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Background: Osteophytes are commonly used to diagnose and guide knee osteoarthritis (OA) treatment, but their causes are unclear. Although they are not typically the focus of knee arthroplasty surgeons, they can predict case difficulty and length. Furthermore, their extent and location may yield much information about the knee joint status. The aims of this computed tomography-based study in patients awaiting total or partial knee arthroplasty were to: (1) measure osteophyte volume in anatomical subregions and relative change as total volume increases; (2) determine whether medial and/or lateral OA affects osteophyte distribution; and (3) explore relationships between osteophytes and OA severity., Methods: Data were obtained from 4,928 computed tomography scans. Machine-learning-based imaging analyses enabled osteophyte segmentation and quantification, divided into anatomical regions. Mean three-dimensional joint space narrowing was assessed in medial and lateral compartments. A Bayesian model assessed the uniformity of osteophyte distribution. We correlated femoral osteophyte volumes with B-scores, a validated OA status measure., Results: Total tibial (25%) and femoral osteophyte volumes (75%) within each knee correlated strongly (R 2  = 0.85). Medial osteophytes (65.3%) were larger than lateral osteophytes (34.6%), with similar proportions in both the femur and tibia. Osteophyte growth was found in all compartments, and as total osteophyte volume increased, the relative distribution of osteophytes between compartments did not markedly change. No evidence of variation was found in the regional distribution of osteophyte volume between knees with medial, lateral, both, or no three-dimensional joint space narrowing in the femur or tibia. There was a direct relationship between osteophyte volume and OA severity., Conclusions: Osteophyte volume increased in both medial and lateral compartments proportionally with total osteophyte volume, regardless of OA location. The peripheral position of femoral osteophytes does not appear to contribute to load-bearing. This suggests that osteophytic growth represents a 'whole-knee'/global response. This work may have broad applications for knee OA, both surgically and nonoperatively., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain., Objective: To assess symptomatic benefits of methotrexate in knee OA (KOA)., Design: A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41)., Setting: 15 secondary care musculoskeletal clinics in the United Kingdom., Participants: A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion., Intervention: Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia., Measurements: The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs)., Results: A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate ( n  = 77) or placebo ( n  = 78). Follow-up was 86% ( n  = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P  = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P  = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P  = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2)., Limitation: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance., Conclusion: Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months., Primary Funding Source: Versus Arthritis., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0303.

Objectives: To assess non-inferiority of intra-articular injectable polyacrylamide hydrogel (iPAAG) to hyaluronic acid (HA) on symptomatic benefit in individuals with knee osteoarthritis (OA)., Methods: This randomised, controlled, multi-centre trial recruited adults with symptomatic and radiographic knee OA from 3 clinical rheumatology sites in Denmark; two private clinics and one public hospital department. Participants were randomised 1:1 to receive a single intra-articular 6 mL injection of either HA or iPAAG on an outpatient basis. Primary outcome was change from baseline in WOMAC pain subscale after 26 weeks. Secondary outcomes were changes from baseline in WOMAC stiffness and physical function subscales, patients' global assessment of disease impact, EuroQoL-5D-5L, and proportion of positive OMERACT-OARSI responders after 26 and 52 weeks., Results: 239 adults were randomised: 120 to HA and 119 to iPAAG. For the primary outcome, the least squares mean changes in WOMAC pain were -14.8 (95% CI: -18.0 to -11.7) for HA and -18.5 (95% CI: -21.7 to -15.4) for iPAAG; group difference: 3.7 (95% CI: -0.7 to 8.1). The lower boundary of the 95% CI respected the pre-specified non-inferiority margin of 9 WOMAC pain points. No statistically significant differences were observed for the secondary outcomes. For HA, 9 participants (7.6%) reported 13 adverse device effects (ADEs). For iPAAG, 35 participants (28.9%) reported 41 ADEs. All ADEs were mild/moderate, with no serious ADEs reported., Conclusions: iPAAG was found to be as effective and safe as HA for treatment of knee OA symptoms for at least 1 year after a single injection.

Objective: Apocynin (AP) and paeonol (PA) are low molecular weight phenolic compounds with a broad array of anti-inflammatory and immunoregulatory effects. This study assessed of a fixed-dose combination of APPA in people with symptomatic knee osteoarthritis (OA)., Methods: A multi-center, randomized, placebo-controlled, double-blind phase 2a trial enrolled participants with radiographic knee OA (Kellgren-Lawrence, KL, grades 2-3) and pain ≥40/100 on WOMAC pain subscale, and evaluated the efficacy and safety of oral APPA over a 28-day period. APPA 800 mg or matching placebo was administered twice daily in a 1:1 ratio. Post-hoc analyses explored the response to APPA in sub-groups with more severe pain and structural severity., Results: The two groups were comparable at baseline; 152 subjects were enrolled and 148 completed the trial. There was no statistically significant difference between groups with respect to the primary outcome, WOMAC pain (mean difference between groups was -0.89, 95% CI: -5.62, 3.84, p = 0.71), nor WOMAC function or WOMAC total. However, predefined subgroup analyses of subjects with symptoms compatible with nociplastic/neuropathic pain features showed a statistically significant effect of APPA compared to placebo. Adverse events (mainly gastrointestinal) were mild to moderate., Conclusion: Treatment with APPA 800 mg twice daily for 28 days in subjects with symptomatic knee OA was not associated with significant symptom improvement compared to placebo. The treatment was well-tolerated and safe. While the study was not powered for such analysis, pre-planned subgroup analyses showed a significant effect of APPA in subjects with nociplastic pain/severe OA, indicating that further research in the effects of APPA in appropriate patients is warranted., Competing Interests: Declaration of Competing Interest PGC has received consulting fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Galapagos, Genascence, GlaxoSmithKline, Janssen, Levicept, Novartis, Pfizer, Stryker and UCB. RM has no conflict of interest to declare. AR and NL are full-time employees and shareholders of AKL Therapeutics Ltd. ARB and JRA are employees and shareholder in NBCD A/S, and at the time of trial conduct and manuscript preparation, IB was a full-time employee of NBCD A/S. PA is a full-time employee of Sanos Clinic, Vejle, Denmark, and HR a full-time employee of Sanos Clinic Gandrup, Denmark., (Copyright © 2024 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Clinical Practice Guidelines (CPGs) aim to support management of hip and knee osteoarthritis (OA), but recommendations are often conflicting and implementation is poor, contributing to evidence-to-practice gaps. This systematic review investigated the contextual and methodological factors contributing to conflicting recommendations for hip and knee OA., Method: Our systematic review appraised CPGs for managing hip and knee OA in adults ≥18 years (PROSPERO CRD42021276635). We used AGREE-II and AGREE-REX to assess quality and extracted data on treatment gaps, conflicts, biases, and consensus. Heterogeneity of recommendations was determined using Weighted Fleiss Kappa (K). The relationship between (K) and AGREE-II/AGREE-REX scores was explored., Results: We identified 25 CPGs across eight countries and four international organisations. The ACR, EULAR, NICE, OARSI and RACGP guidelines scored highest for overall AGREE-II quality (83%). The highest overall AGREE-REX scores were for BMJ Arthroscopy (80%), RACGP (78%) and NICE (76%). CPGs with the least agreement for pharmacological recommendations were ESCEO and NICE (-0.14), ACR (-0.08), and RACGP (-0.01). The highest agreements were between RACGP and NICE (0.53), RACGP and ACR (0.61), and NICE and ACR (0.91). Decreased internal validity determined by low-quality AGREE scores(<60%) in editorial independence were associated with less agreement for pharmacological recommendations., Conclusion: There were associations between guideline quality and agreement scores. Future guideline development should be informed by robust evidence, editorial independence and methodological rigour to ensure a harmonisation of recommendations. End-users of CPGs must recognise the contextual factors associated with the development of OA CPGs and balance these factors with available evidence., Competing Interests: Declaration of Competing Interest DJH provides consulting advice to Pfizer, Lilly, Merck Serono, and TLC bio. KLB receives royalties from Wolters Kluwer. DJH and KLB are supported by National Health and Medical Research Council (NHMRC) Investigator Grants. AG has received payments from La Trobe University for tutoring physiotherapists involved in GLAD training. CJB is co-lead for the GLAD Australia programme and receives no income from the programme. PGC has received consulting or speaker fees from AbbVie, AstraZeneca, Eli Lilly, Galapagos, GlaxoSmithKline, Grunenthal, Janssen, Levicept, Merck, Novartis, Pfizer, Regeneron, Stryker and UCB. JPE receives royalties from Wolters Kluwer. TEM provides consulting advice to Organogenesis, KolonTissueGene, Remedium-Bio, and Noven. OB has received consultancy or speaker fees from Amgen, Aptissen, Biophytis, IBSA, Mylan, Novartis, Orifarm, Sanofi, UCB and Viatris. The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Hip and knee osteoarthritis (OA) are increasingly common with a significant impact on individuals and society. Non-pharmacological treatments are considered essential to reduce pain and improve function and quality of life. EULAR recommendations for the non-pharmacological core management of hip and knee OA were published in 2013. Given the large number of subsequent studies, an update is needed., Methods: The Standardised Operating Procedures for EULAR recommendations were followed. A multidisciplinary Task Force with 25 members representing 14 European countries was established. The Task Force agreed on an updated search strategy of 11 research questions. The systematic literature review encompassed dates from 1 January 2012 to 27 May 2022. Retrieved evidence was discussed, updated recommendations were formulated, and research and educational agendas were developed., Results: The revised recommendations include two overarching principles and eight evidence-based recommendations including (1) an individualised, multicomponent management plan; (2) information, education and self-management; (3) exercise with adequate tailoring of dosage and progression; (4) mode of exercise delivery; (5) maintenance of healthy weight and weight loss; (6) footwear, walking aids and assistive devices; (7) work-related advice and (8) behaviour change techniques to improve lifestyle. The mean level of agreement on the recommendations ranged between 9.2 and 9.8 (0-10 scale, 10=total agreement). The research agenda highlighted areas related to these interventions including adherence, uptake and impact on work., Conclusions: The 2023 updated recommendations were formulated based on research evidence and expert opinion to guide the optimal management of hip and knee OA., Competing Interests: Competing interests: TPMVV was the Vice president EULAR health professionals 2020–2022 and is part of the EULAR Advocacy Committee 2020–present. MG holds a leadership position in OpenReuma/Spanish Association of Health Professionals in Rheumatology (unpaid). CDM received Grants from Versus Arthritis, MRC, NIHR (paid to Keele University) and is the director of the NIHR School for Primary Care Research. SL received payment as scientific consultant from Arthro Therapeutics AB and received payment from AstraZeneca as a member of DSMB. DC received grants from Fundação para a Ciência e Tecnologia SFRH/BD/148420/2019 and Pfizer (ID 64165707). GZ received payment for expert testimony from Casa di Cura San Francesco, Verona and Support for attending meetings and/or travel from Orthotech and Jtech, payment for participation on a Data Safety Monitoring Board or Advisory Board from VIVENKO for Gruenenthal and Ethos for Angelini and holds other financial interests related to clinical practice as an orthopedic surgeon (performing total joint replacement, arthroscopies and other types of surgeries), either directly from private patients or indirectly from the health system or insurances acting as a private consultant. JEV has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly Netherlands BV. TG has received paid honoraria for lectures by Abbvie, Novartis, Boehringer Ingelheim, UCB, Berlin-Chemie/A. Menarini Bulgaria, Sandoz and received support for attending meetings by Abbvie, Pfizer and UCB. DW is an International Advisory Board Member of DRFZ (Germany) 2019–current and was the EULAR PARE Chair 2015–2017and an EULAR Vice President representing PARE 2017–2021., (© European Alliance of Associations for Rheumatology, EULAR 2024. Re-use permitted under CC BY-NC-ND. No commercial re-use. No derivatives. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: There are few effective osteoarthritis (OA) therapies. A novel injectable polyacrylamide hydrogel (iPAAG) previously demonstrated efficacy and safety up to week 26 in an open-label study of knee OA. Here we report longer-term effectiveness and safety data., Methods: This multi-centre, open-label study included patients with symptomatic and radiographic knee OA. Primary outcome was WOMAC pain (0-100 scale) at 13 weeks, and patients continued to 26 weeks before entering a further 26-week extension phase. Secondary efficacy outcomes included WOMAC stiffness and function subscales, Patient Global Assessment (PGA) and proportion of OMERACT-OARSI responders. Safety outcomes were adverse events (AEs)., Results: 49 participants (31 women, mean age 70) received an ultrasound-guided, intra-articular injection of 6 ml iPAAG; 46 completed the extension phase to 52 weeks. There was a significant reduction in the WOMAC pain score from baseline to 52 weeks (- 17.7 points (95% CI - 23.1; - 12.4); p < 0.0001). Similar sustained improvements were observed for WOMAC stiffness (11.0 points; 95% CI - 17.0; - 4.9), physical function (18.0 points; 95% CI - 19.1; - 10.6), and PGA (16.3 points; 95% CI - 23.1; - 9.4). At 52 weeks 62.2% of patients were OMERACT-OARSI responders. From 26 to 52 weeks, 8 adverse effects (AE), including 1 serious AE (cerebrovascular accident) were reported in 5 subjects. None of the new adverse events were thought to be device related., Conclusion: This open-label study suggests persistent benefits and safety of iPAAG through 52 weeks after a single injection., Trial Registration: Clinicaltrials.gov NCT04179552., (© 2024. The Author(s).)

