Association of Knee Osteoarthritis and Flexion Contracture With Localized Tibial Articular Cartilage Loss: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether a knee flexion contracture (FC) was associated with localized tibial articular cartilage loss over a 1-year period using Osteoarthritis Initiative quantitative data. METHODS: Five hundred seventy-eight participants from a previously established nested case-control study of people with radiographic knee OA with or without progression, based on radiographs and symptoms, had their knee range of extension measured at baseline and received magnetic resonance imaging (MRI) at baseline and 1 year. The tibial articular cartilage of the medial and lateral condyles was segmented into anterior, center, and posterior regions. We tested for associations between knee FC (defined as lack of extension to 0°), and localized changes in tibial articular cartilage thickness or percent of denuded bone (0 mm thickness) after 1 year relative to baseline using ANOVA, controlling for baseline MRI outcomes and clinical factors. RESULTS: Knee FC was associated with denuded bone in the medial condyle center (ß 0.44, 95% CI 0.02-0.86) and preserved cartilage thickness in the medial condyle posterior (ß 0.01, 95% CI 0.002-0.03) regions. CONCLUSION: Knee FC unloading the tibial center region and loading the posterior region was associated with localized articular cartilage loss centrally and preserved articular cartilage posteriorly. These findings are consistent with knee FC negatively affecting unloaded tibial articular cartilage.

Soluble low affinity nerve growth factor receptor (sLNGFR) may regulate pain in knee osteoarthritis.

OBJECTIVES: Nerve growth factor ß (ß-NGF) is a protein which is important to the development of neurons particularly those involved in the transmission of pain and is central to the experience of pain in osteoarthritis (OA). Direct NGF antagonism has been shown to reduce OA pain but is associated with rapidly progressive OA. The aim of the study is to investigate the ability of soluble neurotrophin receptors in the NGF pathway to modulate pain in OA. METHODS: Synovial fluid (SF) was obtained from the knee joints of 43 subjects who underwent total knee arthroplasty. Visual analogue scale (VAS) pain scores were obtained prior to surgery. Customised-automated-ELISAs and commercial-ELISAs and LEGENDplex™ were used to measure soluble low-affinity nerve growth factor (LNGFR), soluble tropomyosin receptor kinase (TrkA), proNGF, ß-NGF, other neurotrophins (NT) and cytokines including inflammatory marker TNF-α. RESULTS: The VAS score positively correlated with ß-NGF (r=0.34) and there was positive association trend with neurotrophin-3 (NT-3), BDNF and negative association trend with ProNGF. sLNGFR positively correlated with VAS (r=0.33). The ß-NGF/soluble TrkA ratio showed a strong positive correlation with VAS (r=0.80). In contrast, there was no correlation between pain and the ß-NGF/sLNGFR ratio (r=-0.08). TNF-α positively correlated with ß-NGF (r=0.83), NT-3 (r=0.66), and brain-derived neurotrophic factor (BDNF) (r=0.50) and negatively with ProNGF (r= -0.74) and positively correlated with both soluble TrkA (r=0.62), sLNGFR (r=0.26). CONCLUSIONS: This study suggests that endogenous or cleaved sLNGFR, but not soluble TrkA may participate in OA pain modulation thus supporting further research into soluble LNGFR as a therapeutic target in OA.

Baseline knee extension may be associated with volumetric cartilage loss in the anterolateral tibia: data from the Osteoarthritis Initiative.

OBJECTIVES: Animal studies suggest regional unloading of the knee due to flexion contracture (FC) results in cartilage loss in the anterior tibia. We looked for an association between the range of knee extension and articular cartilage thickness in the tibia of patients with knee OA, using quantitative MRI data from the OA Initiative. METHODS: Baseline knee extension was measured using a goniometer. Cartilage thickness was measured using 3-Tesla coronal MRI images of the knee. The tibia articular cartilage was segmented into medial and lateral regions, then further divided into anterior, central and posterior subregions. We evaluated differences between participants with and without a knee FC and associations between knee extension and cartilage thickness, including percentage denudation of bones (0 mm thickness), using linear models. RESULTS: A total of 596 participants were included. Participants with a knee FC had a larger percentage of denuded bone in the anterolateral tibia vs participants without FC (2.2 ± 0.7% vs 0.4 ± 0.1%; P = 0.006), and knee extension was associated with anterolateral tibia denuded bone (r = 0.16, P < 0.001). After correcting for demographics, knee alignment, and OA severity, presence of FC and lost knee extension were associated with the percentage of denuded bone in the anterolateral tibia [ß = 1.702 (0.634-2.770) and ß = 0.261 (95% CI 0.134, 0.388), respectively]. CONCLUSION: While causation cannot be determined in this study, limitation in knee extension was statistically associated with the percentage of denuded bone in the anterolateral tibia. These novel data support that maintaining range of motion over the entire joint surface may help preserve articular cartilage health.

