Aims. This study aimed to determine the expression and clinical significance of a cartilage protein, cartilage oligomeric matrix protein (COMP), in knee osteoarthritis (OA) patients. Methods. A total of 270 knee OA patients and 93 healthy controls were recruited. COMP messenger RNA (mRNA) and protein levels in serum, synovial fluid, synovial tissue, and fibroblast-like synoviocytes (FLSs) of knee OA patients were determined using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunohistochemistry. Results. COMP protein levels were significantly elevated in serum and synovial fluid of knee OA patients, especially those in the advanced stages of the disease. Serum COMP was significantly correlated with radiological severity as well as measures of body composition, physical performance, knee pain, and disability. Receiver operating characteristic curve analysis unveiled a diagnostic value of serum COMP as a biomarker of knee OA (41.64 ng/ml, area under the curve (AUC) = 1.00), with a sensitivity of 99.6% and a specificity of 100.0%. Further analysis uncovered that COMP mRNA expression was markedly upregulated in the inflamed synovium of knee OA, consistent with immunohistochemical staining revealing localization of COMP protein in the lining and sub-lining layers of knee OA inflamed synovium. Most notably, relative COMP mRNA expression in knee OA synovium was positively associated with its protein levels in serum and synovial fluid of knee OA patients. In human knee OA FLSs activated with tumour necrosis factor-alpha, COMP mRNA expression was considerably up-regulated in a time-dependent manner. Conclusion. All results indicate that COMP might serve as a supportive diagnostic marker for knee OA in conjunction with the standard diagnostic methods. Cite this article: Bone Joint Res 2024;13(6):261–271

Aims. The purpose of our study was to determine whether mesenchymal stem cells (MSCs) are an effective and safe therapeutic agent for the treatment of knee osteoarthritis (OA), owing to their cartilage regeneration potential. Methods. We searched PubMed, Embase, and the Cochrane Library, with keywords including “knee osteoarthritis” and “mesenchymal stem cells”, up to June 2019. We selected randomized controlled trials (RCTs) that explored the use of MSCs to treat knee OA. The visual analogue scale (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), adverse events, and the whole-organ MRI score (WORMS) were used as the primary evaluation tools in the studies. Our meta-analysis included a subgroup analysis of cell dose and cell source. Results. Seven trials evaluating 256 patients were included in the meta-analysis. MSC treatment significantly improved the VAS (mean difference (MD), –13.24; 95% confidence intervals (CIs) –23.28 to –3.20, p = 0.010) and WOMAC (MD, –7.22; 95% CI –12.97 to –1.47, p = 0.010). The low-dose group with less than 30 million cells showed lower p-values for both the VAS and WOMAC. Adipose and umbilical cord–derived stem cells also had lower p-values for pain scores than those derived from bone marrow. Conclusion. Overall, MSC-based cell therapy is a relatively safe treatment that holds great potential for OA, evidenced by a positive effect on pain and knee function. Using low-dose (25 million) and adipose-derived stem cells is likely to achieve better results, but further research is needed. Cite this article: Bone Joint Res 2020;9(10):719–728

Objectives. Normal sagittal spine-pelvis-lower extremity alignment is crucial in humans for maintaining an ergonomic upright standing posture, and pathogenesis in any segment leads to poor balance. The present study aimed to investigate how this sagittal alignment can be affected by severe knee osteoarthritis (KOA), and whether associated changes corresponded with symptoms of lower back pain (LBP) in this patient population. Methods. Lateral radiograph films in an upright standing position were obtained from 59 patients with severe KOA and 58 asymptomatic controls free from KOA. Sagittal alignment of the spine, pelvis, hip and proximal femur was quantified by measuring several radiographic parameters. Global balance was accessed according to the relative position of the C7 plumb line to the sacrum and femoral heads. The presence of chronic LBP was documented. Comparisons between the two groups were carried by independent samples t-tests or chi-squared test. Results. Patients with severe KOA showed significant backward femoral inclination (FI), hip flexion, forward spinal inclination, and higher prevalence of global imbalance (27.1% versus 3.4%, p < 0.001) compared with controls. In addition, patients with FI of 10° (n = 23) showed reduced lumbar lordosis and significant forward spinal inclination compared with controls, whereas those with FI > 10° (n = 36) presented with significant pelvic anteversion and hip flexion. A total of 39 patients with KOA (66.1%) suffered from LBP. There was no significant difference in sagittal alignment between KOA patients with and without LBP. Conclusions. The sagittal alignment of spine-pelvis-lower extremity axis was significantly influenced by severe KOA. The lumbar spine served as the primary source of compensation, while hip flexion and pelvic anteversion increased for further compensation. Changes in sagittal alignment may not be involved in the pathogenesis of LBP in this patient population. Cite this article: W. J. Wang, F. Liu, Y.W. Zhu, M.H. Sun, Y. Qiu, W. J. Weng. Sagittal alignment of the spine-pelvis-lower extremity axis in patients with severe knee osteoarthritis: A radiographic study. Bone Joint Res 2016;5:198–205. DOI:10.1302/2046-3758.55.2000538

Aims. The aim of this study was to estimate time to arthroplasty among patients with hip and knee osteoarthritis (OA), and to identify factors at enrolment to first-line intervention that are prognostic for progression to surgery. Methods. In this longitudinal register-based observational study, we identified 72,069 patients with hip and knee OA in the Better Management of Patients with Osteoarthritis Register (BOA), who were referred for first-line OA intervention, between May 2008 and December 2016. Patients were followed until the first primary arthroplasty surgery before 31 December 2016, stratified into a hip and a knee OA cohort. Data were analyzed with Kaplan-Meier and multivariable-adjusted Cox regression. Results. At five years, Kaplan-Meier estimates showed that 46% (95% confidence interval (CI) 44.6 to 46.9) of those with hip OA, and 20% (95% CI 19.7 to 21.0) of those with knee OA, had progressed to arthroplasty. The strongest prognostic factors were desire for surgery (hazard ratio (HR) hip 3.12 (95% CI 2.95 to 3.31), HR knee 2.72 (95% CI 2.55 to 2.90)), walking difficulties (HR hip 2.20 (95% CI 1.97 to 2.46), HR knee 1.95 (95% CI 1.73 to 2.20)), and frequent pain (HR hip 1.56 (95% CI 1.40 to 1.73), HR knee 1.77 (95% CI 1.58 to 2.00)). In hip OA, the probability of progression to surgery was lower among those with comorbidities (e.g. ≥ four conditions; HR 0.64 (95% CI 0.59 to 0.69)), with no detectable effects in the knee OA cohort. Instead, being overweight or obese increased the probability of OA progress in the knee cohort (HR 1.25 (95% CI 1.15 to 1.37)), but not among those with hip OA. Conclusion. Patients with hip OA progressed faster and to a greater extent to arthroplasty than patients with knee OA. Progression was strongly influenced by patients’ desire for surgery and by factors related to severity of OA symptoms, but factors not directly related to OA symptoms are also of importance. However, a large proportion of patients with OA do not seem to require surgery within five years, especially among those with knee OA. Cite this article: Bone Joint J 2022;104-B(7):792–800

Abstract. Objectives. Biomechanics is an essential form of measurement in the understanding of the development and progression of osteoarthritis (OA). However, the number of participants in biomechanical studies are often small and there is limited ways to share or combine data from across institutions or studies. This is essential for applying modern machine learning methods, where large, complex datasets can be used to identify patterns in the data. Using these data-driven approaches, it could be possible to better predict the optimal interventions for patients at an early stage, potentially avoiding pain and inappropriate surgery or rehabilitation. In this project we developed a prototype database platform for combining and sharing biomechanics datasets. The database includes methods for importing and standardising data and associated variables, to create a seamless, searchable combined dataset of both healthy and knee OA biomechanics. Methods. Data was curated through calls to members of the OATech Network+ (. https://www.oatechnetwork.org/. ). The requirements were 3D motion capture data from previous studies that related to analysing the biomechanics of knee OA, including participants with OA at any stage of progression plus healthy controls. As a minimum we required kinematic data of the lower limbs, plus associated kinetic data (i.e. ground reaction forces). Any additional, complementary data such as EMG could also be provided. Relevant ethical approvals had to be in place that allowed re-use of the data for other research purposes. The datasets were uploaded to a University hosted cloud platform. The database platform was developed using Javascript and hosted on a Windows server, located and managed within the department. Results. Three independent datasets were curated following the call to OATech Network+ members. These originated from separate studies collected from biomechanics labs at Cardiff University, Keele University, and Imperial College London. Participants with knee OA were at various stages of progression and all datasets included healthy controls. The total sample size of the three datasets is n=244, split approximately equally between healthy and knee OA participants. Naming conventions and formatting of the exported data varied greatly across datasets. Datasets were therefore formatted into a common format prior to upload, with guidelines developed for future contributions. Uploading data at the marker set level was too complicated for combination at the prototype stage. Therefore, processed variables relating to joint angles and joint moments were used. The resulting prototype database included an import function to align and standardise variables. A a simple query tool was further developed to extract outputs from the database, along with a suitable user interface for basic data exploration. Conclusion. Combining biomechanics dataset presents a wide range of challenges from both a technical and data governance context. Here we have taken the first steps to demonstrate a proof-of-concept that can combine heterogenous data from independent OA-related biomechanics studies into a combined, searchable resource. Expanding this in the future to a fully open access database will create an essential resource that will facilitate the application of data-driven models and analyses for better understanding, stratification and prediction of OA progression. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Aims. This study aims to determine the rate of and risk factors for total knee arthroplasty (TKA) after operative management of tibial plateau fractures (TPFs) in older adults. Methods. This is a retrospective cohort study of 182 displaced TPFs in 180 patients aged ≥ 60 years, over a 12-year period with a minimum follow-up of one year. The mean age was 70.7 years (SD 7.7; 60 to 89), and 139/180 patients (77.2%) were female. Radiological assessment consisted of fracture classification; pre-existing knee osteoarthritis (OA); reduction quality; loss of reduction; and post-traumatic OA. Fracture depression was measured on CT, and the volume of defect estimated as half an oblate spheroid. Operative management, complications, reoperations, and mortality were recorded. Results. Nearly half of the fractures were Schatzker II AO B3.1 fractures (n = 85; 47%). Radiological knee OA was present at fracture in 59/182 TPFs (32.6%). Primary management was fixation in 174 (95.6%) and acute TKA in eight (4.4%). A total of 13 patients underwent late TKA (7.5%), most often within two years. By five years, 21/182 12% (95% confidence interval (CI) 6.0 to 16.7) had required TKA. Larger volume defects of greater depth on CT (median 15.9 mm vs 9.4 mm; p < 0.001) were significantly associated with TKA requirement. CT-measured joint depression of > 12.8 mm was associated with TKA requirement (area under the curve (AUC) 0.766; p = 0.001). Severe joint depression of > 15.5 mm (hazard ratio (HR) 6.15 (95% CI 2.60 to 14.55); p < 0.001) and pre-existing knee OA (HR 2.70 (95% CI 1.14 to 6.37); p = 0.024) were independently associated with TKA requirement. Where patients with severe joint depression of > 15.5 mm were managed with fixation, 11/25 ultimately required TKA. Conclusion. Overall, 12% of patients aged ≥ 60 years underwent TKA within five years of TPF. Severe joint depression and pre-existing knee arthritis were independent risk factors for both post-traumatic OA and TKA. These features should be investigated as potential indications for acute TKA in older adults with TPFs. Cite this article: Bone Joint J 2024;106-B(1):28–37