Objective: To assess whether changes in MRI-based measures of thigh muscle quality associated with statin use in participants with and without/at-risk of knee osteoarthritis., Methods: This retrospective cohort study used data from the Osteoarthritis Initiative study. Statin users and non-users were matched for relevant covariates using 1:1 propensity-score matching. Participants were further stratified according to baseline radiographic knee osteoarthritis status. We used a validated deep-learning method for thigh muscle MRI segmentation and calculation of muscle quality biomarkers at baseline, 2nd, and 4th visits. Mean difference and 95% confidence intervals (CI) in longitudinal 4-year measurements of muscle quality biomarkers, including cross-sectional area, intramuscular adipose tissue, contractile percent, and knee extensors and flexors maximum and specific contractile force (force/muscle area) were the outcomes of interest., Results: After matching, 3772 thighs of 1910 participants were included (1886 thighs of statin-users: 1886 of non-users; age: 62 ± 9 years (average ± standard deviation), range: 45-79; female/male: 1). During 4 years, statin use was associated with a slight decrease in muscle quality, indicated by decreased knee extension maximum (mean-difference, 95% CI: - 1.85 N/year, - 3.23 to - 0.47) and specific contractile force (- 0.04 N/cm 2 /year, - 0.07 to - 0.01), decreased thigh muscle contractile percent (- 0.03%/year, - 0.06 to - 0.01), and increased thigh intramuscular adipose tissue (3.06 mm 2 /year, 0.53 to 5.59). Stratified analyses showed decreased muscle quality only in participants without/at-risk of knee osteoarthritis but not those with established knee osteoarthritis., Conclusions: Statin use is associated with a slight decrease in MRI-based measures of thigh muscle quality over 4 years. However, considering statins' substantial cardiovascular benefits, these slight muscle changes may be relatively less important in overall patient care., (© 2023. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Objective: Due to the risk of rapidly progressive osteoarthritis (RPOA), the phase III studies of subcutaneous (SC) tanezumab in patients with moderate to severe hip or knee osteoarthritis (OA) included comprehensive joint safety surveillance. This pooled analysis summarizes these findings., Method: Joint safety events in the phase III studies of SC tanezumab (2 placebo- and 1- nonsteroidal anti-inflammatory drug [NSAID]-controlled) were adjudicated by a blinded external committee. Outcomes of RPOA1 and RPOA2, primary osteonecrosis, subchondral insufficiency fracture, and pathological fracture comprised the composite joint safety endpoint (CJSE). Potential patient- and joint-level risk factors for CJSE, RPOA, and total joint replacement (TJR) were explored., Results: Overall, 145/4541 patients (3.2%) had an adjudicated CJSE (0% placebo; 3.2% tanezumab 2.5 mg; 6.2% tanezumab 5 mg; 1.5% NSAID). There was a dose-dependent risk of adjudicated CJSE, RPOA1, and TJR with tanezumab vs NSAID. Patient-level cross-tabulation found associations between adjudicated RPOA with more severe radiographic/symptomatic (joint pain, swelling, and physical limitation) OA. Risk of adjudicated RPOA1 was highest in patients with Kellgren-Lawrence (KL) grade 2 or 3 OA at baseline. Risk of adjudicated RPOA2 or TJR was highest in patients with KL grade 4 joints at baseline. A higher proportion of joints with adjudicated RPOA2 had a TJR (14/26) than those with adjudicated RPOA1 (16/106)., Conclusion: In placebo- and NSAID controlled studies of SC tanezumab for OA, adjudicated CJSE, RPOA, and TJR most commonly occurred in patients treated with tanezumab and with more severe radiographic or symptomatic OA. NCT02697773; NCT02709486; NCT02528188., Competing Interests: Declaration of Competing Interest John A. Carrino has received consulting fees from Covera Health, Globus, and Pfizer, and is on the medical advisory board of Image Analysis Group, Image Biopsy Lab and Carestream. Timothy E McAlindon has served on an advisory board for Pfizer, Samumed, Seikagaku, Flexion Therapeutics, Sanofi, Roche, Astellas, and Regeneron. Tom J. Schnitzer has received grants from Kolon TissueGene, Pfizer, Regeneron, Galapagos, Eli Lilly & Company, Paradigm, TLC, Ltd, Anika, Novartis; personal fees and non-financial support from Pfizer, Eli Lilly & Company, Regeneron, Aptinyx, Calibr, GSK, Astra-Zeneca, Genascence, Biosplice, Xalud, IBSA, IQVIA and Vertex. Ali Guermazi has received consulting fees from AstraZeneca, Merck Serono, Pfizer, Organogenesis, Novartis and TissueGene, and is a shareholder of Boston Imaging Core Lab LLC. Marc C Hochberg has received consulting fees from Bone Therapeutics, Bristol Myers Squibb, Eli Lilly, EMD Serono, Novartis Pharma AG, Pfizer, Regenosine, Samumed LLC, Theralogix LLC, TissueGene Inc., TLC Biopharmaceuticals, Inc., and Zynerba; is a member of the Data Safety Monitoring Committee for clinical trials conducted by Covance, Galapagos, ICON plc, IQVIA, and SunPharma; received royalties from Elsevier (Editor, Rheumatology 7e and Editor-in-Chief, Seminars in Arthritis and Rheumatism) and UpToDate™; and has stock ownership in BriOri Biotech and Theralogix LLC. Philip Conaghan has received consulting fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Galapagos, Genascence, GlaxoSmithKline, Janssen, Levicept, Novartis, Pfizer, Stryker and UCB. Mark T Brown, Aimee Burr, Robert J. Fountaine, Glenn C Pixton, Christine West and Kenneth M Verburg are employees of Pfizer and have stock/stock options. Lars Viktrup is an employee and stockholder of Eli Lilly and Company., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To compare magnetic resonance imaging (MRI)-detected structural abnormalities in patients with symptomatic midfoot osteoarthritis (OA), patients with persistent midfoot pain, and asymptomatic controls, and to explore the association between MRI features, pain, and foot-related disability., Methods: One hundred seven adults consisting of 50 patients with symptomatic and radiographically confirmed midfoot OA, 22 adults with persistent midfoot pain but absence of radiographic OA, and 35 asymptomatic adults underwent 3T MRI of the midfoot and clinical assessment. MRIs were read for the presence and severity of abnormalities (bone marrow lesions [BMLs], subchondral cysts, osteophytes, joint space narrowing [JSN], effusion-synovitis, tenosynovitis, and enthesopathy) using the Foot Osteoarthritis MRI Score. Pain and foot-related disability were assessed with the Manchester Foot Pain and Disability Index., Results: The severity sum score of BMLs in the midfoot was greater in patients with midfoot pain and no signs of OA on radiography compared to controls (P = 0.007), with a pattern of involvement in the cuneiform-metatarsal joints similar to that in patients with midfoot OA. In univariable models, BMLs (ρ = 0.307), JSN (ρ = 0.423), and subchondral cysts (ρ = 0.302) were positively associated with pain (P < 0.01). In multivariable models, MRI abnormalities were not associated with pain and disability when adjusted for covariates., Conclusion: In individuals with persistent midfoot pain but no signs of OA on radiography, MRI findings suggested an underrecognized prevalence of OA, particularly in the second and third cuneiform-metatarsal joints, where BML patterns were consistent with previously recognized sites of elevated mechanical loading. Joint abnormalities were not strongly associated with pain or foot-related disability., (© 2022 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: Osteoarthritis (OA) is a complex disease comprising diverse underlying patho-mechanisms. To enable the development of effective therapies, segmentation of the heterogenous patient population is critical. This study aimed at identifying such patient clusters using two different machine learning algorithms., Methods: Using the progression and incident cohorts of the Osteoarthritis Initiative (OAI) dataset, deep embedded clustering (DEC) and multiple factor analysis with clustering (MFAC) approaches, including 157 input-variables at baseline, were employed to differentiate specific patient profiles., Results: DEC resulted in 5 and MFAC in 3 distinct patient phenotypes. Both identified a "comorbid" cluster with higher body mass index (BMI), relevant burden of comorbidity and low levels of physical activity. Both methods also identified a younger and physically more active cluster and an elderly cluster with functional limitations, but low disease impact. The additional two clusters identified with DEC were subgroups of the young/physically active and the elderly/physically inactive clusters. Overall pain trajectories over 9 years were stable, only the numeric rating scale (NRS) for pain showed distinct increase, while physical activity decreased in all clusters. Clusters showed different (though non-significant) trajectories of joint space changes over the follow-up period of 8 years., Conclusion: Two different clustering approaches yielded similar patient allocations primarily separating complex "comorbid" patients from healthier subjects, the latter divided in young/physically active vs elderly/physically inactive subjects. The observed association to clinical (pain/physical activity) and structural progression could be helpful for early trial design as strategy to enrich for patients who may specifically benefit from disease-modifying treatments., Competing Interests: Declaration of Competing Interest David Demanse is employee and shareholder of Novartis. Franziska Saxer is employee and shareholder of Novartis, she is affiliated to the University Basel and member of the European Union Medical Devices - Expert Panel section Orthopaedics, traumatology, rehabilitation, rheumatology. Patrick Lustenberger is employee of IBM, Switzerland and shareholder of Novartis. László B. Tankó was employee of Novartis and held shares, he is current employee of Bayer Pharmaceuticals. Philipp Nikolaus was employee of IBM, Switzerland, he is current employee of MSCI Inc. Ilja Rasin is employee of IBM, Switzerland. Damian F. Brennan is a former employee of IBM, Switzerland and in this employment consultant to Novartis. He currently is employee of the Macquarie Group, Australia. Ronenn Roubenoff is employee and shareholder of Novartis. Sumehra Premji is a former employee of IBM Switzerland and in this employment, consultant and account partner to Novartis. She is current employee and shareholder of Novartis. Philip G Conaghan reports fees for speaker’s bureaus (AbbVie, Novartis) and consultancies (AstraZeneca, BMS, Eli Lilly, Galapagos, Genascence, GSK, Merck, Novartis, Pfizer, Regeneron, Stryker and UCB). Matthias Schieker is employee and shareholder of Novartis and owner LivImplant GmbH., (Copyright © 2022 Novartis Institutes of BioMedical Research. Published by Elsevier Inc. All rights reserved.)