Asymmetric Flexion Contracture is Associated With Leg Length Inequality in Patients With Knee Osteoarthritis: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether knee flexion contracture (FC) was associated with leg length inequality (LLI) and/or morbidity in knee osteoarthritis (OA). DESIGN: We accessed 2 databases: (1) the Osteoarthritis Initiative (OAI) cohort, including participants with, or at-risk of OA, and (2) the Ottawa Knee Osteoarthritis cross-sectional database (OKOA), including participants with primary advanced knee OA. Both included demographics, radiographic data, knee range of motion, leg length, pain, and function scales. SETTING: Tertiary care academic rheumatology and orthopedic clinics. PARTICIPANTS: Patients with or at-risk of primary OA. We included 881 OAI and 72 OKOA participants (N=953). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The primary outcome tested the association between the difference in knee extensions of the OA and contralateral knees (the knee extension difference, or KExD) and LLI. This was evaluated using bivariate regression, followed by a multivariable linear regression model. RESULTS: OAI participants had less severe knee OA [Kellgren and Lawrence (KL) score 1.9±1.3] vs OKOA (KL score 3.4±0.6). The KExD correlated with LLI for both databases (OAI: R=0.167; P≤.001; OKOA: R=0.339; P=.004). Multivariable regression showed an effect of KExD on LLI in both databases (OAI: ß=0.37[0.18,0.57]; P<.001, OKOA: ß=0.73[0.20,1.26]; P=.007). When broken down by subgroup, the OAI moderate-severe OA group showed a significant effect of KExD on LLI (ß=0.60 [0.34,0.85]; P<.001). CONCLUSIONS: OA-related loss of knee extension was associated with LLI for those with moderate-severe OA. Because LLI correlates with worse knee OA symptoms, discovering an FC should cue clinicians to evaluate for LLI, an easily-treatable finding that may help reduce OA-associated morbidity for those approaching the need for arthroplasty.

Flexion contracture is associated with knee joint degeneration on magnetic resonance imaging: data from the Osteoarthritis Initiative.

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 (ß=0.709, p<0.001, and ß=0.666, p<0.001, respectively) as were higher osteophyte scores in multiple regions, worse meniscal score in the medial meniscal body (ß=0.164, p<0.040) and posterior horn (ß=0.400, p<0.001), and a worse effusion score (ß=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.

Prevalence, Impact, and Treatment of Co-Occurring Osteoarthritis in Patients With Stroke Undergoing Rehabilitation: A Review.

Background and Purpose: Early, frequent rehabilitation is an important factor for optimizing stroke recovery outcomes. Medical comorbidities, such as osteoarthritis, that affect the ability to participate in rehabilitation could therefore have a detrimental impact on such outcomes. Both stroke and osteoarthritis are becoming more common in developed nations as the population ages. First-line osteoarthritis treatments, such as oral nonsteroidal anti-inflammatory drugs, are often avoided poststroke due to interaction with secondary prevention stroke risk-factor management. Our objective was to summarize the current literature concerning co-occurring osteoarthritis and stroke prevalence, its functional impact, and treatment options. Methods: Narrative review using a comprehensive literature search of PubMed, osteoarthritis, and stroke guidelines. Outcomes related to co-occurrence prevalence, osteoarthritis as a stroke risk-factor, osteoarthritis-related imaging and treatment were extracted and summarized descriptively. Overall quality of the evidence was summarized using Grading of Recommendations Assessment, Development and Evaluation. Results: We identified 23 studies and guidelines related to our objective. Overall quality of the evidence was very low. Conclusions: Few trials have investigated the relationship between osteoarthritis and stroke, nor osteoarthritis-specific pain and function management for stroke survivors. High-quality research evaluating the impact of osteoarthritis on stroke rehabilitation is needed.