The aim of this research was to determine biomechanical markers which differentiate medial knee osteoarthritis (OA) patients who do and do not show structural progression over a 2-year period. A cohort of 36 subjects was selected from a longitudinal study (Meireles et al 2017) using Kellgren-Lawrence (KL) scores at baseline and 2-year follow-up. The cohort consisted of 10 healthy controls (HC) (KL=0 at both time points), 15 medial knee OA non-progressors (NPKOA) (KL≥1 at baseline and no change over 2 years), and 11 medial knee OA progressors (PKOA) (KL≥1 at baseline and increase of ≥1 over 2 years). 3D integrated motion capture data from three walking trials were processed through a musculoskeletal modelling framework (Smith et al 2016) to estimate knee joint loading parameters (i.e., magnitude of mean contact pressure, and centre of pressure (COP)). Parameters at first and second peak were extracted and compared between groups using Kruskal-Wallis and Mann-Whitney tests. Higher magnitudes were observed in PKOA vs NPKOA, and PKOA vs HC groups at both time points. Additionally, a posterior (1st and 2nd peak), and lateral (2nd peak) shift in medial compartment COP was shown between PKOA and NPKOA, and PKOA and HC subjects. Interestingly, in the studied parameters, no differences were observed between NPKOA and HC groups. Significantly higher magnitude, and a more posterior and lateral COP was observed between PKOA and NPKOA patients. These differences, combined with an absence of difference between NPKOA and HC suggest structural OA progression is driven by a combination of altered loading magnitude and location. These results may serve as guidelines for targeted gait retraining rehabilitation to slow or stop knee OA progression whereby shifting COP anterior and medial and reducing magnitude by ~22% may shift patients from a PKOA to a NPKOA trajectory

Abstract. Osteoarthritis (OA) is a degenerative disorder associated with cartilage loss and is a leading cause of disability around the world. In old age, the capacity of cartilage to regenerate is diminished. With an aging population, the burden of OA is set to rise. Currently, there is no definitive treatment for OA. However, cell-based therapies derived from adipose tissue are promising. A PRISMA systematic review was conducted employing four databases (MEDLINE, EMBASE, Cochrane, Web of Science) to identify all clinical studies that utilized adipose tissue derived mesenchymal stem cells (AMSCs) or stromal vascular fraction (SVF) for the treatment of knee OA. Eighteen studies were included, which met the inclusion criteria. Meta-analyses were conducted on fourteen of these studies, which all documented WOMAC scores after the administration of AMSCs. Pooled analysis revealed that cell-based treatments definitively improve WOMAC scores, post treatment. These improvements increased with time. The studies in this meta-analysis have established the safety and efficacy of both AMSC therapy and SVF therapy for knee OA in old adults and show that they reduce pain and improve knee function in symptomatic knee OA suggesting that they may be effective therapies to improve mobility in an aging population

Aberrant infrapatellar fat metabolism is a notable feature provoking inflammation and fibrosis in the progression of osteoarthritis (OA). Irisin, a secretory subunit of fibronectin type III domain containing 5 (FNDC5) regulate adipose morphogenesis, energy expenditure, skeletal muscle, and bone metabolism. This study aims to characterize the biological roles of Irisin signaling in an infrapatellar fat formation and OA development. Injured articular specimens were harvested from 19 patients with end-stage knee OA and 11 patients with the femoral neck fracture. Knee joints in mice that overexpressed Irisin were subjected to intra-articular injection of collagenase to provoke OA. Expressions of Irisin, adipokines, and MMPs probed with RT-quantitative PCR. Infrapatellar adiposity, articular cartilage damage, and synovial integrity verified with histomorphometry and immunohistochemistry. Infrapatellar adipose and synovial tissues instead of articular cartilage exhibited Irisin immunostaining. Human OA specimens showed 40% decline in Irisin expression than the non-OA group. In vitro, the gain of Irisin function enabled synovial fibroblasts but not chondrocytes to display minor responses to the IL-1β provocation of MMP3 and MMP9 expression. Of note, Irisin signaling reduced adipogenic gene expression and adipocyte formation of mesenchymal progenitor cells. In collagenase-mediated OA knee pathogenesis, forced FNDC5 expression in articular compromised the collagenase-induced infrapatellar adipose hypertrophy, synovial hypercellularity, and membrane hyperplasia. These adipose-regulatory actions warded off the affected knees from cartilage destruction and gait aberrance. Likewise, intra-articular injection of Irisin recombinant protein mitigated the development of infrapatellar adiposity and synovitis slowing down the progression of cartilage erosion and walking profile irregularity. Affected joints and adipocytes responded to the Irisin recombinant protein treatment by reducing the expressions of cartilage-deleterious adipokines IL-6, leptin, and adiponectin through regulating PPAR&gamma, function. Irisin dysfunction is relevant to the existence of end-stage knee OA. Irisin signaling protects from excessive adipogenesis of mesenchymal precursor cells and diminished inflammation and cartilage catabolism actions aggravated by adipocytes and synovial cells. This study sheds emerging new light on the Irisin signaling stabilization of infrapatellar adipose homeostasis and the perspective of the therapeutic potential of Irisin recombinant protein for deescalating knee OA development

Aims. The lack of disease-modifying treatments for osteoarthritis (OA) is linked to a shortage of suitable biomarkers. This study combines multi-molecule synovial fluid analysis with machine learning to produce an accurate diagnostic biomarker model for end-stage knee OA (esOA). Methods. Synovial fluid (SF) from patients with esOA, non-OA knee injury, and inflammatory knee arthritis were analyzed for 35 potential markers using immunoassays. Partial least square discriminant analysis (PLS-DA) was used to derive a biomarker model for cohort classification. The ability of the biomarker model to diagnose esOA was validated by identical wide-spectrum SF analysis of a test cohort of ten patients with esOA. Results. PLS-DA produced a streamlined biomarker model with excellent sensitivity (95%), specificity (98.4%), and reliability (97.4%). The eight-biomarker model produced a fingerprint for esOA comprising type IIA procollagen N-terminal propeptide (PIIANP), tissue inhibitor of metalloproteinase (TIMP)-1, a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), monocyte chemoattractant protein (MCP)-1, interferon-γ-inducible protein-10 (IP-10), and transforming growth factor (TGF)-β3. Receiver operating characteristic (ROC) analysis demonstrated excellent discriminatory accuracy: area under the curve (AUC) being 0.970 for esOA, 0.957 for knee injury, and 1 for inflammatory arthritis. All ten validation test patients were classified correctly as esOA (accuracy 100%; reliability 100%) by the biomarker model. Conclusion. SF analysis coupled with machine learning produced a partially validated biomarker model with cohort-specific fingerprints that accurately and reliably discriminated esOA from knee injury and inflammatory arthritis with almost 100% efficacy. The presented findings and approach represent a new biomarker concept and potential diagnostic tool to stage disease in therapy trials and monitor the efficacy of such interventions. Cite this article: Bone Joint Res 2020;9(9):623–632

Abstract. Objectives. To compare the effectiveness of phonophoresis (PH) and conventional therapeutic ultrasound (US) on the functional and pain outcomes of patients with knee osteoarthritis. Methods. We conducted an electronic search through PubMed, Cochrane Central Register of Clinical Trials (CENTRAL), Web of Science (WOS), and Scopus databases. We screened the retrieved articles to include only English full-text randomized controlled trials that examined the effect of phonophoresis versus conventional therapeutic ultrasound on patients with knee osteoarthritis. Two reviewers screened, extracted the data, and independently assessed the quality of the included articles. Results. A total of five randomized controlled trials met our inclusion criteria out of 267 studies screened. Our results showed no statistically significant differences between the PH and US groups (1), (2), (3),(4), and (5). The PH group demonstrated more significant effects than the UT group in reducing VAS pain scores (P=0.009) and improving WOMAC scores, although this did not reach the level of significance (P=0.143) (5). In the long term, PH therapy was found to be superior to US in improving painless walking duration and distance VAS scores (p=0.034, 0.017) respectively, as well as walking and resting walking VAS scores (p=0.03, 0.007) respectively, which were found to be permanent (3). Conclusions. Both therapies improve pain and function. However, we suggest conducting more high-quality trials with larger sample sizes and do not recommend the use of these therapies in clinical practice due to limitations in gender selection and high risk of bias. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Aims. Osteoarthritis (OA) is the most prevalent joint disease. However, the specific and definitive genetic mechanisms of OA are still unclear. Methods. Tissue-related transcriptome-wide association studies (TWAS) of hip OA and knee OA were performed utilizing the genome-wide association study (GWAS) data of hip OA and knee OA (including 2,396 hospital-diagnosed hip OA patients versus 9,593 controls, and 4,462 hospital-diagnosed knee OA patients versus 17,885 controls) and gene expression reference to skeletal muscle and blood. The OA-associated genes identified by TWAS were further compared with the differentially expressed genes detected by the messenger RNA (mRNA) expression profiles of hip OA and knee OA. Functional enrichment and annotation analysis of identified genes was performed by the DAVID and FUMAGWAS tools. Results. We detected 33 common genes, eight common gene ontology (GO) terms, and one common pathway for hip OA, such as calcium and integrin-binding protein 1 (CIB1) (PTWAS = 0.025, FCmRNA = -1.575 for skeletal muscle), adrenomedullin (ADM) (PTWAS = 0.022, FCmRNA = -4.644 for blood), Golgi apparatus (PTWAS <0.001, PmRNA = 0.012 for blood), and phosphatidylinositol 3' -kinase-protein kinase B (PI3K-Akt) signalling pathway (PTWAS = 0.033, PmRNA = 0.005 for blood). For knee OA, we detected 24 common genes, eight common GO terms, and two common pathways, such as histocompatibility complex, class II, DR beta 1 (HLA-DRB1) (PTWAS = 0.040, FCmRNA = 4.062 for skeletal muscle), Follistatin-like 1 (FSTL1) (PTWAS = 0.048, FCmRNA = 3.000 for blood), cytoplasm (PTWAS < 0.001, PmRNA = 0.005 for blood), and complement and coagulation cascades (PTWAS = 0.017, PmRNA = 0.001 for skeletal muscle). Conclusion. We identified a group of OA-associated genes and pathways, providing novel clues for understanding the genetic mechanism of OA. Cite this article:Bone Joint Res. 2020;9(3):130–138