Introduction: MRI bone surface area and femoral bone shape (B-score) measures have been employed as quantitative endpoints in DMOAD clinical trials. Computerized Tomography (CT) imaging is more commonly used for 3D visualization of bony anatomy due to its high bone-soft tissue contrast. We aimed to compare CT and MRI assessments of 3D imaging biomarkers., Methods: We used baseline and 24-month image data from the IMI-APPROACH 2-year prospective cohort study. Femur and tibia were automatically segmented using active appearance models, a machine-learning method, to measure 3D bone shape, area and 3D joint space width (3DJSW). Linear regression was used to test for correlation between measures. Limits of agreement and bias were tested using Bland-Altman analysis., Results: CT-MR pairs of the same knee were available from 434 participants (78% female). B-scores from CT and MR were strongly correlated (CCC = 0.967) with minimal bias of 0.1 (SDD = 0.227). Area measures were also correlated but showed a consistent bias (MR smaller). 3DJSW showed different biases (MR larger) in both lateral and medial compartments., Discussion: The strong correlation and small B-score bias suggests that B-score may be measured reliably using either modality. It is likely that the bone surface identified using MR and CT will be at slightly different positions within the bone/cartilage boundary. The negative bone area bias suggests the MR bone boundary is inside the CT boundary producing smaller areas for MR, consistent with the positive 3DJSW bias. The lateral-medial 3DJSW difference is possibly due to a difference in knee pose during acquisition (extended for CT, flexed for MR)., Trial Registration: NCT03883568., (© 2023. The Author(s).)

Objective: To evaluate the effect of annual infusions of zoledronic acid (ZA) with or without a single injection of methylprednisolone, compared to placebo, on quantitative magnetic resonance imaging 3-D bone area and bone shape in participants with symptomatic knee osteoarthritis (OA)., Methods: This was a post-hoc analysis of the ZAP2 trial. Active appearance modelling was used to assess bone area (mm 2 ) and femur bone shape (B-score) in 262 participants (mean 61.8 ± 8.0 years, 51% female) at baseline, 6, and 24 months. Radiographic joint space narrowing (JSN) was measured at baseline. An 'OA shape' was defined as a B-score of >1.96., Results: At baseline 65% of participants demonstrated an OA shape. Treatment with ZA plus methylprednisolone but not ZA alone, compared to placebo, was associated with significantly slower expansion in bone area at the medial femoral (-33.9 mm 2 , 95% confidence interval [CI] -61.8 to -6.0) and lateral femoral (-22.0 mm 2 , 95%CI -40.7 to -3.4) compartments over 24 months. B-score increased in all groups, with no significant between-group differences. There were significant interactions of JSN (grade 0 vs grade 1-2) and B-score (≤1.96 vs >1.96) with treatment effect on bone area (p < 0.05), such that ZA plus methylprednisolone slowed the expansion of medial and lateral femoral bone area over 24 months in participants with JSN grade 1-2 or a B-score of >1.96., Conclusions: ZA plus methylprednisolone may retard expansion of bone area over 24 months, but ZA alone may not. Neither ZA with or without methylprednisolone slowed progression of bone shape over 6 or 24 months., Competing Interests: Declaration of Competing Interest LLL reports personal fees from Amgen Pty Ltd, outside the submitted work. MB is an employee of Imorphics Ltd, a company providing measurement of imaging biomarkers, which is wholly owned by Stryker Corp, and MB has share options in that company. PGC has done consultancies or speakers bureaus for AbbVie, Amgen, AstraZeneca, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Novartis, Pfizer, Stryker and UCB. LM has received funding unrelated to this study with grants from Janssen and speaker fees from Pfizer, Abbvie, Lilly. TW reports personal fees from AMGEN, outside the submitted work. GJ reports personal fees from BMS, Roche, AbbVie, Amgen, Lilly, Novartis, Jannsen, and grants from Covance, outside the submitted work. Other authors declare that they have no other conflict of interests., (Copyright © 2022. Published by Elsevier Inc.)

Background: Hip and knee osteoarthritis (OA) affect a large and growing proportion of the population. Treatment options are typically conservative making self-management a priority. Using trained peers to support individuals with OA has potential to improve self-management., Purpose: To explore the process of engaging and training volunteers to become peer mentors; and to qualitatively evaluate the feasibility, acceptability and value of being a peer mentor to support others' self-management of OA., Materials and Methods: A qualitative evaluation of a peer mentorship support intervention reporting the processes of recruitment and training; and semi-structured interviews conducted with nine active peer mentors. Transcribed interviews were coded and analysed using framework analysis., Results: It was possible to recruit, train and retain volunteers with OA to become peer mentors. The peer mentors benefitted from their training and felt equipped to deliver the intervention. They enjoyed social elements of the mentorship intervention and gained satisfaction through delivering valued support to mentees. Peer mentors perceived the mentorship intervention to have a positive impact on self-management of OA for mentees., Conclusion: Training volunteers with OA to become peer mentors was feasible and acceptable. Peer mentors perceived their support benefitted others with OA. They positively rated their experience of providing mentorship support.IMPLICATIONS FOR REHABILITATIONThis study demonstrates that it is possible to recruit, train and engage older volunteers to become peer mentors for people with osteoarthritis.Training should highlight the significance of employing key self-management techniques such as goal-setting.Peer mentors acknowledged that they benefitted from training and delivering the mentorship intervention, and this impacted positively on their own osteoarthritis self-management.Careful consideration of matching mentors and mentees appears to enhance the success of mentorship support.Recognising the impact of mentorship support on mentees' self-management is central to peer mentors' sustained engagement with the intervention.

Knee osteoarthritis (OA) is one of the most common and disabling medical conditions. In the case of moderate to severe pain, a single intervention may not be sufficient to allay symptoms and improve quality of life. Examples include first-line, background therapy with symptomatic slow-acting drugs for OA (SYSADOAs) or non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) performed a review of a multimodal/multicomponent approach for knee OA therapy. This strategy is a particularly appropriate solution for the management of patients affected by knee OA, including those with pain and dysfunction reaching various thresholds at the different joints. The multimodal/multicomponent approach should be based, firstly, on different combinations of non-pharmacological and pharmacological interventions. Potential pharmacological combinations include SYSADOAs and NSAIDs, NSAIDs and weak opioids, and intra-articular treatments with SYSADOAs/NSAIDs. Based on the available evidence, most combined treatments provide benefit beyond single agents for the improvement of pain and other symptoms typical of knee OA, although further high-quality studies are required. In this work, we have therefore provided new, patient-centered perspectives for the management of knee OA, based on the concept that a multimodal, multicomponent, multidisciplinary approach, applied not only to non-pharmacological treatments but also to a combination of the currently available pharmacological options, will better meet the needs and expectations of patients with knee OA, who may present with various phenotypes and trajectories., (© 2022. The Author(s).)