Patient tolerability of suprascapular and median nerve blocks for the management of pain in post-stroke shoulder-hand syndrome.

BACKGROUND: Current management options for pain in stroke patients with the shoulder-hand syndrome (SHS) are limited and often ineffective. The use of peripheral nerve blocking in SHS has been limited due to concerns of hyperalgesia and allodynia in these patients. This study assessed the tolerability of suprascapular nerve (SSN) and median nerve blocks for acute control of pain in patients with post-stroke SHS. METHODS: All SHS patients fulfilled diagnosis using the Budapest criteria. Patient tolerability was defined by a composite score that included a change on the visual analog scale (VAS) from baseline for shoulder and hand pain, presence of adverse events, and a self-reported patient satisfaction score. Pain assessment was performed 1 h before (baseline), and 1 h and 2 weeks after the procedure. RESULTS: Five patients (68.5 ± 9.5 years) with post-stroke SHS underwent SSN and median nerve blocks. Participant assessment 1 h after the procedure indicated that the 2 blocking procedures were well tolerated and that VAS scores for shoulder and hand pain decreased by 79% (- 62.6 mm ± 25.6; p = 0.043) and 48% (- 33 mm ± 40.2; p = 0.080), respectively from baseline. After 2 weeks, average VAS scores remained 56% and 37% below baseline, respectively. There were no adverse events and all patients were satisfied after the procedure. CONCLUSIONS: Suprascapular and median nerve blocks are safe and well-tolerated procedures for acute pain control in post-stroke SHS. Further studies should address the benefit of these procedures on overall pain reduction, functional recovery, and quality of life in SHS patients.

Knee Flexion Contracture Associated With a Contracture and Worse Function of the Contralateral Knee: Data From the Osteoarthritis Initiative.

OBJECTIVE: Patients at risk of developing knee osteoarthritis (OA) or those already diagnosed with knee OA may present with a knee flexion contracture (FC). A knee FC can cause pain and can decrease function. By altering lower extremity biomechanics, the effect of a knee FC goes beyond the affected joint. Compensatory movements during gait can chronically affect other joints in both lower limbs. Few studies describe the effect of a knee FC on, or direct assessment toward, the contralateral knee. We investigated the associations between knee FC with range of extension, function, pain, and stiffness of the contralateral knee. DESIGN: Cross-sectional, using the Osteoarthritis Initiative Database. PARTICIPANTS: Outpatient cohort study, recruiting from 4 United States academic health care centers (N=4796). Two groups were included: those at risk of developing OA (n=3284 knees), and those already with radiographic OA (n=1390 knees). MAIN OUTCOMES MEASURES: Maximum contralateral knee extension and Western Ontario and McMaster Osteoarthritis Index (WOMAC) scores. Statistical analysis included a mixed linear model evaluating for independent associations between the index knee FC and contralateral knee outcome measures. RESULTS: A knee FC was associated with a contralateral knee FC (P<.001) with contralateral FC severity dependent on severity of the index knee FC (P<.001). Participants at risk of developing OA with moderate FC showed worse function in the contralateral knee than those with mild FC (WOMAC functional subscale ± SD: 7.6±10.1 vs 5.5±8.8; P=.036). Mixed linear analysis confirmed an independent association between knee FC severity and contralateral WOMAC function. CONCLUSIONS: Having an FC in 1 knee was associated with an FC in the contralateral knee for participants who were at risk of developing OA and for those with a current diagnosis of OA. For those at risk of developing OA, the severity of knee FC was an independent predictor for loss of contralateral knee function. Rehabilitation of patients with or at risk of developing OA should consider the restoration of extension and function for both knees.

Tendon contains more stem cells than bone at the rotator cuff repair site.