Precision health aims to develop personalised and proactive strategies for predicting, preventing, and treating complex diseases such as osteoarthritis (OA). Due to OA heterogeneity, which makes developing effective treatments challenging, identifying patients at risk for accelerated disease progression is essential for efficient clinical trial design and new treatment target discovery and development. To create a reliable and interpretable precision health tool that predicts rapid knee OA progression over a 2-year period from baseline patient characteristics using an advanced automated machine learning (autoML) framework, “Autoprognosis 2.0”. All available 2-year follow-up periods of 600 patients from the FNIH OA Biomarker Consortium were analysed using “Autoprognosis 2.0” in two separate approaches, with distinct definitions of clinical outcomes: multi-class predictions (categorising disease progression into pain and/or radiographic progression) and binary predictions. Models were developed using a training set of 1352 instances and all available variables (including clinical, X-ray, MRI, and biochemical features), and validated through both stratified 10-fold cross-validation and hold-out validation on a testing set of 339 instances. Model performance was assessed using multiple evaluation metrics. Interpretability analyses were carried out to identify important predictors of progression. Our final models yielded higher accuracy scores for multi-class predictions (AUC-ROC: 0.858, 95% CI: 0.856-0.860) compared to binary predictions (AUC-ROC: 0.717, 95% CI: 0.712-0.722). Important predictors of rapid disease progression included WOMAC scores and MRI features. Additionally, accurate ML models were developed for predicting OA progression in a subgroup of patients aged 65 or younger. This study presents a reliable and interpretable precision health tool for predicting rapid knee OA progression. Our models provide accurate predictions and, importantly, allow specific predictors of rapid disease progression to be identified. Furthermore, the transparency and explainability of our methods may facilitate their acceptance by clinicians and patients, enabling effective translation to clinical practice

To design osteoarthritis (OA) care based on prognosis, we need to identify individuals who are most likely of disease progression. We estimated survival time of the native hip and knee joint and evaluated what patient-related and OA disease-related factors associated with progression to joint replacement surgery. We included 72,069 patients referred to first-line OA intervention (patient education and exercise) during 2008 and 2016 and registered in the Swedish quality register Better Management of Patients with Osteoarthritis (BOA). Kaplan–Meier survival analyses were used to estimate joint survival time. Hazard ratios (HR) with 95% confidence interval [CI] were calculated using multiple Cox regression. The 5-year survival time of the native joint was 56% for hip OA and 80% for knee OA. Disease-related factors were more strongly associated with progression to joint replacement (e.g. willingness for surgery HR; hip 2.9 [95% CI, 2.7–3.1], knee 2.7 [2.6–2.9] and walking difficulties (HR; hip 2.2 [2.0–2.5], knee 1.9 [1.7–2.2]), than patient-related factors such socioeconomic factors (e.g. highest income quartile HR; hip 1.3 [1.2–1.3], knee 1.3 [1.2–1.4]) and comorbidities (e.g. ≥6 conditions HR; hip: 0.7 [0.6–0.7], knee; 1.1 [1.0–1.2]). Patients with hip OA were more likely to undergo surgery and at an earlier time compared with those with knee OA. Progression was strongly influenced by factors associated with the OA disease, but other patient-related factors are important. However, a large proportion of patients with OA do not seem to require surgery, especially among those with knee OA

Abstract. Introduction. Precision health aims to develop personalised and proactive strategies for predicting, preventing, and treating complex diseases such as osteoarthritis (OA), a degenerative joint disease affecting over 300 million people worldwide. Due to OA heterogeneity, which makes developing effective treatments challenging, identifying patients at risk for accelerated disease progression is essential for efficient clinical trial design and new treatment target discovery and development. Objectives. This study aims to create a trustworthy and interpretable precision health tool that predicts rapid knee OA progression based on baseline patient characteristics using an advanced automated machine learning (autoML) framework, “Autoprognosis 2.0”. Methods. All available 2-year follow-up periods of 600 patients from the FNIH OA Biomarker Consortium were analysed using “Autoprognosis 2.0” in two separate approaches, with distinct definitions of clinical outcomes: multi-class predictions (categorising patients into non-progressors, pain-only progressors, radiographic-only progressors, and both pain and radiographic progressors) and binary predictions (categorising patients into non-progressors and progressors). Models were developed using a training set of 1352 instances and all available variables (including clinical, X-ray, MRI, and biochemical features), and validated through both stratified 10-fold cross-validation and hold-out validation on a testing set of 339 instances. Model performance was assessed using multiple evaluation metrics, such as AUC-ROC, AUC-PRC, F1-score, precision, and recall. Additionally, interpretability analyses were carried out to identify important predictors of rapid disease progression. Results. Our final models yielded high accuracy scores for both multi-class predictions (AUC-ROC: 0.858, 95% CI: 0.856–0.860; AUC-PRC: 0.675, 95% CI: 0.671–0.679; F1-score: 0.560, 95% CI: 0.554–0.566) and binary predictions (AUC-ROC: 0.717, 95% CI: 0.712–0.722; AUC-PRC: 0.620, 95% CI: 0.616–0.624; F1-score: 0.676, 95% CI: 0.673–0679). Important predictors of rapid disease progression included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and MRI features. Our models were further successfully validated using a hold-out dataset, which was previously omitted from model development and training (AUC-ROC: 0.877 for multi-class predictions; AUC-ROC: 0.746 for binary predictions). Additionally, accurate ML models were developed for predicting OA progression in a subgroup of patients aged 65 or younger (AUC-ROC: 0.862, 95% CI: 0.861–0.863 for multi-class predictions; AUC-ROC: 0.736, 95% CI: 0.734–0.738 for binary predictions). Conclusions. This study presents a reliable and interpretable precision health tool for predicting rapid knee OA progression using “Autoprognosis 2.0”. Our models provide accurate predictions and offer insights into important predictors of rapid disease progression. Furthermore, the transparency and interpretability of our methods may facilitate their acceptance by clinicians and patients, enabling effective utilisation in clinical practice. Future work should focus on refining these models by increasing the sample size, integrating additional features, and using independent datasets for external validation. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Aims. Although knee osteoarthritis (OA) is diagnosed and monitored radiologically, actual full-thickness cartilage loss (FTCL) has rarely been correlated with radiological classification. This study aims to analyze which classification system correlates best with FTCL and to assess their reliability. Methods. A prospective study of 300 consecutive patients undergoing unilateral total knee arthroplasty (TKA) for OA (mean age 69 years (44 to 91; standard deviation (SD) 9.5), 178 (59%) female). Two blinded examiners independently graded preoperative radiographs using five common systems: Kellgren-Lawrence (KL); International Knee Documentation Committee (IKDC); Fairbank; Brandt; and Ahlbäck. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC). Intraoperatively, anterior cruciate ligament (ACL) status and the presence of FTCL in 16 regions of interest were recorded. Radiological classification and FTCL were correlated using the Spearman correlation coefficient. Results. Knees had a mean of 6.8 regions of FTCL (SD 3.1), most common medially. The commonest patterns of FTCL were medial ± patellofemoral (143/300, 48%) and tricompartmental (89/300, 30%). ACL status was associated with pattern of FTCL (p = 0.023). All radiological classification systems demonstrated moderate ICC, but this was highest for the IKDC: whole knee 0.68 (95% confidence interval (CI) 0.60 to 0.74); medial compartment 0.84 (95% CI 0.80 to 0.87); and lateral compartment 0.79 (95% CI 0.73 to 0.83). Correlation with actual FTCL was strongest for Ahlbäck (Spearman rho 0.27 to 0.39) and KL (0.30 to 0.33) systems, although all systems demonstrated medium correlation. The Ahlbäck score was the most discriminating in severe knee OA. Osteophyte presence in the medial compartment had high positive predictive value (PPV) for FTCL, but not in the lateral compartment. Conclusion. The Ahlbäck and KL systems had the highest correlation with confirmed cartilage loss at TKA. However, the IKDC system displayed the best interobserver reliability, with favourable correlation with FTCL in medial and lateral compartments, although it was less discriminating in more severe disease. Cite this article: Bone Joint J 2020;102-B(3):301–309

Aims. The aetiologies of common degenerative spine, hip, and knee pathologies are still not completely understood. Mechanical theories have suggested that those diseases are related to sagittal pelvic morphology and spinopelvic-femoral dynamics. The link between the most widely used parameter for sagittal pelvic morphology, pelvic incidence (PI), and the onset of degenerative lumbar, hip, and knee pathologies has not been studied in a large-scale setting. Methods. A total of 421 patients from the Cohort Hip and Cohort Knee (CHECK) database, a population-based observational cohort, with hip and knee complaints < 6 months, aged between 45 and 65 years old, and with lateral lumbar, hip, and knee radiographs available, were included. Sagittal spinopelvic parameters and pathologies (spondylolisthesis and degenerative disc disease (DDD)) were measured at eight-year follow-up and characteristics of hip and knee osteoarthritis (OA) at baseline and eight-year follow-up. Epidemiology of the degenerative disorders and clinical outcome scores (hip and knee pain and Western Ontario and McMaster Universities Osteoarthritis Index) were compared between low PI (< 50°), normal PI (50° to 60°), and high PI (> 60°) using generalized estimating equations. Results. Demographic details were not different between the different PI groups. L4 to L5 and L5 to S1 spondylolisthesis were more frequently present in subjects with high PI compared to low PI (L4 to L5, OR 3.717; p = 0.024 vs L5 to S1 OR 7.751; p = 0.001). L5 to S1 DDD occurred more in patients with low PI compared to high PI (OR 1.889; p = 0.010), whereas there were no differences in L4 to L5 DDD among individuals with a different PI. The incidence of hip OA was higher in participants with low PI compared to normal (OR 1.262; p = 0.414) or high PI (OR 1.337; p = 0.274), but not statistically different. The incidence of knee OA was higher in individuals with a high PI compared to low PI (OR 1.620; p = 0.034). Conclusion. High PI is a risk factor for development of spondylolisthesis and knee OA. Low pelvic incidence is related to DDD, and may be linked to OA of the hip. Level of Evidence: 1b. Cite this article: Bone Joint J 2020;102-B(9):1261–1267