Introduction: Persistent, knee pain is a common cause of disability. Education and exercise treatment are advocated in all clinical guidelines; however, the increasing prevalence of persistent knee pain presents challenges for health services regarding appropriate and scalable delivery of these treatments. Digital technologies may help address this, and this trial will evaluate the feasibility and acceptability of two electronic-rehabilitation interventions: 'My Knee UK' and 'Group E-Rehab'., Methods and Analysis: This protocol describes a non-blinded, randomised feasibility trial with three parallel groups. The trial aims to recruit 90 participants (45 years or older) with a history of persistent knee pain consistent with a clinical diagnosis of knee osteoarthritis. Participants will be randomly assigned in a 1:1:1 allocation ratio. The 'My Knee UK' intervention arm will receive a self-directed unsupervised internet-based home exercise programme plus short message service support (targeting exercise behaviour change) for 12 weeks; the 'Group E-Rehab' intervention arm will receive group-based physiotherapist-prescribed home exercises delivered via videoconferencing accompanied by internet-interactive educational sessions for 12 weeks; the control arm will receive usual physiotherapy care or continue with their usual self-management (depending on their recruitment path). Feasibility variables, patient-reported outcomes and clinical findings measured at baseline, 3 and 9 months will be assessed and integrated with qualitative interview data from a subset of Group E-Rehab and My Knee UK participants. If considered feasible and acceptable, a definitive randomised controlled trial can be conducted to investigate the clinical effectiveness and cost-effectiveness of one or both interventions with a view to implementation in routine care., Ethics and Dissemination: The trial was approved by the West of Scotland Research Ethics Committee 5 (Reference: 20/WS/0006). The results of the study will be disseminated to study participants, the study grant funder and will be submitted for publication in peer-reviewed journals., Trial Registration Number: ISRCTN15564385., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: To define meaningful within-patient change (MWPC) in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)., Methods: Data were analyzed separately from 3 phase III clinical trials (ClinicalTrials.gov: NCT02697773, NCT02709486, NCT02528188) of tanezumab, a novel treatment intended for the relief of signs and symptoms of moderate-to-severe osteoarthritis (OA), administered subcutaneously every 8 weeks. Patients with moderate-to-severe OA of the hip or knee completed the WOMAC and patient global assessment of OA (PGA-OA) at regular timepoints. A repeated measures longitudinal model with change in WOMAC Pain, Physical Function, or Stiffness domain score as the outcome and change in PGA-OA as the anchor was used to establish MWPC for WOMAC domains., Results: In the 3 studies, there were 688, 844, and 2948 subjects available for analyses, respectively. Analysis showed that a linear relationship between changes in WOMAC domains and changes in PGA-OA was supported and justified. Moreover, the relationships between these changes were very similar for 2 trials and close for the third. The estimated MWPC for the 3 WOMAC domains were from 0.84-1.16 (0-10 numerical rating scale) and from 12.50-16.23%, depending on study and domain, that corresponded to a 1-category change on PGA-OA. For a 2-category change those values were from 1.68-2.31 and from 25.01-32.46%, respectively., Conclusion: These results establish MWPCs for WOMAC domains, at the individual patient level, for patients with moderate-to-severe OA of the hip or knee. [ClinicalTrials.gov: NCT02697773, NCT02709486, and NCT02528188]., (Copyright © 2022 by the Journal of Rheumatology.)

Objectives: To determine the association between statin therapy and knee MRI-detected subchondral bone marrow lesion (BML) longitudinal worsening in patients with Heberden's nodes (HNs) as the hallmark of generalized osteoarthritis (OA) phenotype., Methods: All participants gave informed consent, and IRB approved HIPAA-compliant protocol. We assessed the worsening in BML volume and number of affected subregions in the Osteoarthritis Initiative (OAI) participants with HNs at baseline clinical examination (HN + ), using the semi-quantitative MRI Osteoarthritis Knee Scores at baseline and 24 months. Participants were classified according to baseline BML involvement as "no/minimal" (≤ 2/14 knee subregions affected and maximum BML score ≤ 1) or "moderate/severe." Statin users and non-users were selected using 1:1 propensity-score (PS) matching for OA and cardiovascular disease (CVD)-related potential confounding variables. We assessed the association between statin use and increasing BML score and affected subregions using adjusted mixed-effect regression models., Results: The PS-matched HN + participants (63% female, aged 63.5 ± 8.5-year-old) with no/minimal and moderate/severe BML cohorts consisted of 332 (166:166, statin users: non-users) and 380 (190:190) knees, respectively. In the HN + participants with no/minimal BML, statin use was associated with lower odds of both BML score worsening (odds ratio, 95% confidence interval: 0.62, 0.39-0.98) and increased number of affected subregions (0.54, 0.33-0.88). There was no such association in HN - participants or those HN + participants with baseline moderate/severe BML., Conclusion: In patients with CVD indications for statin therapy and generalized OA phenotype (HN + ), statin use may be protective against the OA-related subchondral bone damage only in the subgroup of participants with no/minimal baseline BML., Key Points: • Statin use may reduce the risk of subchondral bone damage in specific osteoarthritis patients with a generalized phenotype, minimal subchondral bone damage, and cardiovascular statin indications., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Objectives: Osteoarthritis (OA) development programmes face challenges due to discordance between structural changes and symptoms. A novel cathepsin-K inhibitor, MIV-711, recently reported structural benefits, but did not demonstrate a significant difference from placebo in symptoms. Previous work suggests that pain from non-target joints may confound OA pain outcomes. We therefore conducted an exploratory analysis in participants with predominantly unilateral knee pain from the MIV-711-201 trial., Methosd: Participants scoring below median contralateral knee NRS pain at baseline from the MIV-711-201 phase 2a clinical trial (n=119) were analysed by treatment group for differences in change from baseline in WOMAC pain, quantitative magnetic resonance imaging bone area and cartilage thickness with a repeated-measures mixed model adjusting for relevant co-variates., Results: In the subgroup with unilateral knee pain, treatment with MIV-711 100 mg led to greater reduction in WOMAC pain compared to placebo (-5.0, 95% CI: -8.69 to -1.3, p=0.008), while 200 mg did not (-2.5, 95% CI: -6.5 to 1.6, p=0.23). MIV-711 treatment was associated with a reduced change in bone area compared to placebo (200 mg; -19.6 mm2 , 95% CI: -36.2 to -3.0, p=0.02, and 100 mg; -12.5 mm2 , 95% CI: -27.8 to 2.8, p=0.11,). No observed differences between treatment groups in cartilage thickness were found in this subgroup., Conclusions: In a subgroup with predominantly unilateral knee pain, significant reduction in OA pain by MIV-711 100 mg treatment was found, with concurrent beneficial structural effects, highlighting the importance of appropriate pain inclusion criteria in OA trials.

Objectives: Knee osteoarthritis (OA) is often accompanied by a flexion contracture (FC), resulting in worse clinical outcomes. Our objective was to determine associations between knee FC and specific regional and/or structural alterations on magnetic resonance imaging (MRI) using the Osteoarthritis Initiative (OAI)., Methods: 600 knees from the Foundation for the National Institutes of Health sub-study of the OAI were included. Knee extension was measured with a goniometer and FC was defined as inability to extend the knee to 0°. Structural alterations within the MRI Osteoarthritis Knee Score (MOAKS)-assessed regions that could potentially obstruct knee extension were primarily analysed. Multivariable linear regression models evaluated the effect size of MRI outcomes on knee extension., Results: One-third (33.4%) of all participants had knee FC: 155 mild (1-5°, 26.0%), 44 moderate-severe (≥6°, 7.4%). Mean knee alignment was 0.3±3.7° valgus. Cartilage morphology and bone marrow lesion (BML) scores on the femoral side of the lateral patellofemoral joint were associated with lost knee extension (β=0.709, p<0.001, and β=0.666, p<0.001, respectively) as were higher osteophyte scores in multiple regions, worse meniscal score in the medial meniscal body (β=0.164, p<0.040) and posterior horn (β=0.400, p<0.001), and a worse effusion score (β=0.711, p<0.001)., Conclusions: Knee flexion contractures were associated with non-specific, widespread MRI degenerative changes including cartilage loss and BMLs in the lateral patellofemoral joint, osteophytes, meniscal alterations and whole-joint effusion. Loss of knee extension in OA is likely a structurally-multifactorial outcome.

Background: Hip and knee osteoarthritis (OA) are common musculoskeletal conditions. Treatment is usually conservative, making self-management a priority. We developed and trialled an OA peer mentorship intervention to support self-management in older people. Our objectives were to gain understanding of the perceived challenges of living with OA and explore how a peer mentorship intervention can support tackling these challenges; and to explore mentees' experiences of receiving the intervention to understand how this affected their OA self-management., Methods: Qualitative semi-structured interviews focussing on acceptability and feasibility of being in the study were conducted with mentees. Transcribed interviews were double coded and subject to framework analysis. To address the objectives of this paper, three main themes were subject to focused analysis: mentees' experiences of OA, experience of peer mentorship support and factors influencing self-management., Results: Seventeen mentees participated in an interview following completion of the peer support intervention. Themes emerging from focused analysis were the following: tackling the challenges of living with OA pre- and post-intervention; and the interplay of the peer mentorship intervention and self-management. Key elements of the latter theme are enabling factors provided by peer mentorship, and mentees' readiness to self-manage., Conclusion: To effectively support OA self-management, peer mentorship interventions should include core educational components and focus on strategies that enhance key enablers of self-management. Paying attention to the mentor-mentee relationship and timing of intervention engagement can maximise opportunities for older people to adjust and transition from supported to independent self-management., (© 2021 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Background: To evaluate the impact of tanezumab on health status, non-work activities, and work productivity in a pooled analysis of two large phase 3 osteoarthritis (OA) studies., Methods: Subcutaneous tanezumab (2.5 mg and 5 mg) was tested in double-blind, placebo-controlled, 16-week (NCT02697773) and 24-week (NCT02709486) clinical trials in patients with moderate-to-severe OA of the hip or knee. At baseline and week 16, all patients completed EQ-5D-5L and the Work Productivity and Activity Impairment-OA (WPAI-OA) activity impairment item. Those currently employed also completed WPAI-OA work time missed, impairment while working, and overall work impairment items. Between-group differences in least squares (LS) mean changes from baseline at week 16 were tested using analysis of covariance., Results: Of 1545 pooled patients, 576 were employed at baseline. Improvements in EQ-5D-5L index value at week 16 were significantly greater for the tanezumab 2.5-mg group (difference in LS means [95% confidence interval (CI), 0.03 [0.01, 0.05]; p = 0.0083) versus placebo. Percent improvements (95% CI) in activity impairment (- 5.92 [- 8.87, - 2.98]; p < 0.0001), impairment while working (- 7.34 [- 13.01, - 1.68]; p = 0.0112), and overall work impairment (- 7.44 [- 13.22, - 1.67]; p = 0.0116) at week 16 were significantly greater for the tanezumab 2.5-mg group versus placebo. Results for the tanezumab 5-mg group were generally comparable to the tanezumab 2.5-mg group, although, compared with placebo, percent improvement (95% CI) in work time missed was significantly greater for the tanezumab 5-mg group (- 3.40 [- 6.47, - 0.34]; p = 0.0294), but not the tanezumab 2.5-mg group (- 0.66 [- 3.63, 2.32]; p = 0.6637)., Conclusions: These pooled analyses showed that health status, non-work activities, and work productivity were significantly improved following tanezumab administration, compared with placebo., Trial Registration: ClinicalTrials.gov: NCT02697773, NCT02709486., (© 2022. The Author(s).)