BACKGROUND: The rotator cuff (RC) repair failure rate is high. Tendon and bone represent sources of mesenchymal stem cells (MSCs), but the number of MSCs from each has not been compared. Bone channeling may increase bone-derived MSC numbers participating in enthesis re-formation at the "footprint" repair site. The effect of preoperative channeling on increasing bone MSC numbers has never been reported. We asked (1) whether bone contains more MSCs than tendon at the time of arthroscopic repair and (2) whether bone preoperative channeling at the RC repair site increases the number of bone-derived MSCs at the time of surgery. METHODS: In 23 participants undergoing arthroscopic RC repair, bone was sampled from the footprint and tendon was sampled from the distal supraspinatus. We randomized participants to the channeling or no-channeling group 5 to 7 days before surgery. We enumerated MSCs from both tissues using the colony-forming unit-fibroblast (CFU-F) assay (10 per group). We identified MSC identity using flow cytometry and MSC tri-differentiation capacity (n = 3). RESULTS: Tendon CFU-F per gram exceeded bone CFU-F per gram for both groups (479 ± 173 CFU-F/g vs. 162 ± 54 CFU-F/g for channeling [P = .036] and 1334 ± 393 CFU-F/g vs. 284 ± 88 CFU-F/g for no channeling [P = .009]). Ninety-nine percent of cultured cells satisfied the MSC definition criteria. CONCLUSIONS: The distal supraspinatus tendon contained more MSCs per gram than the humeral footprint. Tendon may represent an important and overlooked MSC source for postoperative enthesis re-formation. Further studies are needed to evaluate the repair role of tendon MSCs and to recommend bone channeling in RC repair.

Shoe Lifts for Leg Length Discrepancy in Adults With Common Painful Musculoskeletal Conditions: A Systematic Review of the Literature.

OBJECTIVE: To determine whether shoe lifts effectively treat leg length discrepancy (LLD)-associated morbidities in adults with common painful musculoskeletal conditions. DATA SOURCES: Trip database, Cochrane Central Register of Controlled Trials database, PubMed database, Physiotherapy Evidence Database, and National Guideline Clearinghouse database. The search was performed in September 2017, was limited to English only, and had no time constraints. STUDY SELECTION: Two reviewers independently determined study eligibility. Inclusion criteria were (1) participants ≥18 years old with musculoskeletal-related complaints and LLD; (2) a shoe lift intervention was used; and (3) the study reported on pain, function, range of motion, patient satisfaction, quality of life, or adverse events. Randomized controlled trials (RCTs) and controlled intervention, cohort, before-and-after, case series, and case report studies were included. Three-hundred and nineteen articles were screened, and 9 guidelines were reviewed. DATA EXTRACTION: We extracted data pertaining to participant demographic characteristics, study setting, recruitment, randomization, method of LLD measurement, shoe lift characteristics, treatment duration, and outcome measures. We included 10 studies, including 1 RCT. DATA SYNTHESIS: LLD was associated with low back pain, scoliosis, and osteoarthritis of the hip and knee. Description of LLD correction strategy was often inadequate. Study quality was very low or poor. In non-RCT studies reporting on the proportion of participants who improved with a shoe lift, 88%±3% of 349 participants treated had partial or complete pain relief (effect size range, 66.7%-100%). All 22 RCT participants receiving treatment experienced pain relief (mean pain reduction, 27±9mm on a 150-mm visual analog scale). Two of 9 guidelines recommended shoe lift use based on consensus and were of moderate-to-high quality. CONCLUSIONS: There is low-quality evidence that shoe lifts reduce pain and improve function in patients with LLD and common painful musculoskeletal conditions. High-quality research evaluating a threshold LLD to correct and a strategy to do so is necessary. Developing an appropriate comparison group to test clinically relevant outcome measures would make a valuable contribution in this regard.

Protecting the regenerative environment: selecting the optimal delivery vehicle for cartilage repair-a narrative review.