The tendency towards using inertial sensors for remote monitoring of the patients at home is increasing. One of the most important characteristics of the sensors is sampling rate. Higher sampling rate results in higher resolution of the sampled signal and lower amount of noise. However, higher sampling frequency comes with a cost. The main aim of our study was to determine the validity of measurements performed by low sampling frequency (12.5 Hz) accelerometers (SENS) in patients with knee osteoarthritis compared to standard sensor-based motion capture system (Xsens). We also determined the test-retest reliability of SENS accelerometers. Participants were patients with unilateral knee osteoarthritis. Gait analysis was performed simultaneously by using Xsens and SENS sensors during two repetitions of over-ground walking at a self-selected speed. Gait data from Xsens were used as an input for AnyBody musculoskeletal modeling software to measure the accelerations at the exact location of two defined virtual sensors in the model (VirtualSENS). After preprocessing, the signals from SENS and VirtualSENS were compared in different coordinate axes in time and frequency domains. ICC for SENS data from first and second trials were calculated to assess the repeatability of the measurements. We included 32 patients (18 females) with median age 70.1[48.1 – 85.4]. Mean height and weight of the patients were 173.2 ± 9.6 cm and 84.2 ± 14.7 kg respectively. The correlation between accelerations in time domain measured by SENS and VirtualSENS in different axes was r = 0.94 in y-axis (anteroposterior), r = 0.91 in x-axis (vertical), r = 0.83 in z-axis (mediolateral), and r = 0.89 for the magnitude vector. In frequency domain, the value and the power of fundamental frequencies (F. 0. ) of SENS and VirtualSENS signals demonstrated strong correlation (r = 0.98 and r = 0.99 respectively). The result of test-retest evaluation showed excellent repeatability for acceleration measurement by SENS sensors. ICC was between 0.89 to 0.94 for different coordinate axes. Low sampling frequency accelerometers can provide valid and reliable measurements especially for home monitoring of the patients, in which handling big data and sensors cost and battery lifetime are among important issues

An increased number of neutrophils (NEUs) has long been associated with infections in the knee joints; their contribution to knee osteoarthritis (KOA) pathophysiology remains largely unexplored. This study aimed to compare the phenotypic and functional characteristics of synovial fluid (SF)-derived NEUs in KOA and knee infection (INF). Flow cytometric analysis, protein level measurements (ELISA), NEU oxidative burst assays, detection of NEU phagocytosis (pHrodo. TM. Green Zymosan Biparticles. TM. Conjugate for Phagocytosis), morphological analysis of the SF-derived/synovial tissue NEUs, and cultivation of human umbilical vein endothelial cells (HUVECs) using SF supernatant were used to characterise NEUs functionally/morphologically. Results: Compared with INF NEUs, KOA NEUs were characterised by a lower expression of CD11b, CD54 and CD64, a higher expression of CD62L, TLR2 and TLR4, and lower production of inflammatory mediators and proteases, except CCL2. Functionally, KOA NEUs displayed an increased production of radical oxygen species and phagocytic activity compared with INF NEUs. Morphologically, KOA and INF cells displayed different cell sizes and morphology, histological characteristics of the surrounding synovial tissues and influence on endothelial cells. KOA NEUs were further subdivided into two groups: SF containing <10% and SF with 10%–60% of NEUs. Analyses of two KOA NEU subgroups revealed that NEUs with SF <10% were characterised by 1) higher CD54, CD64, TLR2 and TLR4 expression on their surface; 2) higher concentrations of TNF-α, sTREM-1, VILIP-1, IL-1RA and MMP-9 in SFs. Our findings reveal a key role for NEUs in the pathophysiology of KOA, indicating that these cells are morphologically and functionally different from INF NEUs. Further studies should explore the mechanisms that contribute to the increased number of NEUs and their crosstalk with other immune cells in KOA. This study was supported by the Ministry of Health of the Czech Republic (NU20-06-00269; NU21-06-00370)

With the rising rates, and associated costs, of total knee arthroplasty (TKA), enhanced clarity regarding patient appropriateness for TKA is warranted. Towards addressing this gap, we elucidated in qualitative research that surgeons and osteoarthritis (OA) patients considered TKA need, readiness/willingness, health status, and expectations of TKA most important in determining patient appropriateness for TKA. The current study evaluated the predictive validity of pre-TKA measures of these appropriateness domains for attainment of a good TKA outcome. This prospective cohort study recruited knee OA patients aged 30+ years referred for TKA at two hip/knee surgery centers in Alberta, Canada. Those receiving primary, unilateral TKA completed questionnaires pre-TKA assessing TKA need (WOMAC-pain, ICOAP-pain, NRS-pain, KOOS-physical function, Perceived Arthritis Coping Efficacy, prior OA treatment), TKA readiness/willingness (Patient Acceptable Symptom State (PASS), willingness to undergo TKA), health status (PHQ-8, BMI, MSK and non-MSK comorbidities), TKA expectations (HSS KR Expectations survey items) and contextual factors (e.g., age, gender, employment status). One-year post-TKA, we assessed for a ‘good outcome’ (yes/no), defined as improved knee symptoms (OARSI-OMERACT responder criteria) AND overall satisfaction with TKA results. Multiple logistic regression, stepwise variable selection, and best possible subsets regression was used to identify the model with the smallest number of independent variables and greatest discriminant validity for our outcome. Receiver Operating Characteristic (ROC) curves were generated to compare the discriminative ability of each appropriateness domain based on the ‘area under the ROC curve’ (AUC). Multivariable robust Poisson regression was used to assess the relationship of the variables to achievement of a good outcome. f 1,275 TKA recipients, 1,053 (82.6%) had complete data for analyses (mean age 66.9 years [SD 8.8]; 58.6% female). Mean WOMAC pain and KOOS-PS scores were 11.5/20 (SD 3.5) and 52.8/100 (SD 17.1), respectively. 78.1% (95% CI 75.4–80.5%) achieved a good outcome. Stepwise variable selection identified optimal discrimination was achieved with 13 variables. The three best 13-variable models included measures of TKA need (WOMAC pain, KOOS-PS), readiness/willingness (PASS, TKA willingness), health status (PHQ-8, troublesome hips, contralateral knee, low back), TKA expectations (the importance of improved psychological well-being, ability to go up stairs, kneel, and participate in recreational activities as TKA outcomes), and patient age. Model discrimination was fair for TKA need (AUC 0.68, 95% CI 0.63-0.72), TKA readiness/willingness (AUC 0.61, 95% CI 0.57-0.65), health status (AUC 0.59, 95% CI 0.54-0.63) and TKA expectations (AUC 0.58, 95% CI 0.54-0.62), but the model with all appropriateness variables had good discrimination (AUC 0.72, 95% CI 0.685-0.76). The likelihood of achieving a good outcome was significantly higher for those with greater knee pain, disability, unacceptable knee symptoms, definite willingness to undergo TKA, less depression who considered improved ability to perform recreational activities or climb stairs ‘very important’ TKA outcomes, and lower in those who considered it important that TKA improve psychological wellbeing or ability to kneel. Beyond surgical need (OA symptoms) and health status, assessment of patients’ readiness and willingness to undergo, and their expectations for, TKA, should be incorporated into assessment of patient appropriateness for surgery

Introduction. The use of stem cell and platelet-rich plasma (PRP) injections for knee osteoarthritis (OA) is extremely controversial and at best experimental. These treatments are being given to patients across the nation for “cash only payments”. Our objectives were (1) to determine the proportion of board certified orthopedic surgeons who offer stem cell or PRP treatment for knee OA, (2) how much the practices charge for those treatments and (3) if members of the knee society use these therapies. Methods. Board certified orthopedic surgeons’ offices in our county were identified by their AAOS active membership. Knee society membership roll was also utilized. Offices were contacted by telephone and presented with a hypothetical patient with end stage knee osteoarthritis searching for specific treatment (stem cells or PRP injections). T-test was used to compare the Dade county board certified orthopedists to knee society members. Results. A total of 186 board certified orthopedic surgeons’ offices were contacted. 17.6% of all contacted orthopedics offices offered PRP and 12.5% offered stem cell treatments. 61.2% of the offices were transparent on the pricing of PRP while 31.8% gave a price for stem cell therapy. The remaining practices stated that pricing would be “determined or discussed” during a scheduled visit. Mean cost for a PRP injection was $887 (SE 101; range: $350–$1700) and for a stem cell injection was $2800 (SE 852; range: $1000–$6000). Usage of these therapies amongst general AAOS members and Knee Society members was found to be significantly different for both PRP and stem cells (17% vs. 10%; p<0.001 and 26% vs. 13%; p<0.001, respectively). No practice had a “free” research protocol to study the treatments. Conclusions. Biological injectables as a treatment for knee OA has theoretical potential promise in the management of arthritis but continues to be at best investigational. Knee Society members demonstrated significantly more caution using these treatments

Abstract. Introduction. The effectiveness of single intra-articular injections of polyacrylamide hydrogel (iPAAG) and hyaluronic acid (HA) was compared in subgroups of participants from an RCT based on baseline age, BMI or Kellgren-Lawrence (KL) grade. Methodology. 239 participants were randomised to 6 mL iPAAG (Arthrosamid; n=119) or 6 mL HA (Synvisc-One; n=120). Participants continued analgesics (except 48 hours prior to visits) and non-pharmacological therapy. Topical therapies and intra-articular corticosteroids were not allowed. Pre-specified subgroup analyses (age: <70 years, ≥70 years; BMI: normal, overweight, obese; KL grade: 2, 3, 4, 2–3) of change from baseline in WOMAC pain subscale at 52 weeks were based on the least squares means for the treatment-by-week interaction effect using a mixed model for repeated measurement with a restricted maximum likelihood-based approach. Results. Across all patients, change from baseline in WOMAC pain subscale in the iPAAG group was non-inferior to HA at 26 weeks and approached superiority (p=0.0572) at 52 weeks. Treatment differences for change from baseline in WOMAC pain subscale in favour of iPAAG over HA were statistically significant for the age <70 years (p=0.019), BMI normal (p=0.011) and KL grade 2–3 (p=0.033) subgroups. Treatment differences for all other subgroups favoured iPAAG, except for KL grade 4 which favoured HA, without reaching statistical significance. Conclusion. iPAAG approached superiority to HA across all participants at 52weeks, but demonstrated statistical superiority in participants with normal BMI, participants <70 years old or participants with KL score 2–3. iPAAG represents a useful alternative to HA for the treatment of knee OA