Purpose of Review: To review the recent literature on bone in osteoarthritis (OA), with a focus on imaging and intervention studies., Recent Findings: Most studies focused on knee OA; hip and hand studies were uncommon. Bone shape studies demonstrated that shape changes precede radiographic OA, predict joint replacement, and have demonstrated high responsiveness. Novel quantitative 3D imaging markers (B-score) have better characterized OA severity, including preradiographic OA status. The addition of computerized tomography-derived 3D metrics has improved the prediction of hip joint replacement when compared to radiographs alone.Recent studies of bisphosphonates for knee OA have reported no benefits on pain or bone marrow lesion (BML) size. A meta-analysis on Vitamin D supplementation in knee OA suggested minimal symptom improvement and no benefits on the structure. Cathepsin K inhibition demonstrated reduction in OA bone change progression, but with no symptom benefit. Studies of injections of bone substitutes into BMLs (subchondroplasty) have generally been small and potential benefits remain unclear., Summary: Subchondral bone features are associated with pain, incidence and progression of OA. Recent studies have validated quantitative bone shape as a biomarker for OA trials. Trials of bone-targeted OA therapies have been disappointing although cathepsin K inhibition may slow structural progression., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results., Methods: Patients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40-90, a subgroup at risk (SAR) of progression., Results: 378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, p<0.001) and a 0.05 mm mean difference with sprifermin 100 µg q6mo versus placebo (95% CI 0.00 to 0.10; p=0.015) were sustained to year 5. WOMAC pain scores improved ~50% from baseline in all groups. No patient in the 100 µg q6mo group had replacement of the treated knee. 96%-98% of patients receiving sprifermin and 98% placebo reported adverse events, most were mild or moderate and deemed unrelated to treatment. Adverse event-related study withdrawals were <10%. Differentiation in WOMAC pain between sprifermin 100 µg q6mo and placebo in the SAR (n=161) at year 3 was maintained to year 5 (-10.08; 95% CI -25.68 to 5.53)., Conclusion: In the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR., Trial Registration Number: NCT01919164., Competing Interests: Competing interests: FE is an employee and co-owner of Chondrometrics GmbH and reported receiving grants and consulting fees from Merck KGaA, Darmstadt, Germany, Samumed LLC, AbbVie, Bioclinica, Orthotrophix, Kolon TissueGene, Servier, Roche, Galapagos, Novartis, ICM and Healthlink. MH reports being the president of Rheumcon and receiving consulting fees from Bone Therapeutics, Bristol-Myers Squibb, Eli Lilly, Galapagos, IBSA Insititut Biotechniq SA, Novartis Pharma AG, Pfizer, Samumed LLC, Theralogix LLC and Kolon TissueGene. HG, BD, OG, CL and MM are employees of Merck KGaA, Darmstadt, Germany. FM and VO are employees of EMD Serono (a business of Merck KGaA, Darmstadt, Germany). ARB, IB and JRA are employees and shareholders in Nordic Bioscience. PGC has received consultancy or speaker’s bureau fees from AbbVie, AstraZeneca, BMS, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Flexion Therapeutics, Galapagos, Kolon Tissue-Gene, Novartis, Pfizer, Samumed and Stryker., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the feasibility of conducting a randomised controlled trial (RCT) of a peer mentorship intervention to improve self-management of osteoarthritis (OA)., Design: Six-month parallel group non-blinded randomised feasibility trial., Setting: One secondary care and one primary care UK National Health Service Trust., Participants: Fifty adults aged ≥55 years old with hip and/or knee OA., Interventions: Participants were allocated 1:1 to the intervention or control group using an online randomisation service. Intervention group participants received usual care (information resources) and up to eight community-based self-management support sessions delivered by a peer mentor (trained volunteer with hip and/or knee OA). Control group participants received usual care only., Outcome Measures: Key feasibility outcomes were participant and peer mentor recruitment and attrition, intervention completion and the sample size required for a definitive RCT. Based on these feasibility outcomes, four success criteria for proceeding to a definitive RCT were prespecified. Patient-reported outcomes were collected via questionnaires at baseline, 8 weeks and 6 months., Results: Ninety-six individuals were screened, 65 were eligible and 50 were randomised (25 per group). Of the 24 participants who commenced the intervention, 20 completed it. Four participants did not complete the 6-month questionnaire. Twenty-one individuals were eligible for the peer mentor role, 15 were trained and 5 withdrew prior to being matched with a participant. No intervention-related harms occurred. Allowing for 20% attrition, the sample size required for a definitive RCT was calculated as 170 participants. The intervention group showed improvements in self-management compared with the control group., Conclusions: The feasibility outcomes achieved the prespecified criteria for proceeding to an RCT. The exploratory analyses suggest peer mentorship may improve OA self-management. An RCT of the OA peer mentorship intervention is therefore warranted with minor modifications to the intervention and trial procedures., Trial Registration Number: ISRCTN:50675542., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Osteoarthritis (OA) structural status is imperfectly classified using radiographic assessment. Statistical shape modelling (SSM), a form of machine-learning, provides precise quantification of a characteristic 3D OA bone shape. We aimed to determine the benefits of this novel measure of OA status for assessing risks of clinically important outcomes., Methods: The study used 4796 individuals from the Osteoarthritis Initiative cohort. SSM-derived femur bone shape (B-score) was measured from all 9433 baseline knee MRIs. We examined the relationship between B-score, radiographic Kellgren-Lawrence grade (KLG) and current and future pain and function as well as total knee replacement (TKR) up to 8 years., Results: B-score repeatability supported 40 discrete grades. KLG and B-score were both associated with risk of current and future pain, functional limitation and TKR; logistic regression curves were similar. However, each KLG included a wide range of B-scores. For example, for KLG3, risk of pain was 34.4 (95% CI 31.7 to 37.0)%, but B-scores within KLG3 knees ranged from 0 to 6; for B-score 0, risk was 17.0 (16.1 to 17.9)% while for B-score 6, it was 52.1 (48.8 to 55.4)%. For TKR, KLG3 risk was 15.3 (13.3 to 17.3)%; while B-score 0 had negligible risk, B-score 6 risk was 35.6 (31.8 to 39.6)%. Age, sex and body mass index had negligible effects on association between B-score and symptoms., Conclusions: B-score provides reader-independent quantification using a single time-point, providing unambiguous OA status with defined clinical risks across the whole range of disease including pre-radiographic OA. B-score heralds a step-change in OA stratification for interventions and improved personalised assessment, analogous to the T-score in osteoporosis., Competing Interests: Competing interests: MAB and AB are employees of Imorphics, a wholly owned subsidiary of Stryker Corporation. KK is a consultant for Flexion Therapeutics Inc. OA and BD have no conflicts of interest to disclose. NB is an employee of Flexion Therapeutics. PGC has done consultancies or speakers bureaus for AbbVie, Bristol Myers Squibb, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GlaxoSmithKline, Novartis, Pfizer, Roche, Samumed and Stryker., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objective: To assess pain outcomes and cartilage thickness change in a subgroup at risk (SAR) of further progression in the FORWARD trial of knee osteoarthritis patients treated with sprifermin., Methods: Patients were randomised 1:1:1:1:1 to: sprifermin 100 µg every 6 months (q6mo), 100 µg q12mo, 30 µg q6mo, 30 µg q12mo, or placebo for 18 months. SAR was defined as baseline medial or lateral minimum joint-space width (mJSW) 1.5-3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 40-90 units. Follow-up to 3 years was included in the analysis. Treatment benefit was explored by repeated measures, linear dose-effect trends by timepoint., Results: The SAR comprised 161 (29%) of 549 patients. Mean difference (95% CI) in WOMAC pain at year 3 for sprifermin 100 µg q6mo vs placebo SAR was -8.75 (-22.42, 4.92) for SAR vs 0.97 (-6.22, 8.16) for the intent-to-treat population. SAR placebo patients lost more cartilage over 2 years than the modified ITT (mITT) placebo arm (mean change from baseline, mm [SD]: -0.05 [0.10] vs -0.02 [0.07]). Net total femorotibial joint thickness gain with sprifermin 100 µg q6mo (adjusted mean difference from placebo [95% CI] was similar in the SAR and in the mITT group: 0.06 [0.01, 0.11] vs 0.05 [0.03, 0.07])., Conclusions: Selection for low mJSW and moderate-to-high pain at baseline resulted in more rapid disease progression and demonstrated translation of structure modification (with maintained net benefit on total cartilage thickness) into symptomatic benefit. This subgroup may represent a target population for future trials., Clinical Trial Registration: NCT01919164., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Current management of osteoarthritis (OA) is primarily focused on symptom control. Intra-articular corticosteroid (IACS) injections are often used for pain management of hip and knee OA in patients who have not responded to oral or topical analgesics. Recent case series suggested that negative structural outcomes including accelerated OA progression, subchondral insufficiency fracture, complications of pre-existing osteonecrosis, and rapid joint destruction (including bone loss) may be observed in patients who received IACS injections. This expert panel report reviews the current understanding of pain in OA, summarizes current international guidelines regarding indications for IACS injection, and considers preinterventional safety measures, including imaging. Potential profiles of those who would likely benefit from IACS injection and a suggestion for an updated patient consent form are presented. As of today, there is no established recommendation or consensus regarding imaging, clinical, or laboratory markers before an IACS injection to screen for OA-related imaging abnormalities. Repeating radiographs before each subsequent IACS injection remains controversial. The true cause and natural history of these complications are unclear and require further study. To determine the cause and natural history, large prospective studies evaluating the risk of accelerated OA or joint destruction after IACS injections are needed. However, given the relatively rare incidence of these adverse outcomes, any clinical trial would be challenging in design and a large number of patients would need to be included., (© RSNA, 2020.)

Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear., Objective: To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR)., Design: Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846)., Setting: 1091 clinical sites in 39 countries., Participants: 10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants., Intervention: Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months., Measurements: The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases., Results: Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P  = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis., Limitation: Because the parent trial was not designed to examine the efficacy of IL-1β inhibitors in osteoarthritis, information on structural joint outcomes was not collected., Conclusion: Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1β inhibition for treatment of large joint osteoarthritis., Primary Funding Source: Novartis Pharmaceuticals.

There is controversy over whether bone or cartilage is primarily involved in osteoarthritis (OA) pathogenesis; this is important for targeting early interventions. We explored evidence from animal models of knee OA by preforming a systematic review of PubMed, Scopus, and Web of Science for original articles reporting subchondral bone and cartilage pathology in animal models with epiphyseal closure. Extracted data included: method of induction; animal model; cartilage and bone assessment and method; meniscal assessment; skeletal maturity; controls; and time points assessed. Quality scoring was performed. The best evidence was synthesized from high-quality skeletally mature models, without direct trauma to tissues of interest and with multiple time points. Altogether, 2849 abstracts were reviewed. Forty-seven papers were included reporting eight different methods of inducing OA, six different species, six different methods of assessing cartilage, five different bone structural parameters, and four assessed meniscus as a potential initiator. Overall, the simultaneous onset of OA in cartilage and bone was reported in 82% of datasets, 16% reported bone onset, and 2% reported cartilage onset. No dataset containing meniscal data reported meniscal onset. However, using the best evidence synthesis (n = 8), five reported simultaneous onset when OA was induced, while three reported bone onset when OA occurred spontaneously; none reported cartilage onset. In summary, there is a paucity of well-designed studies in this area which makes the conclusions drawn conjectures rather than proven certainties. However, within the limitation of data quality, this review suggests that in animal models, the structural onset of knee OA occurs either in bone prior to cartilage pathology or simultaneously., (© 2020 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society.)

Background: Patients' pre-operative health and physical function is known to influence their post-operative outcomes. In patients with knee osteoarthritis, pharmacological and non-pharmacological options are often not optimised prior to joint replacement. This results in some patients undergoing surgery when they are not as fit as they could be. The aim of this study is to assess the feasibility and acceptability of a pre-operative package of non-operative care versus standard care prior to joint replacement., Methods/design: This is a multicentre, randomised controlled feasibility trial of patients undergoing primary total knee replacement for osteoarthritis. Sixty patients will be recruited and randomised (2:1) to intervention or standard care arms. Data will be collected at baseline (before the start of the intervention), around the end of the intervention period and a minimum of 90 days after the planned date of surgery. Adherence will be reviewed each week during the intervention period (by telephone or in person). Participants will be randomised to a pre-operative package of non-operative care or standard care. The non-operative care will consist of (1) a weight-loss programme, (2) a set of exercises, (3) provision of advice on analgesia use and (4) provision of insoles. The intervention will be started as soon as possible after patients have been added to the waiting list for joint replacement surgery to take advantage of the incentive for behavioural change that this will create. The primary outcomes of this study are feasibility outcomes which will indicate whether the intervention and study protocol is feasible and acceptable and whether a full-scale effectiveness trial is warranted. The following will be measured and used to inform study feasibility: rate of recruitment, rate of retention at 90-day follow-up review after planned surgery date, and adherence to the intervention estimated through review questionnaires and weight change (for those receiving the weight-loss aspect of intervention). In addition the following information will be assessed qualitatively: analysis of qualitative interviews exploring acceptability, feasibility, adherence and possible barriers to implementing the intervention, and acceptability of the different outcome measures., Discussion: The aims of the study specifically relate to testing the feasibility and acceptability of the proposed effectiveness trial intervention and the feasibility of the trial methods. This study forms the important first step in developing and assessing whether the intervention has the potential to be assessed in a future fully powered effectiveness trial. The findings will also be used to refine the design of the effectiveness trial., Trial Registration: ISRCTN registry, ID: ISRCTN96684272. Registered on 18 April 2018.

Background: MIV-711 is a novel selective cathepsin K inhibitor with beneficial effects on bone and cartilage in preclinical osteoarthritis models., Objective: To evaluate the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographic knee osteoarthritis., Design: 26-week randomized, double-blind, placebo-controlled phase 2a study with a 26-week open-label safety extension substudy. (EudraCT: 2015-003230-26 and 2016-001096-73)., Setting: Six European sites., Participants: 244 participants with primary knee osteoarthritis, Kellgren-Lawrence grade 2 or 3, and pain score of 4 to 10 on a numerical rating scale (NRS)., Intervention: MIV-711, 100 (n = 82) or 200 (n = 81) mg daily, or matched placebo (n = 77). Participants (46 who initially received 200 mg/d and 4 who received placebo) received 200 mg of MIV-711 daily during the extension substudy., Measurements: The primary outcome was change in NRS pain score. The key secondary outcome was change in bone area on magnetic resonance imaging (MRI). Other secondary end points included cartilage thickness on quantitative MRI and type I and II collagen C-telopeptide biomarkers. Outcomes were assessed over 26 weeks., Results: Changes in NRS pain scores with MIV-711 were not statistically significant (placebo, -1.4; MIV-711, 100 mg/d, -1.7; MIV-711, 200 mg/d, -1.5). MIV-711 significantly reduced medial femoral bone area progression (P = 0.002 for 100 mg/d and 0.004 for 200 mg/d) and medial femoral cartilage thinning (P = 0.023 for 100 mg/d and 0.125 for 200 mg/d) versus placebo and substantially reduced bone and cartilage biomarker levels. Nine serious adverse events occurred in 6 participants (1 in the placebo group, 3 in the 100 mg group, and 2 in the 200 mg group); none were considered to be treatment-related., Limitation: The trial was relatively short., Conclusion: MIV-711 was not more effective than placebo for pain, but it significantly reduced bone and cartilage progression with a reassuring safety profile. This treatment may merit further evaluation as a disease-modifying osteoarthritis drug., Primary Funding Source: Medivir.

Background The exact contribution of statins to knee osteoarthritis (OA) radiographic outcomes and the characteristics of patients with OA as potential responders to statins remain unclear. Purpose To evaluate the effect of statin use on the incidence of radiographic knee OA (development of Kellgren-Lawrence grade ≥2) and progression of joint space narrowing (JSN) according to the nodal OA status defined according to the presence of Heberden nodes (HNs). Materials and Methods Institutional review boards approved this HIPAA-compliant protocol, and all participants gave informed consent. The Osteoarthritis Initiative (OAI) cohort, which began in 2004 and is ongoing ( https://clinicaltrials.gov identifier, NCT00080171), was used to conduct a longitudinal 1:1 propensity score-matched retrospective analysis of prospectively collected data. Participants were classified as having HN-positive or HN-negative findings according to the presence of HNs at baseline physical examination. In each cohort, per-protocol and new-user design were used to match statin initiators (participants who reported ≤1 year of statin use before enrollment) and nonusers (participants who reported no statin use before enrollment) for variables that potentially contributed to confounding by indication bias. Participants were followed up annually over 8 years. Any associations between statin use and longitudinal knee OA radiographic incidence, JSN progression, or nonacceptable symptomatic state incidence was assessed by using hazard ratios (HRs) of Cox regression. Results In the longitudinal analysis, there were 832 knees of 602 participants (pair-matched knees of statin initiators and nonusers) in the HN-positive cohort (mean age, 64.7 years ± 8.0 [standard deviation]; 377 patients were female [62.6%]) and 386 knees of 285 participants in the HN-negative cohort (mean age, 58.9 years ± 8.2; 144 patients were female [50.5%]). In the HN-positive cohort, statin users had 46% lower risk of JSN progression in comparison with matched nonusers (HR, 0.54; 95% confidence interval [CI]: 0.36, 0.93; P = .02). In contrast, in the HN-negative cohort, statin use had no association with radiographic JSN progression (HR, 1.37; [95% CI: 0.74, 2.53]; P = .32). Conclusion Statin use was associated with reduced risk of radiographic knee osteoarthritis joint space narrowing progression in patients with nodal osteoarthritis. © RSNA, 2019 Online supplemental material is available for this article.

Flare in knee and hip osteoarthritis (OA) is more than just an exacerbation of pain. Unstructured, semistructured, and focus group interviews followed by Delphi surveys with patients and health professionals (HP) generated candidate domains of an OA flare. Content analysis of interviews with 29 patients and 16 HP extracted 180 statements, which were grouped into 9 clusters. Delphi consensus with 50 patients (Australia, Canada, and France) and 116 HP (17 countries on 4 continents) identified 5 flare domains: pain, swelling, stiffness, psychological aspects, and effect of symptoms. Elements for a preliminary definition of an OA flare are proposed. Registered at clinicaltrials.gov NCT02892058.