Focal cartilage defects are common in youth and older adults, cause significant morbidity and constitute a major risk factor for developing osteoarthritis (OA). OA is the most common musculoskeletal (MSK) disease worldwide, resulting in pain, stiffness, loss of function, and is currently irreversible. Research into the optimal regenerative approach and methods in the setting of either focal cartilage defects and/or OA holds to the ideal of resolving both diseases. The two fundamentals required for cartilage regenerative treatment are 1) the biological element contributing to the regeneration (e.g., direct application of stem cells, or of an exogenous secretome), and 2) the vehicle by which the biological element is suspended and delivered. The vehicle provides support to the regenerative process by providing a protective environment, a structure that allows cell adherence and migration, and a source of growth and regenerative factors that can activate and sustain regeneration. Models of cartilage diseases include osteochondral defect (OCD) (which usually involve one focal lesion), or OA (which involves a more diffuse articular cartilage loss). Given the differing nature of these models, the optimal regenerative strategy to treat different cartilage diseases may not be universal. This could potentially impact the translatability of a successful approach in one condition to that of the other. An analogy would be the repair of a pothole (OCD) versus repaving the entire road (OA). In this narrative review, we explore the existing literature evaluating cartilage regeneration approaches for OCD and OA in animal then in human studies and the vehicles used for each of these two conditions. We then highlight strengths and challenges faced by the different approaches presented and discuss what might constitute the optimal cartilage regenerative delivery vehicle for clinical cartilage regeneration.

Navigating the path of progress: The OMERACT 2023 emerging leaders program.

OBJECTIVES: The Outcome Measures in Rheumatology Clinical Trials (OMERACT) Emerging Leaders Program (ELP) aims to cultivate a cohort of skilled leaders within the OMERACT community empowering them with expertise and knowledge to help shape and steer the organization into the future. This publication highlights the significance of the ELP in driving leadership excellence, its impact on OMERACT's evolution, and the outcomes and learnings from the OMERACT 2023 ELP. METHODS: Insights from the 2018 ELP report informed 2023 program improvements. Engagement was measured by attendance and WhatsApp interactions. Positive program aspects, areas for improvement and ideas for enhancing future ELPs were captured via anonymous survey and participant focus groups. RESULTS: Engagement with the ELP was high with 9 participants, 96 % attendance at all workshops, 154 WhatsApp interactions. All program components were highly rated, with the highest being the 'Psychological Safety' and 'Methodology/Process/Politics' workshops. Future enhancements included creating further networking, connection and support activities, practical leadership and methodological skill development opportunities, and a new stream focussing on organisational advancement. CONCLUSIONS: The 2023 OMERACT ELP was well received and successfully addressed areas previously identified as requiring improvement. New educational enhancements were valued, and the importance of fostering psychological safety at all levels was highlighted. The ELP fortifies OMERACT by nurturing a diverse array of skilled leaders who embody OMERACTs core values. Continuing to refine and evolve the ELP over time will help OMERACT sustain its global influence in patient-centered outcome research.

Stretching, Bracing, and Devices for the Treatment of Osteoarthritis-Associated Joint Contractures in Nonoperated Joints: A Systematic Review and Meta-Analysis.

CONTEXT: Many patients with osteoarthritis (OA) develop range of motion (ROM) restrictions in their affected joints (contractures), associated with worse outcomes and rising healthcare costs. Effective treatment guidance for lost ROM in OA-affected joints is lacking. OBJECTIVE: A systematic review and meta-analysis evaluating the effectiveness of stretching and/or bracing protocols on native (nonoperated) joint ROM in the setting of radiographically diagnosed OA. DATA SOURCES: Seven databases, English-language. STUDY SELECTION: Studies including participants with radiographically diagnosed OA in any native joint evaluating the effect of stretching or bracing on ROM. STUDY DESIGN: Systematic review and meta-analysis. LEVEL OF EVIDENCE: Level 2. DATA EXTRACTION: Two reviewers independently screened articles for inclusion and assessed risk of bias in included trials. Primary outcomes were ROM, pain, and adverse events (AEs). RESULTS: We identified 6284 articles. A total of 9 randomized controlled trials, all evaluating the knee, met eligibility criteria. For stretching, 3 pooled studies reported total ROM, which improved by mean difference (MD) of 9.3° (95% CI 5.0°,13.5°) versus controls. Two pooled studies showed improved knee flexion ROM (MD 10.8° [7.3°,14.2°]) versus controls. Five studies were pooled for knee extension with mean improvement 9.1° [3.4°,14.8°] versus controls. Seven pooled studies showed reduced pain (standardized MD 1.9 [1.2,2.6]). One study reported improved knee extension of 3.7° [2.9°,4.5°] with use of a device. No studies used orthoses. One study reported on AEs, with none noted. Performance bias was present in all included studies, and only 3 studies clearly reported blinding of outcome assessors. Strength of evidence for primary outcomes was considered moderate. CONCLUSION: There was moderate-quality evidence that stretching is an effective strategy for improving knee total, flexion and extension ROM, and pain. Our findings suggest that stretching to regain joint ROM in OA is not futile and that stretching appears to be an appropriate conservative intervention to improve patient outcomes as part of a comprehensive knee OA treatment plan before arthroplasty.