Aims. To analyze the potential role of synovial fluid peptidase activity as a measure of disease burden and predictive biomarker of progression in knee osteoarthritis (KOA). Methods. A cross-sectional study of 39 patients (women 71.8%, men 28.2%; mean age of 72.03 years (SD 1.15) with advanced KOA (Ahlbäck grade ≥ 3 and clinical indications for arthrocentesis) recruited through the (Orthopaedic Department at the Complejo Asistencial Universitario de León, Spain (CAULE)), measuring synovial fluid levels of puromycin-sensitive aminopeptidase (PSA), neutral aminopeptidase (NAP), aminopeptidase B (APB), prolyl endopeptidase (PEP), aspartate aminopeptidase (ASP), glutamyl aminopeptidase (GLU) and pyroglutamyl aminopeptidase (PGAP). Results. Synovial fluid peptidase activity varied significantly as a function of clinical signs, with differences in levels of PEP (p = 0.020), ASP (p < 0.001), and PGAP (p = 0. 003) associated with knee locking, PEP (p = 0.006), ASP (p = 0.001), GLU (p = 0.037), and PGAP (p = 0.000) with knee failure, and PEP (p = 0.006), ASP (p = 0.001), GLU (p = 0.037), and PGAP (p < 0.001) with knee effusion. Further, patients with the greatest functional impairment had significantly higher levels of APB (p = 0.005), PEP (p = 0.005), ASP (p = 0.006), GLU (p = 0.020), and PGAP (p < 0.001) activity, though not of NAP or PSA, indicating local alterations in the renin-angiotensin system. A binary logistic regression model showed that PSA was protective (p = 0.005; Exp (B) 0.949), whereas PEP (p = 0.005) and GLU were risk factors (p = 0.012). Conclusion. These results suggest synovial fluid peptidase activity could play a role as a measure of disease burden and predictive biomarker of progression in KOA. Cite this article: Bone Joint Res 2020;9(11):789–797

Abstract. Objectives. Exploring the relationship of gait function pre and post total knee replacement (TKR) in two groups of patients. Methods. Three-dimensional gait analysis was performed at Cardiff University, UK, and Karolinska University Hospital, Sweden, on 29 and 25 non-pathological (NP) volunteers, and 39 and 28 patients with end-stage knee osteoarthritis (OA), respectively. Patients were assessed pre and one-year post-TKR. Data reduction was performed via Principal Component (PC) analysis on twenty-four kinematic and kinetic waveforms in both NP and pre/post-TKR. Cardiff's and Karolinska's cohorts were analysed separately. The Cardiff Classifier, a classification system based on the Dempster-Shafer theory, was trained with the first 3 PCs of each variable for each cohort. The Classifier classifies each participant by assigning them a belief in NP, belief in OA (BOA) and belief in uncertainty, based on their biomechanical features. The correlation between patient's BOA values (range: 0–1, 0 indicates null BOA and 1 high BOA) pre and post-TKR was tested through Spearman's correlation coefficient in each cohort. The related-samples Wilcoxon signed-rank test (α=0.05) determined the significant changes in BOA in each cohort of patients. The Mann-Whitney U test (α=0.05) was run to explore differences between the patients’ cohorts. Results. There were no significant differences between patients’ cohorts in median age (p=0.096), height (p=0.673), weight (p=0.064) or KOOS sub-scores pre or post-TKR (p-value ranged 0.069 to 0.955) but Cardiff's patients had a significantly higher BMI (p=0.047). There was a significant, median decrease of 0.12 and 0.19 in the BOA pre to post TKR (p<0.001) in Cardiff's and Karolinska's patients, respectively. There was a statistically significant, strong positive correlation between the BOA pre and post-TKR (Cardiff:r. s. =0.706, p<0.001; Karolinska:r. s. =0.669, p<0.001). Conclusions. In two distinct cohorts of patients, having a more compromised gait function in end-stage knee OA was correlated with poorer gait function post-TKR

Aims. Osteoarthritis (OA) is prevalent among the elderly and incurable. Intra-articular parathyroid hormone (PTH) ameliorated OA in papain-induced and anterior cruciate ligament transection-induced OA models; therefore, we hypothesized that PTH improved OA in a preclinical age-related OA model. Methods. Guinea pigs aged between six and seven months of age were randomized into control or treatment groups. Three- or four-month-old guinea pigs served as the young control group. The knees were administered 40 μl intra-articular injections of 10 nM PTH or vehicle once a week for three months. Their endurance as determined from time on the treadmill was evaluated before kill. Their tibial plateaus were analyzed using microcalculated tomography (μCT) and histological studies. Results. PTH increased the endurance on the treadmill test, preserved glycosaminoglycans, and reduced Osteoarthritis Research Society International score and chondrocyte apoptosis rate. No difference was observed in the subchondral plate bone density or metaphyseal trabecular bone volume and bone morphogenetic 2 protein staining. Conclusion. Subchondral bone is crucial in the initiation and progression of OA. Although previous studies have shown that subcutaneous PTH alleviates knee OA by improving subchondral and metaphyseal bone mass, we demonstrated that intra-articular PTH injections improved spontaneous OA by directly affecting the cartilage rather than the subchondral or metaphyseal bone in a preclinical age-related OA model. Cite this article: Bone Joint Res 2021;10(8):514–525

Summary Statement. This study provides preliminary evidence that people with knee osteoarthritis have greater asymmetry in joint loading than healthy controls. Altered loading of the contralateral limb may signify increased risk of injury to other lower limb joints in knee osteoarthritis. Introduction. Compensatory overloading of other lower limb joints is a potential reason for the non-random evolution of osteoarthritis (OA). In individuals with knee OA altered joint loading exists of the contralateral cognate joints. However, previous studies have neglected the temporal features of asymmetry in joint loading. The study aimed to identify the amount and temporal features of asymmetry in lower limb joint loading in advanced knee OA. Patients and Methods. Participants (n=15) were awaiting primary unilateral total knee replacement for OA (age 67.0 SD 8.9 years, height 1.66 SD 0.13 m, mass 84.2 SD 15.8 kg, BMI 30.7 SD 6.2 kg/m. 2. , median KL grade 4). Data were compared to asymptomatic age and sex matched controls. Kinematic and kinetic data during walking was acquired with 12 cameras (VICON MX-F20) and two Kistler force platforms at 100 Hz and 400 Hz respectively. Data were analysed in Visual3D (C-Motion Inc., USA). Asymmetry was computed in MatLab using a recently published symmetry index (SI) and symmetry function (SF). Variables (computed using inverse dynamics) were the peak external moments (%BW∗Height) of the hip, knee and ankle. Differences between means of the SI variables in the OA and control groups were compared using Student's t-tests. Discrete variables were also compared between limbs (paired t-test) or between the affected limb and matched control limb. Effect sizes (Cohen's d) for the differences were also computed. Results. A significant between group difference (OA and control) for SI was observed for the transverse plane ankle joint moment (16.1 SD 8.0 vs. 10.4 SD 4.8 d = 0.8 p = 0.049). A large effect size for the sagittal plane knee joint moment (22.9 SD 12.1 vs. 12.7 SD 5.1 d = 1.1 p = 0.178) and a medium effect size for the transverse plane hip joint moment (26.4 SD 15.9 vs. 16.6 SD 9.0 d = 0.7 p = 0.098) were observed. The unaffected limb (OA group) had higher peak hip flexion (5.76 SD 1.49 vs.5.32 SD 1.51 p = 0.041) and internal rotation moments (−0.67 SD 0.34 vs. −0.41 SD 0.18 d = 0.004) and a lower ankle inversion moment (0.16 SD 0.14 vs. 0.34 SD 0.24 d = 0.9 p = 0.030) compared to the affected limb. Only the difference in the first peak knee adduction moment for the affected and matched control limb was statistically significant (−2.65 SD 1.38 vs. −2.16 SD 1.16 d = 0.7 p = 0.031). Discussion and Conclusion. This study provides preliminary evidence of more asymmetry in joint moments of the lower limb in people with knee OA compared to controls. Further investigation with a larger sample is required to verify these findings. Altered loading of the contralateral cognate joints may signify increased risk of injury at the hip and ankle and highlights the need for monitoring of other lower limb joints in knee OA

Abstract. Objectives. Current tools to measure pain are broadly subjective impressions of the impact of the nociceptive impulse felt by the patient. A direct measure of nociception may offer a more objective indicator. Specifically, movement-induced physiological responses to nociception may offer a useful way to monitor knee OA. In this proof-of-concept study, we evaluated whether integrated biomechanical and physiological sensor datasets could display linked and quantifiable information to a nociceptive stimulus. Method. Following ethical approval, we applied a quantified thermal pain stimulus to a volunteer during stationary standing in a gait lab setting. An inertial measurement unit (IMU) and an electromyography (EMG) lower body marker set were tested and integrated with ground reaction force (GRF) data collection. Galvanic skin response electrodes and skin thermal sensors were manually timestamp linked to the integrated system. Results. The integrated EMG, GRF and IMU data show fluctuations within 0.5 seconds of each other when a thermal pain trigger is applied at several time points during a stationary standing test. Manually timestamped physiology measures displayed increased values during testing for skin conductivity (up to 5 µSiemens, 37% compared to baseline) and skin temperature (up to 0.3˚C, 1% compared to baseline). Conclusions. This proof-of-concept study suggests that physiological data mimics biomechanical data in response to a known pain stimuli. While this protocol requires further evaluation as to the measurement parameters, the association of the physiological output to the known pain stimulus suggests the potential development of wearable nociceptive sensors that can measure disease progression and treatment effectiveness

Aims. Platelet-rich plasma (PRP) intra-articular injections may provide a simple and minimally invasive treatment for early-stage knee osteoarthritis (OA). This has led to an increase in its adoption as a treatment for knee OA, although there is uncertainty about its efficacy and benefit. We hypothesized that patients with early-stage symptomatic knee OA who receive multiple PRP injections will have better clinical outcomes than those receiving single PRP or placebo injections. Methods. A double-blinded, randomized placebo-controlled trial was performed with three groups receiving either placebo injections (Normal Saline), one PRP injection followed by two placebo injections, or three PRP injections. Each injection was given one week apart. Outcomes were prospectively collected prior to intervention and then at six weeks, three months, six months, and 12 months post-intervention. Primary outcome measures were Knee Injury and Osteoarthritis Outcome Score (KOOS) and EuroQol five-dimension five-level index (EQ-5D-5L). Secondary outcomes included visual analogue scale for pain and patient subjective assessment of the injections. Results. A total of 102 patients were recruited. The follow-up period was 12 months, at intervals of six weeks, 12 weeks, six months, and 12 months. KOOS-Total significantly improved in all groups at these time intervals compared to pre-injection. There was an improvement in EQ-5D-5L index scores in saline and single injection groups, but not in the multiple injection group. Comparison of treatment groups showed no additional beneficial effect of single or multiple PRP injections above that displayed in the saline injection group. Subjective patient satisfaction and recommendation of treatment received demonstrated a similar pattern in all the groups. There was no indication of superiority of either single or multiple PRP injections compared to saline injections. Conclusion. There is no evidence that single or multiple PRP had any additional beneficial effect compared to saline injection up to 12 months, follow-up after treatment of early stage symptomatic OA of the knee. Cite this article: Bone Joint J 2022;104-B(6):663–671