Objective: To update the 1997 OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) core domain set for clinical trials in hip and/or knee osteoarthritis (OA)., Methods: An initial review of the COMET database of core outcome sets (COS) was undertaken to identify all domains reported in previous COS including individuals with hip and/or knee OA. These were presented during 5 patient and health professionals/researcher meetings in 3 continents (Europe, Australasia, North America). A 3-round international Delphi survey was then undertaken among patients, healthcare professionals, researchers, and industry representatives to gain consensus on key domains to be included in a core domain set for hip and/or knee OA. Findings were presented and discussed in small groups at OMERACT 2018, where consensus was obtained in the final plenary., Results: Four previous COS were identified. Using these, and the patient and health professionals/researcher meetings, 50 potential domains formed the Delphi survey. There were 426 individuals from 25 different countries who contributed to the Delphi exercise. OMERACT 2018 delegates (n = 129) voted on candidate domains. Six domains gained agreement as mandatory to be measured and reported in all hip and/or knee OA clinical trials: pain, physical function, quality of life, and patient's global assessment of the target joint, in addition to the mandated core domain of adverse events including mortality. Joint structure was agreed as mandatory in specific circumstances, i.e., depending on the intervention., Conclusion: The updated core domain set for hip and/or knee OA has been agreed upon. Work will commence to determine which outcome measurement instrument should be recommended to cover each core domain.

Objective: To assess the uptake of the OMERACT-OARSI (Outcome Measures in Rheumatology- Osteoarthritis Research Society International) core outcome set (COS) domains in hip and/or knee osteoarthritis (OA) trials., Methods: There were 382 trials of hip and/or knee OA identified from the ClinicalTrial.gov registry from 1997 to 2017. Frequency of COS adoption was assessed by year and per 5-yearly phases., Results: COS adoption decreased from 61% between 1997 and 2001 to 38% between 2012 and 2016. Pain (95%) and physical function (86%) were most consistently adopted. Patient's global assessment (48%) was the principal missing domain., Conclusion: Limited adoption of the COS domains indicates that further consideration to improve uptake is required.

Objective: To assess the efficacy and safety of the anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis., Methods: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26., Results: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom- and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations., Conclusion: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis., (© 2019, American College of Rheumatology.)

Introduction: Osteoarthritis (OA) is common and its prevalence is increased in military service members. In a phase 3 randomized controlled trial (NCT02357459), a single intra-articular injection of an extended-release formulation of triamcinolone acetonide (TA-ER) in participants with unilateral or bilateral knee OA demonstrated substantial improvement in pain and symptoms. Bilateral knee pain has emerged as a confounding factor in clinical trials when evaluating the effect of a single intra-articular injection. Furthermore, unilateral disease is frequently first to emerge in active military personnel secondary to prior traumatic joint injury. In this post hoc analysis, we assessed efficacy and safety of TA-ER in a subgroup of participants with unilateral knee OA., Methods: Participants ≥ 40 years of age with symptomatic knee OA were randomized to a single intra-articular injection of TA-ER 32 mg, TA crystalline suspension (TAcs) 40 mg, or saline-placebo. Average daily pain (ADP)-intensity and rescue medication use were collected at each of weeks 1-24 postinjection; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A (pain), WOMAC-B (stiffness), WOMAC-C (function), and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QoL) were collected at weeks 4, 8, 12, 16, 20, and 24 postinjection. Adverse events (AEs) were assessed throughout the study. Participants with unilateral knee OA were selected for this analysis., Results: Of 170 participants with unilateral OA (TA-ER, N = 51; saline-placebo, N = 60; TAcs, N = 59), 42% were male and 89% were white. TA-ER significantly (p < 0.05) improved ADP-intensity vs. saline-placebo (weeks 1-24) and TAcs (weeks 4-21). TA-ER significantly (p < 0.05) improved WOMAC-A vs. saline-placebo (all time points) and TAcs (weeks 4, 8, 12, 24). Consistent outcomes were observed for rescue medication, WOMAC-B, WOMAC-C, and KOOS-QoL. AEs were similar in frequency/type across treatments., Conclusion: TA-ER provided 5-6 months' pain relief that consistently exceeded saline-placebo and TAcs, suggesting that TA-ER injected intra-articularly into the affected knee may be an effective non-opioid treatment option. Although the participants included in this analysis did not fully represent the diverse demographics of active service members, the substantial unmet medical need in the military population suggests that TA-ER may be an important treatment option; additional studies of TA-ER in active military patients are needed., Trial Registration: ClinicalTrials.gov NCT02357459., Funding: Flexion Therapeutics, Inc. Plain language summary available for this article.

Objective: Approximately 30% of patients with type 2 diabetes mellitus have knee osteoarthritis. IA corticosteroids used to manage osteoarthritis pain can elevate blood glucose in these patients. We compared blood glucose levels following intra-articular injection of triamcinolone acetonide extended-release (TA-ER), an extended-release, microsphere-based triamcinolone acetonide formulation, vs standard triamcinolone acetonide crystalline suspension (TAcs) in patients with knee osteoarthritis and comorbid type 2 diabetes., Methods: In this double-blind, randomized, parallel-group, phase 2 study (NCT02762370), 33 patients with knee osteoarthritis (American College of Rheumatology criteria) and type 2 diabetes mellitus (HbA1c 6.5-9.0% [48-75 mmol/mol]; 1-2 oral hypoglycaemic agents) were treated with intra-articular TA-ER (32 mg n = 18) or TAcs 40 mg (n = 15). Continuous glucose monitoring-measured glucose (CGMG) was assessed from 1 week pre-injection through 2 weeks postinjection. Endpoints included change in average daily CGMG from baseline (days -3 to -1) to days 1-3 postinjection (CGMGdays1-3) (primary) and percent time average hourly CGMG levels remained in prespecified glycaemic ranges., Results: The change CGMGdays1-3 was significantly lower following TA-ER vs TAcs (14.7 vs 33.9 mg/dl, least-squares-mean-difference [95% CI]: -19.2 [-38.0, -0.4]; P = 0.0452). The percentage of time over days 1-3 that CGMG was in the target glycaemic range (70-180 mg/dl) was numerically greater for TA-ER (63.3%) vs TAcs (49.7%), and that CGMG was >180 mg/dl was lower for TA-ER (34.5%) vs TAcs (49.9%). Non-glycaemic adverse events were mild and comparable between groups., Conclusion: TA-ER may enable intra-articular corticosteroid treatment with minimal blood glucose disruption in patients with knee osteoarthritis and type 2 diabetes mellitus., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02762370.

Background: Intra-articular corticosteroids relieve osteoarthritis pain, but rapid systemic absorption limits efficacy. FX006, a novel, microsphere-based, extended-release triamcinolone acetonide (TA) formulation, prolongs TA joint residence and reduces systemic exposure compared with standard TA crystalline suspension (TAcs). We assessed symptomatic benefits and safety of FX006 compared with saline-solution placebo and TAcs., Methods: In this Phase-3, multicenter, double-blinded, 24-week study, adults ≥40 years of age with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) and average-daily-pain (ADP)-intensity scores of ≥5 and ≤9 (0 to 10 numeric rating scale) were centrally randomized (1:1:1) to a single intra-articular injection of FX006 (32 mg), saline-solution placebo, or TAcs (40 mg). The primary end point was change from baseline to week 12 in weekly mean ADP-intensity scores for FX006 compared with saline-solution placebo. Secondary end points were area-under-effect (AUE) curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with saline-solution placebo, AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, and AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 24 for FX006 compared with saline-solution placebo. Exploratory end points included week-12 changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QOL) subscale scores for FX006 compared with saline-solution placebo and TAcs. Adverse events were elicited at each inpatient visit., Results: The primary end point was met. Among 484 treated patients (n = 161 for FX006, n = 162 for saline-solution placebo, and n = 161 for TAcs), FX006 provided significant week-12 improvement in ADP intensity compared with that observed for saline-solution placebo (least-squares mean change from baseline: -3.12 versus -2.14; p < 0.0001) indicating ∼50% improvement. FX006 afforded improvements over saline-solution placebo for all secondary and exploratory end points (p < 0.05). Improvements in osteoarthritis pain were not significant for FX006 compared with TAcs using the ADP-based secondary measures. Exploratory analyses of WOMAC-A, B, and C and KOOS-QOL subscales favored FX006 (p ≤ 0.05). Adverse events were generally mild, occurring at similar frequencies across treatments., Conclusions: FX006 provided significant, clinically meaningful pain reduction compared with saline-solution placebo at week 12 (primary end point)., Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Objective: To present the current status of knowledge in the field of patellofemoral (PF) osteoarthritis (OA) and formulate a research agenda in order to guide future research on this topic., Design: A 1-day meeting was organized with the aim to bring together international experts in the field to discuss the current state of knowledge on PF OA. Experts from multiple disciplines were invited based on their scientific publications in the field of PF OA and interest in the subject. Topics discussed include the diagnosis, impact, prognosis, and treatment of PF OA., Methods: Following context-setting presentations, an interactive discussion was held in order to achieve consensus on the PF OA topics of interest: (1) diagnosis and definition; (2) burden; (3) outcome measures; (4) prognosis; (5) risk factors, and (6) treatment. Groups of meeting attendees reviewed the literature on these topics and narratively summarized the current state of knowledge, and each group formulated research agenda items relevant to the specific topics of interest. Each consortium member consequently ranked the importance of all items on a 0-10 Numerical Rating Scale (NRS) (10 = extremely important, to 0 = not at all important)., Results: After ranking all formulated items on importance, 6 of the 28 research agenda items formulated received an average of 7.5 points on the NRS. The most highly ranked items covered the fields of treatment, diagnosis, and definition of PF OA., Conclusions: We recommend to develop clear clinical criteria for PF OA and to reach consensus on the definition of PF OA by both radiographs and MRI. Additionally, more understanding is necessary to be able to distinguish PF symptoms from those arising from the tibiofemoral joint. More insight is needed on effective treatment strategies for PF OA; specifically, tailoring nonpharmacological treatments to individuals with PF OA, and determining whether isolated PF OA requires different treatment strategies than combined PF and tibiofemoral OA., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: FX006 is a novel, microsphere-based, extended-release formulation of triamcinolone acetonide for intraarticular (IA) injection designed to maintain treatment concentration in the joint and provide prolonged analgesic benefits in patients with osteoarthritis (OA) of the knee. This study was undertaken to compare the analgesic benefits of 2 FX006 doses with saline placebo injection., Methods: In this phase IIb study, participants with knee OA (Kellgren/Lawrence grade 2-3) and average daily pain (ADP) intensity ≥5 to ≤9 (on a 0-10 Numerical Rating Scale) were randomized (1:1:1) to receive single IA injections of FX006 32 mg (n = 104) or 16 mg (n = 102) or saline placebo (n = 100). The primary end point was the least squares mean (LSM) change from baseline to week 12 in weekly mean ADP intensity scores for FX006 32 mg versus saline placebo., Results: The primary end point was not met (LSM change at week 12 -3.1 with FX006 32 mg versus -2.5 with saline placebo; LSM difference [95% confidence interval] -0.58 [-1.22, 0.07]) (P = 0.08). However, improvements in ADP intensity were significantly greater with FX006 32 mg than saline placebo at weeks 1-11 and week 13. Improvements in ADP intensity were significantly greater with FX006 16 mg versus saline placebo at weeks 1-9. A dose-response effect in duration of maximal analgesic effect was evident (13 weeks with 32 mg versus 9 weeks with 16 mg), with FX006 32 mg providing increased therapeutic benefit relative to FX006 16 mg. All treatments were well tolerated., Conclusion: Although the primary end point was not met, our findings indicate a prolonged reduction in symptoms with FX006 with an evident dose response and a safety profile similar to saline placebo., (© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