The Hunt Is On! In Pursuit of the Ideal Stem Cell Population for Cartilage Regeneration.

Cartilage injury and degeneration are hallmarks of osteoarthritis (OA), the most common joint disease. OA is a major contributor to pain, loss of function, and reduced quality of life. Over the last decade, considerable research efforts have focused on cell-based therapies, including several stem cell-derived approaches to reverse the cartilage alterations associated with OA. Although several tissue sources for deriving cell-based therapies have been identified, none of the resident stem cell populations have adequately fulfilled the promise of curing OA. Indeed, many cell products do not contain true stem cells. As well, issues with aggressive marketing efforts, combined with a lack of evidence regarding efficacy, lead the several national regulatory bodies to discontinue the use of stem cell therapy for OA until more robust evidence becomes available. A review of the evidence is timely to address the status of cell-based cartilage regeneration. The promise of stem cell therapy is not new and has been used successfully to treat non-arthritic diseases, such as hematopoietic and muscle disorders. These fields of regenerative therapy have the advantage of a considerable foundation of knowledge in the area of stem cell repair mechanisms, the role of the stem cell niche, and niche-supporting cells. This foundation is lacking in the field of cartilage repair. So, where should we look for the ideal stem cell to regenerate cartilage? It has recently been discovered that cartilage itself may contain a population of SC-like progenitors. Other potential tissues include stem cell-rich dental pulp and the adolescent growth plate, the latter of which contains chondrocyte progenitors essential for producing the cartilage scaffold needed for bone growth. In this article, we review the progress on stem cell therapies for arthritic disorders, focusing on the various stem cell populations previously used for cartilage regeneration, successful cases of stem cell therapies in muscle and hemopoietic disorders, some of the reasons why these other fields have been successful (i.e., "lessons learned" to be applied to OA stem cell therapy), and finally, novel potential sources of stem cells for regenerating damaged cartilage in vivo.

MSC-Derived Extracellular Vesicles in Preclinical Animal Models of Bone Injury: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising treatment for bone injuries, although studies remain preclinical. A systematic review and meta-analysis can assess the efficacy of MSC-EVs and identify treatment aspects associated with enhanced bone repair. METHODS: English language, preclinical, controlled, in vivo studies identified in our systematic search (up to May 8, 2020) examining the use of MSC-EVs in bone healing were included. Risk of bias (ROB) was assessed using the SYRCLE tool. Aggregate Data Meta-Analysis was performed to determine the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) and New Bone Formation (NBF). RESULTS: Thirteen studies were included. Twelve reported either BV/TV or NBF and were included in meta-analysis. ROB was unclear in all studies. Overall, MSC-EVs displayed benefit in terms of bone healing for both BV/TV (22.2% mean difference (MD); 95% CI: 15.8-28.5%, p < 0.001) and NBF (26.1% MD; 10.3-41.8%, p = 0.001) versus controls. Substantial heterogeneity, however, was observed between studies. MSC-EVs were reported to activate multiple signaling pathways including mTOR/AKT, AMPK and BMP2. Subgroup analysis indicated no significant difference in the improvement of BV/TV when using modified EVs isolated after gene transfection, preconditioning (p = 0.61), or using EVs in combination with a tissue scaffold and/or hydrogel versus other delivery methods (p = 0.20). CONCLUSION: Use of MSC-EVs to promote healing of bone injury appears promising, however, heterogeneity between studies and the potential for reporting bias limits confidence in the extent of benefit. Reducing bias between studies and addressing aspects of potential reporting bias should augment confidence in future meta-analyses and propel the field towards clinical studies. Forest Plot analysis assessing the percentage change in bone volume (BV) / total volume (TV) in the presence (experimental) or absence (control) of MSC-EVs.