Modern gait analysis offers a unique means to measure the biomechanical response to diseases of the musculoskeletal system during activities of daily living. The objective of this on-going study is to quantify the biomechanical environment of the knee joint in subjects with moderate knee osteoarthritis (OA). We collected 3-D motion, ground reaction force, and electromyographic data from seven normal subjects and five subjects with moderate knee OA. There were no differences in stride characteristics or joint motion patterns between the two groups. In contrast, we found differences in knee joint kinetics between the moderate OA subjects and the normal control subjects. The objective of this on-going study is to quantify the biomechanical environment of the knee joint in subjects with moderate knee osteoarthritis (OA). Our goal is to identify biomechanical characteristics related to treatment interventions. The moderate knee OA patients walked with a visibly normal gait as measured by stride characteristics and joint angles. Differences were detected in the joint loading (ie adduction and flexion moments). The biomechanical differences between normal and osteoarthritic knees will provide the basis upon which to design and evaluate non-invasive treatments for knee OA. Subjects performed, in random order, five trials of their normal selected speed, and a fast walk (150% of the normal speed). Three-dimensional motion and force data were used to calculate three dimensional joint angles, moments and forces. There were no differences in stride characteristics (walking speeds, stride lengths, or stride times) between the two groups. The moderate OA patients walked with normal knee joint motion patterns. In contrast, we found differences in knee joint kinetics between the moderate OA subjects and the normal control subjects. The magnitude of the adduction moment during stance was larger for the moderate OA patients at both walking speeds (p< 0.05). We also identified differences in the pattern of the flexion moment, but only at the higher walking speed (p< 0.05). Gait analysis can provide insight into the mechanical factors of knee osteoarthritis by quantifying the dynamic loading and alignment of the knee during activities of daily living

Knee osteoarthritis (OA) affects an estimated 250 million people worldwide, with a cure yet to be found. Consequently, there is an urgent need to improve our understanding of OA physiopathology. While knee OA has long been mostly described as a loss of cartilage thickness (CTh) and research has focused on this characteristic, the role of bone alterations is rapidly gaining in interest. Analyzing subchondral bone mineral density (sBMD) is particularly interesting because this could inform on the mechanical environment at the knee. However, there is a paucity of data on sBMD in literature mainly because of the lack of prior methods to measure this parameter. A method for 3D sBMD assessment based on computed tomography (CT) scans was recently proposed, thus allowing testing for sBMD differences in knee OA. This study aimed at comparing non-OA and medial OA knees in terms of tibial sBMD and CTh. Specifically, it was hypothesized that sBMD and CTh differ with OA. Ten knees with severe medial OA and 10 matched non-OA knees were analyzed after ethical approval (50% male; 60 ± 3 years old). The arthro-CT scans of the 20 knees were segmented using custom software to build 3D mesh models of the tibial bone and cartilage. CTh maps were obtained by calculating the distance between cartilage and bone meshes, while sBMD maps were calculated based on the intensity of the CT in the first 3mm of bone. For each knee, the average CTh and sBMD values over the entire medial and lateral compartments were calculated and used to determine the medial-to-lateral (M/L) CTh and sBMD ratios. Unpaired t-tests and receiver operating characteristic (ROC) were used for statistical analysis. The M/L sBMD ratio was significantly higher in OA compared to non-OA knees (1.14 ± 0.04 vs. 1.08 ± 0.03; p<0.01), whereas the CTh ratio was not significantly different between groups (0.70 ± 0.21 vs. 0.85 ± 0.10; p=0.06). No significant differences were found between OA and non-OA knees for the average medial CTh and sBMD (p>0.4). High classification performance was obtained for the sBMD ratio and low performance for the average sBMD in the medial compartment (areas under the ROC curve of 0.9 and 0.6, respectively). CTh ratio and medial compartment average provided medium classification performances (areas under the curve of 0.7). This study showed that sBMD differed between non-OA and severe medial OA knees and that sBMD M/L ratio was more sensitive to OA severity than CTh variables. These results brought new insights into the pathogenesis of knee OA, by supporting the idea that sBMD is altered with OA and suggesting that sBMD could play a role in disease development. Indeed, the mechanical stresses on the cartilages are related to the mechanical characteristics of the bones. Indirectly, this study also demonstrated the value of arthro-CT scans to simultaneously assess sBMD and CTh. Additional studies with larger cohorts of patients at different stages of the disease are necessary to better understand when changes in sBMD occur

Introduction. Pain related to knee osteoarthritis (OA) is a complex phenomenon that cannot be fully explained by radiographic disease severity. We hypothesized that pain phenotypes are likely to be derived from a confluence of factors across multiple domains: knee OA pathology, psychology, and neurophysiological pain processing. The purpose of this study was to identify distinct phenotypes of knee OA, using measures from the proposed domains. Methods. Data from 3494 subjects participating in the Osteoarthritis Initiative (OAI) study was analyzed. Variables analyzed included: radiographic OA severity (Kellgren-Lawrence grade), isometric quadriceps strength, Body Mass Index (BMI), comorbidities, CES-D Depression subscale score, Coping Strategies Questionnaire Catastrophizing subscale score, number of pain sites, and knee tenderness on physical examination. Variables used for comparison across classes included pain severity, WOMAC disability score, sex and age. Latent Class Analysis was performed. Model solutions were evaluated using the Bayesian Information Criterion. One-way ANOVAs and post hoc least significance difference tests were used for comparison of classes. Results. A four-class model was identified. Class 1 (57% of study population) had lesser radiographic OA, little psychological involvement, greater strength, and less pain sensitivity. Class 2 (28%) had higher rates of knee joint tenderness. Class 3 (10%) had greater psychological distress and more bodily pain sites. Class 4 (4%) had more comorbidities. Additionally, Class 1 was the youngest, had the lowest disability, and least pain. Class 4 was the oldest. Class 2 had a higher proportion of females. Class 3 had the worst disability and most pain. Conclusions. Four distinct pain phenotypes for knee OA were identified. Psychological factors, knee tenderness, and comorbidities appear to be important in defining phenotypes of OA-related pain. Therapies in knee OA should take a multicomponent approach, recognizing the factors most relevant to an individual's experience of pain

Osteoarthritis (OA) is the most common form of arthritis worldwide. It is a major cause of disability in the adult population with its prevalence expected to increase dramatically over the next 20 years. Although current therapies can alleviate symptoms and improve function in early course of the disease, OA inevitably progresses to end-stage disease requiring total joint arthroplasty. Mesenchymal stromal cells (MSCs) have emerged as a candidate cell type with great potential for intra-articular (IA) repair therapy. However, there is still a considerable lack of knowledge concerning their behaviour, biology and therapeutic effects. To start addressing this, we explored the secretory profile of bone marrow derived MSCs in early and end-stage knee OA synovial fluid (SF). Subjects were recruited and categorised into early [Kellgren-Lawrence (KL) grade I and II, n=12] and end-stage (KL grade III and IV, n=11) knee OA groups. The SF proteome of early and end-stage OA was tested before and three days after the addition of bone marrow MSCs (16.5×10^3, single donor) using multiplex ELISA (64 cytokines) and mass spectrometry (302 proteins detected). Non parametric Wilcoxon-signed rank test for paired samples was used to compare the levels of proteins before and after addition of MSCs in early and end-stage knee OA SF. Significant differences were determined after multiple comparisons correction (FDR) with a p<0.05. Gender distribution and BMI were not statistically different between the two cohorts (p>0.05). However, patients in early knee OA cohort were significantly younger (44.7 years, SD=7.1) than patients in the end-stage cohort (58.6 years, SD=4.4; p<0.05). In both early and end-stage knee OA, MSCs increased the levels of VEGF-A (by 320.24 pg/mL), IL-6 (by 826.78 pg/mL) and IL-8 (by 128.85 pg/mL), factors involved in angiogenesis; CXCL1/2/3 (by 103.35 pg/mL), CCL2 (by 1187.27 pg/mL), CCL3 (by 15.82 pg/mL) and CCL7 (by 10.43 pg/mL), growth factors and chemokines. However, CXCL5 (by 48.61 pg/mL) levels increased only in early knee OA, whereas PDGF-AA (by 15.36 pg/mL) and CXCL12 (by 497.19 pg/mL) levels increased only in end-stage knee OA. This study demonstrates that bone marrow derived MSCs secrete angiogenic and chemotactic factors both in early and end-stage knee OA. More importantly, MSCs show a differential reaction between early and end-stage OA. Functional assays are required to further understand on how the therapeutic effect of MSCs is modulated when exposed to OA SF

Knee osteoarthritis (OA) is a major cause of pain and disability in elder people. The prevalence of radiographic OA in a population aged 35–74 years is 5–15% and about one third of involved people complain of symptoms. In the „Ulm Osteoarthritis Study“ patients undergoing total knee replacement reported a mean duration of knee pain of 10 years prior to surgery. Multiple genetic, constitutional and environmental factors contribute to the development of OA. Initial cartilage degradation leads to joint space narrowing and early osteophyte formation which can be observed radiographically. Whether elevated subchondral bone mineral density is contributing to manifestation of the disease or just a secondary reaction process is still under debate. OA finally involves not only cartilage and subchondral bone but also soft tissues in and around the joint (synovial membrane, ligaments and muscles), which often results in painful effusions, muscular shortening and stiffness. Many conservative treatment options have been developed in the past to relief these symptoms and to slow down or even stop the cartilage degradation process. Evidence to support the effectiveness of individual treatments, however, is variable. Recently the EULAR Committee for Clinical Trials determined an approach for the development of evidence based guidelines for conservative treatment of knee OA (. Pendleton et al, . Ann Rheum Dis. 2000. ;. 59. :. 936. –944. ). Through a process of quality assessment of available publications and determination of expert consensus employing a Delphi approach propositions relating to a rationale conservative management could be made:. Treatment of knee OA must be tailored to individual patients, taking into account factors such as age, comorbidity and the presence of inflammation. Optimal management requires a combination of non-pharmacological treatment modalities (regular education, exercise, appliances and weight reduction) and pharmacological approaches. Paracetamol generally is the preferred analgesic and there is enough evidence to support its application, as the pain controlling effects are comparable to NSAIDS and long term application is safe enough. NSAIDS (oral or even topical) can be considered in patients with effusion. Although some studies found NSAIDS to have better efficacy than paracetamol in the treatment of painful knee OA, the gastrointestinal side effects limit their long-term application. Therefore most experts consider their application only in patients unresponsive to paracetamol and in major effusions. In such situations long-acting steroids can be injected intra-articularly as well. While the effects of steroids in knee OA have been assessed in a number of studies, the predictors of response are still somewhat unclear and further investigations are necessary. Recent data seems to support the theory that some symptomatic slow acting drugs (glucosamine sulfate, chondroitin sulfate, diacerein and hyaluronic acid) may possess structure modifying properties. Further studies, however, are necessary to determine the pharmacoeconomic aspects of that treatment and to define the indications more precisely. Education should be an integral part in the management of knee OA. Several large randomised controlled trials have shown benefits of different educational techniques in reducing pain and increasing coping skills. Function can reliably be improved by quadriceps strengthening exercises and there is enough evidence to show the positive effects of weight reduction on the progression of the disease process. In conclusion, evidence based guidelines in the conservative management of knee OA exist. Orthopaedic Surgeons should have knowledge of the various approaches and be aware of the fact that certain clinical propositions are supported by substantial research based evidence, while others are not