The increased information provided by modern imaging has led to its more extensive use. Our aim was to develop evidence-based recommendations for the use of imaging in the clinical management of the most common arthropathy, osteoarthritis (OA). A task force (including rheumatologists, radiologists, methodologists, primary care doctors and patients) from nine countries defined 10 questions on the role of imaging in OA to support a systematic literature review (SLR). Joints of interest were the knee, hip, hand and foot; imaging modalities included conventional radiography (CR), MRI, ultrasonography, CT and nuclear medicine. PubMed and EMBASE were searched. The evidence was presented to the task force who subsequently developed the recommendations. The strength of agreement for each recommendation was assessed. 17 011 references were identified from which 390 studies were included in the SLR. Seven recommendations were produced, covering the lack of need for diagnostic imaging in patients with typical symptoms; the role of imaging in differential diagnosis; the lack of benefit in monitoring when no therapeutic modification is related, though consideration is required when unexpected clinical deterioration occurs; CR as the first-choice imaging modality; consideration of how to correctly acquire images and the role of imaging in guiding local injections. Recommendations for future research were also developed based on gaps in evidence, such as the use of imaging in identifying therapeutic targets, and demonstrating the added value of imaging. These evidence-based recommendations and related research agenda provide the basis for sensible use of imaging in routine clinical assessment of people with OA., Competing Interests: Competing interests: None., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: To analyze the 3-D bone area from an osteoarthritis (OA) cohort demonstrating no change in cartilage thickness., Methods: Twenty-seven women with painful medial knee OA had magnetic resonance images at 0, 3, and 6 months. Images were analyzed using active appearance models., Results: At 3 and 6 months, the mean change in medial femoral bone area was 0.34% (95% CI 0.04-0.64) and 0.61% (95% CI 0.32-0.90), respectively. Forty-one percent of the subjects had progression greater than the smallest detectable difference at 6 months., Conclusion: In this small cohort at high risk of OA progression, bone area changed at 3 and 6 months when cartilage morphometric measures did not.

Objective: To define a minimum Standard Set of outcome measures and case-mix factors for monitoring, comparing, and improving health care for patients with clinically diagnosed hip or knee osteoarthritis (OA), with a focus on defining the outcomes that matter most to patients., Methods: An international working group of patients, arthroplasty register experts, orthopedic surgeons, primary care physicians, rheumatologists, and physiotherapists representing 10 countries was assembled to review existing literature and practices for assessing outcomes of pharmacologic and nonpharmacologic OA therapies, including surgery. A series of 8 teleconferences, incorporating a modified Delphi process, were held to reach consensus., Results: The working group reached consensus on a concise set of outcome measures to evaluate patients' joint pain, physical functioning, health-related quality of life, work status, mortality, reoperations, readmissions, and overall satisfaction with treatment result. To support analysis of these outcome measures, pertinent baseline characteristics and risk factor metrics were defined. Annual outcome measurement is recommended for all patients., Conclusion: We have defined a Standard Set of outcome measures for monitoring the care of people with clinically diagnosed hip or knee OA that is appropriate for use across all treatment and care settings. We believe this Standard Set provides meaningful, comparable, and easy to interpret measures ready to implement in clinics and/or registries globally. We view this set as an initial step that, when combined with cost data, will facilitate value-based health care improvements in the treatment of hip and knee OA., (© 2016, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objective: To assess whether the "spread" of joint pain is related to pain-associated muscle loss in 1 joint leading to increased loading and subsequent pain in other joints., Methods: Associations between persistent knee pain (pain in 1 or 2 knees over 0-3 years vs no persistent pain) and incident shoulder pain at Year 4 were examined in participants from the longitudinal National Institutes of Health Osteoarthritis Initiative. Associations were assessed using log multinomial modeling, adjusted for age, sex, body mass index, depression score, other lower limb pain, and baseline leg weakness (difficulty standing from a sitting position)., Results: In older adults with clinically significant knee osteoarthritis (OA) or at risk of knee OA (n = 3486), the number of painful joints increased yearly, from 2.1 joints (95% CI 2.0-2.2) at baseline increasing by 5.2% (95% CI 2.2-8.3) at Year 4. Shoulders were the next most commonly affected joints after knees (28.5%). Persistent pain in 1 or 2 knees increased risk of bilateral shoulder pain at Year 4 [1 knee: relative risk (RR) 1.59, 95% CI 0.97-2.61; 2 knees: RR 2.02, 95% CI 1.17-3.49] after adjustment for confounders. Further adjustment for leg weakness attenuated effect sizes (1 knee: RR 1.13, 95% CI 0.60-2.11; 2 knees: RR 1.44, 95% CI 0.75-2.77), indicating mediation by functional leg weakness., Conclusion: Spread of joint pain is not random. Persistently painful knees predict new bilateral shoulder pain, which is likely mediated by leg weakness, suggesting that biomechanical factors influence the spread of pain.

Objectives: The aetiology of bone marrow lesions (BMLs) in knee osteoarthritis (OA) is poorly understood. We employed three-dimensional (3D) active appearance modelling (AAM) to study the spatial distribution of BMLs in an OA cohort and compare this with the distribution of denuded cartilage., Methods: Participants were selected from the Osteoarthritis Initiative progressor cohort with Kellgren-Lawrence scores ≥2, medial joint space narrowing and osteophytes. OA and ligamentous BMLs and articular cartilage were manually segmented. Bone surfaces were automatically segmented by AAM. Cartilage thickness of <0.5 mm was defined as denuded and ≥0.5-1.5 mm as severely damaged. Non-quantitative assessment and 3D population maps were used for analysing the comparative position of BMLs and damaged cartilage., Results: 88 participants were included, 45 men, mean age (SD) was 61.3 (9.9) years and mean body mass index was 31.1 (4.6) kg/m(2). 227 OA and 107 ligamentous BMLs were identified in 86.4% and 73.8% of participants; OA BMLs were larger. Denuded cartilage was predominantly confined to a central region on the medial femur and tibia, and the lateral facet of the trochlear femur. 67% of BMLs were colocated with denuded cartilage and a further 21% with severe cartilage damage. In the remaining 12%, 25/28 were associated with cartilage defects. 74% of all BMLs were directly opposing (kissing) another BML across the joint., Conclusions: There was an almost exclusive relationship between the location of OA BML and cartilage denudation, which itself had a clear spatial pattern. We propose that OA, ligamentous and traumatic BMLs represent a bone response to abnormal loading., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: There is growing understanding of the importance of bone in OA. Our aim was to determine the relationship between 3D MRI bone shape and total knee replacement (TKR)., Methods: A nested case-control study within the Osteoarthritis Initiative cohort identified case knees with confirmed TKR for OA and controls that were matched using propensity scores. Active appearance modelling quantification of the bone shape of all knee bones identified vectors between knees having or not having OA. Vectors were scaled such that -1 and +1 represented the mean non-OA and mean OA shapes., Results: Compared to controls (n = 310), TKR cases (n = 310) had a more positive mean baseline 3D bone shape vector, indicating more advanced structural OA, for the femur [mean 0.98 vs -0.11; difference (95% CI) 1.10 (0.88, 1.31)], tibia [mean 0.86 vs -0.07; difference (95% CI) 0.94 (0.72, 1.16)] and patella [mean 0.95 vs 0.03; difference (95% CI) 0.92 (0.65, 1.20)]. Odds ratios (95% CI) for TKR per normalized unit of 3D bone shape vector for the femur, tibia and patella were: 1.85 (1.59, 2.16), 1.64 (1.42, 1.89) and 1.36 (1.22, 1.50), respectively, all P < 0.001. After including Kellgren-Lawrence grade in a multivariable analysis, only the femur 3D shape vector remained significantly associated with TKR [odds ratio 1.24 (1.02, 1.51)]., Conclusion: 3D bone shape was associated with the endpoint of this study, TKR, with femoral shape being most associated. This study contributes to the validation of quantitative MRI bone biomarkers for OA structure-modification trials., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: There are unique challenges to designing and carrying out high-quality trials testing therapeutic devices in OA and other rheumatic diseases. Such challenges include determining the mechanisms of action of the device and the appropriate sham. Design of device trials is more challenging than that of placebo-controlled drug trials. Our aim was to develop recommendations for designing device trials., Methods: An Arthritis Research UK study group comprised of 30 rheumatologists, physiotherapists, podiatrists, engineers, orthopaedists, trialists and patients, including many who have carried out device trials, met and (using a Delphi-styled approach) came to consensus on recommendations for device trials., Results: Challenges unique to device trials include defining the mechanism of action of the device and, therefore, the appropriate sham that provides a placebo effect without duplicating the action of the active device. Should there be no clear-cut mechanism of action, a three-arm trial including a no-treatment arm and one with presumed sham action was recommended. For individualized devices, generalizable indications and standardization of the devices are needed so that treatments can be generalized., Conclusion: A consensus set of recommendations for device trials was developed, providing a basis for improved trial design, and hopefully improvement in the number of effective therapeutic devices for rheumatic diseases., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)