genetically modified mice administered with the JAK inhibitor for the confirmation of our findings. RESULTS: scRNA-seq analysis revealed that oncostatin M (OSM) driven macrophage-fibroblast interaction is highly activated under arthritic conditions. OSM derived from macrophages, acts on OSM receptor (OSMR)-expressing synovial fibroblasts, activating both inflammatory and tissue-destructive subsets. Inflammatory synovial fibroblasts stimulate macrophages, mainly through IL-6, to exacerbate inflammation. Tissue-destructive synovial fibroblasts promote osteoclast differentiation by producing RANKL to accelerate bone destruction. scRNA-seq analysis also revealed that OSM-signaling in synovial fibroblasts is the main signaling pathway targeted by JAK inhibitors in vivo. Mice specifically lacking OSMR in synovial fibroblasts (Osmr∆Fibro) displayed ameliorated inflammation and joint destruction in arthritis. The JAK inhibitor was effective on the arthritis of the control mice while it had no effect on the arthritis of Osmr∆Fibro mice. CONCLUSIONS: OSM functions as one of the key cytokines mediating pathogenic macrophage-fibroblast interaction. OSM-signaling in synovial fibroblasts is one of the main signaling pathways targeted by JAK inhibitors in vivo. The critical role of fibroblast-OSM signaling in autoimmune arthritis was shown by a combination of mice specifically deficient for OSMR in synovial fibroblasts and administration of the JAK inhibitor. Thus, the OSM-driven synovial macrophage-fibroblast circuit is proven to be a key driver of autoimmune arthritis, serving as a crucial drug target in vivo.

A crossover comparison of patient satisfaction with two teriparatide regimens: primary results of the Japanese Osteoporosis Intervention Trial 06 (JOINT-06).

INTRODUCTION: This study aimed to compare treatment satisfaction with two dosing regimens (two teriparatide [TPTD] self-injection systems) in osteoporosis patients at high risk of fracture. MATERIALS AND METHODS: In this open-label crossover randomized trial comparing self-injected once-daily (1/D)-TPTD with self-injected twice-weekly (2/W)-TPTD, three satisfaction variables were evaluated by questionnaire for 2 years. The primary endpoint was overall satisfaction and secondary endpoints were satisfaction with treatment effectiveness and with utility of the self-injection device. Changes in quality of life (QOL) assessed by EuroQol-5 Dimension, pain assessed by visual analogue scale (VAS), and anthropometric parameters were also analyzed. Safety was evaluated based on the incidence and severity of adverse events (AEs). RESULTS: The 1/D-TPTD and 2/W-TPTD groups consisted of 180 (75.9 ± 7.3 years) and 179 (age: 75.5 ± 6.9 years) patients, respectively. After 26 weeks of treatment, no significant between-group difference in the persistence rate (79.4% vs 72.6% in the 1/D-TPTD and 2/W-TPTD groups, respectively), distributions of overall satisfaction scores, and satisfaction with treatment (p > 0.05) were observed. However, several items of satisfaction with the utility of the injection device were significantly higher in the 2/W-TPTD group (p < 0.05). Statistical improvements from baseline values were observed in QOL and pain VAS in both groups (p < 0.05). No serious AEs were reported. CONCLUSION: The between-group similarity of overall treatment satisfaction and effectiveness scores and between-group difference in satisfaction with the utility of the self-injection device was useful information for real-world treatment of osteoporosis. Both medication regimens were well tolerated.

Inflammatory diseases causing joint and bone destruction: rheumatoid arthritis and hemophilic arthropathy.

Various diseases and conditions cause joint disorders. Osteoarthritis (OA) is characterized by the degeneration of articular cartilage, synovitis, and anabolic changes in surrounding bone tissues. In contrast, rheumatoid arthritis (RA) and hemophilic arthropathy (HA) display marked destruction of bone tissues caused by synovitis. RA is a representative autoimmune disease. The primary tissue of RA pathogenesis is the synovial membrane and involves various immune cells that produce catabolic cytokines and enzymes. Hemophilia is a genetic disorder caused by a deficiency in blood clotting factors. Recurrent intra-articular bleeding leads to chronic synovitis through excessive iron deposition and results in the destruction of affected joints. Although the triggers for these two joint diseases are completely different, many cytokines and enzymes are common in the pathogenesis of both RA and HA. This review focuses on the similarities between joint and bone destruction in RA and HA. The insights may be useful in developing better treatments for hemophilia patients with arthropathy and osteoporosis by leveraging advanced therapeutics for RA.

A longitudinal population-based study identifies THBS2 as a susceptibility gene for intervertebral disc degeneration.

PURPOSE: Intervertebral disc degeneration (IDD) is a common degenerative disease associated with ageing. Additionally, IDD is recognized as one of the leading causes of low back pain and disability in the working-age population and is the first step in the process leading to degenerative spinal changes. However, the genetic factors and regulatory mechanisms of IDD remain unknown. Therefore, we selected eight single nucleotide polymorphisms of genes to reveal the progression of IDD in a 7-year longitudinal study of the general population in Japan. METHODS: IDD was evaluated in the Wakayama Spine Study (WSS), which is a population-based cohort study. Overall, 574 participants from the general population cohort who underwent whole spine magnetic resonance imaging and provided clinical information were included in this longitudinal survey. RESULTS: The progression of IDD was affected only by THBS2 at the lumbar region, T12-L1 (p = 0.0044) and L3-4 (p = 0.0045). The significant interaction between THBS2 and age with IDD negatively affected the thoracic spines and passively influenced both the thoracolumbar junction and thoracic spines. The higher progression per year of Pfirrmann's score was rapid in young people with age; however, this decelerated the IDD progression per year in different ages. CONCLUSION: Our longitudinal study found the genes associated with IDD progression and that genetic factors' impact on IDD differs depending on disc level and age.