The objective of this study was to evaluate the safety and the effect of platelet-rich plasma (PRP) intra-articular injections obtained from blood donors (homologous PRP) on elderly patients with early or moderate knee osteoarthritis (OA) who are not candidates for autologous PRP treatment. A total of 60 symptomatic patients, aged 65–86 years, affected by hematologic disorders and early or moderate knee OA, were treated with 5 ml of homologous PRP intraarticular injections every 14 days for a total of three injections. Clinical evaluations before the treatment, and after 2 and 6 months were performed by International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS) and Equal Visual Analogue Scale (EQ VAS) scores. Adverse events and patient satisfaction were recorded. No severe complications were noted during the treatment and the follow-up period. A statistically significant improvement from basal evaluation to the 2-month follow-up visit was observed, whereas a statistically significant worsening from the 2-month to the 6-month follow-up visit was showed. The overall worst results were observed in patients aged 80 years or over and in those affected by minor bone attrition. It was found that 90% of patients were satisfied at the 6-month evaluation. Homologous PRP has an excellent safety profile but offers only a short-term clinical improvement in selected elderly patients with knee OA who are not candidates for autologous PRP treatment. Increasing age and developing degeneration result in a decreased potential for homologous PRP injection therapy. Further studies are needed to confirm these findings

We aimed to determine the rate of and risk factors for post-traumatic osteoarthritis (PTOA) and total knee arthroplasty (TKA) requirement after operative management of tibial plateau fractures (TPF) in older adults. We conducted a retrospective cohort study of 182 operatively managed TPFs in 180 patients ≥60 years old over a 12-year period with minimum follow up 1 year. Data including patient demographics, clinical frailty scores, mechanism of injury, management, reoperation and mortality were recorded. Radiographs were reviewed for: Schatzker classification; pre-existing knee osteoarthritis (KOA); severe joint depression >15mm; and development of PTOA. Kaplan Meier survival analysis was performed. Regression analysis was used to identify risk factors for radiographic indication for TKA and actual TKA. Forty-seven percent were Schatzker II fractures. Radiographic KOA was present at fracture in 32.6%. Fracture fixation was performed in 95.6% cases and acute TKA in 4.4%. Thirteen patients underwent late TKA (7.5%). At five-years, 11.8% (6.0-16.7 95% CI) had required TKA and 20.9% (14.4-27.4 95% CI) had a radiographic indication for TKA. Severe joint depression and pre-existing KOA were associated with worse survival for endpoints radiographic indication for TKA and actual TKA. Severe joint depression (HR 2.49(1.35-4.61 95% CI), p=0.004), pre-existing KOA (HR 2.23(1.17-4.23), p=0.015) and inflammatory arthropathy (HR 2.4(1.04-5.53), p=0.039) were independently associated with radiographic indication for TKA. In conclusion, severe joint depression and pre-existing arthritis are independent risk factors for both severe PTOA and TKA after TPFs in older adults. These features should be considered as an indication for primary management with acute TKA

The pathogenesis of knee osteoarthritis is complex and involves many correlated factors that can be measured with gait analysis. Important biomechanical factors may lie in the interrelationships between variables. This study demonstrated the use of a multidimensional gait data analysis technique that simultaneously considered multiple time varying and constant measures. The gait patterns of normal and knee osteoarthritic subjects were successfully separated with a misclassification error rate of < 6%. One of the most discriminatory features identified an important knee osteoarthritis difference during the loading response phase of the gait cycle. The objective of this study was to detect biomechanical factors of knee osteoarthritis with a multidimensional gait data analysis technique. A multidimensional gait data analysis technique detected a very discriminatory feature that described a knee osteoarthritis difference during the loading response phase of the gait cycle. The combination of variables involved in the loading response feature may be important to the onset and development of knee osteoarthritis. Discriminatory gait features associated with knee osteoarthritis were identified with a misclassification error rate of < 6%. In a very discriminatory feature, the loading response phase of the gait cycle was completely isolated as important. Body mass index (BMI) was the greatest contributing factor to the loading response feature. Three-dimensional gait analysis was performed on fifty elderly patients with severe knee osteoarthritis and sixty-three elderly asymptomatic subjects. Three components of knee joint angles, moments and forces were calculated. Body mass index (BMI), radiographic measures and stride characteristics were also measured. A multivariate statistical technique extracted important features from the data and a discrimination procedure defined the optimal separation between the two groups. The importance of loading response had been hypothesized previously, and this study quantitatively identified a very discriminatory gait pattern difference during loading response. The difference described was multidimensional. Although BMI was the largest contributing factor, there was no univariate difference in BMI between the two groups. Funding: NSERC

Knee osteoarthritis is a common, debilitating condition. Intra articular corticosteroid injections are a commonly used non-operative treatment strategy. Intra articular hip injection with Ketorolac (an NSAID) has proven to be as efficacious as corticosteroids. No prior study compares the efficacy of Ketorolac relative to corticosteroids for relief of discomfort in knee osteoarthritis. The study design was a single centre double blinded RCT. Severity of osteoarthritic changes were graded on plain film weightbearing radiographs using the Kellgren and Lawrence system. Injection was with either 30mg Ketorolac or 40mg Methylprednisolone, given by intra-articular injection, in a syringe with 5mls 0.5% Marcaine. Pre-injection clinical outcomes were assessed using the Numerical Pain Score (NPS), WOMAC, and Oxford knee scores. Patients' NPS scores were assessed at Day 1 and Day 14 post-injection. An assessment of all clinical outcomes took place in clinic at six weeks. There were 72 participants (83 knees) in the study. No patients were lost to follow-up. Mean age was 62.66 years (Range 29–85). 42 knees received a corticosteroid injection, 41 a NSAID injection. Mean Kellgren and Lawrence score was 3.1. There was no significant difference in pre-injection clinical scores in either group. There was a significant improvement of NPS on Day 1 and 14 in both injection groups(p<0.05). These improved pain scores were sustained at 6 weeks in both groups. WOMAC and Oxford Knee Scores showed a statistically significant improvement in the corticosteroid group. WOMAC scores showed significant improvement in the NSAID group, however these improvements didn't achieve statistical significance using the Oxford Knee Score. Corticosteroid or NSAID injectate are a safe and effective non-operative treatment strategy in the patient with knee osteoarthritis. Ketorolac appears to provide effective medium-term improvement of pain and clinical scores. Further follow-up is recommended to investigate if this trend in sustained

In addition to mechanical stresses, an inflammatory mediated association between obesity and knee osteoarthritis (OA) is increasingly being recognised. Adipokines, such as adiponectin and leptin, have been postulated as likely mediators. Clinical and epidemiological differences in OA by race have been reported. What contributes to these differences is not well understood. In this study, we examined the profile of adipokines in knee synovial fluid (SF) and the gene expression profile of the infra-patellar fat pad (IFP) by race among patients with end-stage knee OA scheduled for knee arthroplasty. Age, sex, weight and height (used to derive body mass index (BMI)) and race (White, Asian and Black) were elicited through self-report questionnaire prior to surgery. SF and IFP samples were collected at the time of surgery. Adipokines (adiponectin and leptin) were examined in the SF using MAGPIX Multiplex platform. IFP was profiled using Human Adipogenesis PCRArray and genes of interest were further validated via quantitative relative RT-PCR using Student's t-test. Overall differences in adiponectin and leptin concentrations were tested across race. Linear regression modeling was used to investigate the association between adiponectin and leptin concentrations (outcomes) and race (predictor; referent group: White), adjusting for age, sex and BMI. 67 patients (18 White, 33 Asian, 16 Black) were included. Mean SF adiponectin concentration was greatest in Whites (1175.05 ng/mL), followed by Blacks (868.53 ng/mL) and Asians (702.23 ng/mL) (p=0.034). The mean SF leptin concentration was highest in Blacks (44.88 ng/mL), followed by Whites (29.86 ng/mL) and Asians (20.18 ng/mL) (p=0.021). Regression analysis showed Asians had significantly lower adiponectin concentrations compared to Whites (p<0.05). However, leptin concentrations did not differ significantly by race after adjusting for covariates. Testing of the IFP, using the Adipogenesis PCRArray, showed significant higher expression of LEP gene (leptin, p=0.03) in Asians (n=4) compared to Whites (n=4). There appears to be important racial differences in the SF adiponectin profile among individuals with end-stage knee OA. Differential gene expression in the IFP across racial groups could be a potential contributory source for the noted SF variations. Further work to determine the source and function of adipokines in knee OA pathophysiology across racial groups is warranted