Flexion contracture is a risk factor for knee osteoarthritis incidence, progression and earlier arthroplasty: Data from the Osteoarthritis Initiative.

BACKGROUND: Knee joint osteoarthritis (OA) is often accompanied by flexion contracture (FC), but the impact of FC on important outcomes across the spectrum of OA, such as the incidence, progression and need for total knee arthroplasty (TKA), is not well established. OBJECTIVE: We evaluated whether the presence and/or severity of knee FC were risk factors for worse OA clinical outcomes, radiographic incidence and progression as well as time to TKA. METHODS: We evaluated longitudinal 9-year data from the Osteoarthritis Initiative (OAI) database for 3 sub-cohorts: at-risk of knee OA (n=3284), radiographically established knee OA (n=1390), and low-risk controls (n=122). We classified knee FC as none, mild, moderate or severe based on knee extension at enrolment. Knee OA outcomes were extracted from the database. RESULTS: FC was present in 32.4% of knees. Participants with FC had increased knee OA incidence with joint space narrowing in the definition (corrected odds ratio 1.31 [95% confidence interval (CI) 1.04-1.64]). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for pain, stiffness and function were worse with than without FC at nearly all times (p<0.001). Effect estimates were significant for all 3 WOMAC sub-scales comparing FC to no FC (pain: 0.15 [95% CI 0.02-0.28], stiffness: 0.11 [0.05-0.18], function: 0.49 [0.05-0.93]). Individuals with knee FC had higher Kellgren and Lawrence grade (effect size 0.31 [95% CI 0.25-0.37]) and were more likely to undergo TKA (corrected odds ratio 1.37 [95% CI 1.10-1.71]) than those without FC. All outcomes were worse with increasing FC severity. CONCLUSION: The presence of knee FC at enrolment was a risk factor for radiographic OA incidence including joint space narrowing, worse clinical outcomes, radiographic progression and the need for early TKA. Treatment of knee FC may represent an option across the OA spectrum. Further research is needed to evaluate the pathophysiology, joint structure alterations and longitudinal impact of treating FC in individuals with knee OA.

Knee Flexion Contractures Are Associated with Worse Pain, Stiffness, and Function in Patients with Knee Osteoarthritis: Data from the Osteoarthritis Initiative.

BACKGROUND: Patients with or at risk of developing knee osteoarthritis (OA) can acquire a knee flexion contracture (FC). The prevalence, severity, and association of knee FC on OA outcomes such as pain, stiffness, and function are not well described and clinical scales may omit measuring joint range of motion. OBJECTIVE: (1) To determine if the presence and severity of a knee FC was associated with worse joint pain, stiffness and/or function and (2) to determine if this association was present in participants with or at risk of knee OA. METHODS: Following a detailed standardized protocol, maximum knee extension was obtained from the baseline physical examination data using a goniometer with the fulcrum over the knee joint line, the upper arm directed towards the greater trochanter and the lower arm directed towards the lateral malleolus. DESIGN: Cross-sectional, using the Osteoarthritis Initiative database. SETTING AND PARTICIPANTS: Baseline cross-sectional data collected from a prospective outpatient cohort study, recruiting from four academic health care centers in the United States. Three subcohorts were included: those at-risk of OA (n = 5995 knees), those with radiographic OA (n = 2610 knees), and controls (n = 62 knees). MAIN OUTCOME MEASURES: We categorized knee FCs as none, mild, moderate, or severe. Pain scales included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale and numeric pain rating scale; stiffness, the WOMAC stiffness subscale; and function, the WOMAC function subscale and 400-m walk time. RESULTS: Participants with FC reported overall worse pain, stiffness, and function compared to those without FC in a severity-dependent manner. OA participants' scores showed between 1.8- and 11.0-fold mean relative worsening versus at-risk participants (P < .05 for all). Knee FC was independently associated in a severity-dependent manner with all outcomes (P < .01). CONCLUSIONS: Knee FCs were associated with worse pain, stiffness, and function in a severity-dependent manner in a population with or at risk of knee OA. There was an interaction between OA subcohort and FC severity (P-for-interaction <.01 for all WOMAC outcomes). Evaluation of the longitudinal effects of contracture on OA and at-risk patient outcomes is necessary.