Introduction and Objective. Knee osteoarthritis (KOA) is a frequent disease for which therapeutic possibilities are limited. In current recommendations, the first-line analgesic is acetaminophen. However, low efficacy of acetaminophen, frequently leads to the use of weak opioids (WO) despite their poor tolerance, especially in elderly patients. The primary objective was to compare the analgesic efficacy and safety of a new wearable transcutaneous electrical nerve stimulation (W-TENS) to weak opioids (WO) in the treatment of moderate to severe, nociceptive, chronic pain in knee osteoarthritis patients. Materials and Methods. ArthroTENS study is a phase 3, non-inferiority, multicentric, prospective, randomized, single-blinded for primary efficacy outcome, controlled, in 2-parallel groups, clinical study comparing W-TENS versus WO over a 3-month controlled period with an additional, optional, non-controlled, 3-month follow-up for patients in W-TENS group. The co-primary outcome was KOA pain intensity (PI) at month 3 and the number of adverse events (AEs) over 3 months. Results. The non-inferiority of W-TENS was demonstrated in both the PP and ITT populations. At M3, PI in PP population was 3.87 (2.12) compared to 4.66 (2.37) (delta: −0.79 (0.44); 95% CI (−1.65; 0.08)) in W-TENS and WO groups, respectively. Since the absolute value of the 95% CI of the between-treatments mean PI difference [−1.71, – 0.12] was above 0 in ITT set, the planned superiority analysis was performed, demonstrating that W-TENS was significantly superior to WO at M3 (P=0.0124). At M1 and M3, the W-TENS group reached the absolute minimal clinically important difference (MCID) for an analgesic (1.8 (2.1) and 2.1 (2.3), respectively), corresponding to a 20 mm reduction in PI (interquartile range: 15–30) on a 0–100 mm visual analogic scale – i.e. 2 points on a numerical rating scale – which equates to “much better”. Conversely, in the WO group, a 0.5 (1.8) and a 1.1 (2.1) reduction in PI were observed at M1 and M3, respectively, while a 1-point reduction in PI is required to be considered as a “slightly better” improvement. In WO group, AEs were the common systemic AEs reported with WO (nausea, constipation, drowsiness, dizziness, pruritus, vomiting, dry mouth). AEs in W-TENS group were local, such as local cutaneous reaction (erythema). Thirty-nine (70.9%) patients wished to extend W-TENS treatment for 3 additional months. Only one patient discontinued this additional period and results were maintained at M6. Conclusions. W-TENS was more effective and better tolerated than WO in the treatment of nociceptive KOA chronic pain and could represent an interesting non-pharmacological alternative to WO

Introduction. The mortality and serious side effects risk of both medical and surgical management of hip and knee osteoarthritis (OA) has been widely published. To date however, there are no studies comparing safety between the two treatment modalities. We aimed to systematically review the published evidence on the mortality and serious complications risk of the various treatments for hip and knee OA. Methods. We searched for studies investigating the safety of arthroplasty, arthroscopy, opioids, non-steroidal anti-inflammatory drugs (NSAIDS), and paracetamol using PubMed, Score, Cochrane, PEDRO, and Google Scholar. The phrase “osteoarthritis treatment” was searched and then combined using Boolean connectors (“OR and “AND) with “serious complications” or “serious adverse events” or “mortality”. The quality of included studies was assessed based on the approach used by the AAOS in judging the quality of treatment studies. Results. 19 studies were included in the review. Mortality risk was highest for Naproxen HR = 3 (1.9; 4.6) and lowest for total hip replacement RR = 0.7 (0.7; 0.7). Highest serious gastrointestinal complication risk was reported for diclofenac OR = 4.77 (3.94; 5.76) and lowest for total knee replacement HR = 0.6 (0.49; 0.75). Ibuprofen had the highest renal complications risk OR=2.32 (1.45; 3.71) whereas celecoxib had the lowest RR = 0.61 (0.4; 0.94). Celecoxib users had the highest cardiovascular (CV) complication risk OR=2.26 (1; 5.1) and the lowest was for tramadol RR = 1.1 (0.87; 1.4). Discussion. Long term medical management of hip and knee OA particularly with NSAIDS may carry a higher mortality risk compared to surgery. Conclusion. The practitioner and patient should carefully consider the risks of medications as well as surgery prior to commencing treatment. Treatment choice should also be tailored to the patient taking into account known GI, CVS, and renal co-morbidities

Introduction. Patients with knee osteoarthritis (OA) often tell us that they put extra load on the joints of the opposite leg as they walk. Multiple joint OA is common and has previously been related to gait changes due to hip OA (Shakoor et al 2002). The aim of this study was to determine whether patients with medial compartment knee OA have abnormal biomechanics of the unaffected knee and both hips during normal level gait. Methods. Twenty patients (11 male, 9 female), with severe medial compartment knee OA and no other joint pain were recruited. The control group comprised 20 adults without musculoskeletal pain. Patients were reviewed, x-rays were examined and WOMAC and Oxford knee scores were completed. A 12 camera Vicon (Vicon, Oxford) system was used to collect kinematic data (100Hz) on level walking and the ground reaction force was recorded using three AMTI force plates (1000Hz). Surface electrodes were placed over medial and lateral quadriceps and hamstrings bilaterally to record EMG data (1000Hz). Kinematics and kinetics were calculated using the Vicon ‘plug-in-gait’ model. A co-contraction index was calculated for the EMG signals on each side of the knee, representing the magnitude of the combined readings relative to their maximum contraction during the gait cycle. Statistical comparisons were performed using t-tests with Bonferroni's correction for two variables and ANOVA for more than two variables (SPSS v16). Results. The mean age of the patients was 69 (SD 8.8). Mean gait speed was 0.95m/s (study group) and 1.44m/s (control group). Peak adduction moments for the OA group [OA Knee; Unaffected Knee; Ipsilateral Hip; Contralateral Hip; in Nm/Kg(±95% CI)] were: 0.55(0.06); 0.47(0.06); 0.73(0.09); 0.73(0.08). Control values for peak moments were 0.64 (0.06) for the knee and 0.81(0.07) at the hip. Mid-stance adduction moments for the OA group (listed as before) were: 0.44(0.08); 0.33(0.06); 0.64(0.06); 0.61(0.08). Control values for mid-stance moments were 0.14(0.03) and 0.40(0.04). [OA group vs. Controls: p=NS for peak moments at all 4 joints; p<0.01 for mid-stance moments at all joints]. Co-contraction indices for hamstrings and quads, [OA knee medial; and lateral; unaffected knee medial; and lateral; control medial; and lateral; 0<X. Discussion. Although the affected subjects all had only single joint OA, abnormal moments were present in the hips and knees of both legs during normal level gait, despite the reduced gait speed of the OA cohort. Abnormal hamstring and quadriceps co-contraction occurs bilaterally in patient with single joint OA. Increased trunk sway is a recognised compensation in knee OA and may be the cause of the abnormal hip and contra-lateral knee loading found in this study. Further investigation is warranted and may lead to improvements in the long term outcome for these patients. Acknowledgement. The study was funded by the North Wales NHS Trust

To study the association between hip and ankle biomechanics during gait and moderate knee osteoarthritis (OA). Gait analysis was performed on a group of forty-four patients clinically diagnosed with moderate knee OA, and on a group of sixty asymptomatic subjects. Three-dimensional net joint angles and net joint reaction moments at the hip, knee and ankle joints were calculated. Peak values were extracted from the gait waveform patterns and compared between the two subject groups with Student’s t-tests. The peak hip extension moment, the peak hip adduction moment, the peak hip internal and external rotation moments, and the peak ankle dorsiflexion and plantarflexion moments were all reduced in the knee osteoarthritis population compared to the asymptomatic population. Differences in knee joint loading patterns with moderate knee osteoarthritis have been previously reported, but these data suggest that changes in the mechanical environment of all lower extremity joints are associated with early stages of knee osteoarthritis. Other studies have associated reduced peak hip adduction moments with reduced likelihood of OA progression. These data provide a rationale for hip abductor muscle strengthening as a means to lower knee joint loading

Introduction and Objective. The geometry of the proximal tibia and distal femur is intimately linked with the biomechanics of the knee and it is to be considered in total knee arthroplasty (TKA) component positioning. The aim of the present study was to evaluate the proximal tibial torsion in relation to the flexion-extension axis of the knee in healthy and pathological cohort affected by knee osteoarthritis (OA). Materials and Methods. We retrospectively analyzed computed tomography scans of OA knee of 59 patients prior to TKA and non-arthritic knee of 39 patients as control. Posterior condylar angle (PCA), femoral tibial torsion (TEAs-PTC and TEAs-PTT), proximal tibial torsion (PTC-PTT and PCAx-PTC) and distance between tibial tuberosity and the trochlear groove (TT-TG) were measured. Results. No differences were found for gender, age, TG-TT and PCAn angles. Statistically significant differences were found for all the other angles considered. Significant relation was found between Tibial Torsion and TEA-PTT angles, between PCAx-PTC and TEA-PTC, between TEA-PTT and TEA-PTC and between PCAx-PTC and TEA-PTT. All measures, except TG-TT and PCAn angles, showed high validity (AUC > 75%) in detecting OA, with TEA-PTT displaying the highest validity with an AUC of 94.38%. Conclusions. This is the first study to find significant differences in terms of proximal tibia geometry and anatomy between non arthritic and OA knees. It is conceivable that such anatomy could be implicated in the development of OA. Based on our data, the TEAs is a valid reference for correct positioning of tibial component in TKA. Indeed, setting the tibial component parallel to TEAs makes the prosthetic knee more similar to the native non-arthritic knee

To identify the differences in inflammatory profiles between hip OA, knee OA and non-OA control cohorts and investigate the association between cytokine expression and clinical outcome measurements, specifically pain. A total of 250 individuals were recruited in three cohorts (100 knee OA, 50 hip OA, 100 control). Serum was collected and inflammatory profiles analysed using the Multiplex Human Cytokine Panel (Millipore) on the Luminex 100 platform (Luminex Corp., Austin, TX). The pain, physical function and activity limitations of hip OA cohort were scored using the WOMAC, SF-36, HHS and UCLA scores. All cytokine levels were compared between cohorts individually using Mann–Whitney–Wilcoxon (MWW) test with Bonferroni multiple comparison correction. Within hip OA cohorts, the effect of hip alignment (impingement and dysplasia) and radiographic grade (Kellgren and Lawrence grade, K/L grade) on cytokine levels were accessed by MWW test. Spearman's rank correlation test used to assess the association between cytokines and pain levels. The three cohorts showed distinct inflammatory profiles. Specifically, EGF, FGF-2, MCP-3, MIP-1a, IL-8 were significant different between knee and hip OA; FGF-2, GRO, IL-8, MCP-1, VEGF were significant different between hip OA and control; Eotaxin, GRO, MCP-1, MIP-1b, VEGF were significant different between knee OA and control (p-value < 0.0012). For hip OA cohorts, cytokines do not differ between K/L grade three and K/L grade four or between patients that displayed either impingement or dysplasia. Three cytokines were significant associated with pain: IL-6 (p-value = 0.045), MDC (p-value = 0.032) and IP-10 (p-value = 0.038). We have demonstrated that differences in serum inflammatory profiles exist between hip and knee OA patients. These differences suggest that OA may include different inflammatory subtypes according to affected joints. We also identified that the cytokine IL-6, MDC and IP-10 are associated with pain level in hip OA patients. These cytokines might help explain the inconsistent of presentation of pain with radiographical severity of OA joints. Future studies are needed to validate our findings and then to understand the following questions: (1) how differently affected joints are reflected in systematic biomarkers; (2) how these cytokines are biologically involved in the OA pain pathway

Individuals with multi-compartment knee osteoarthritis (KOA) frequently experience challenges in activities of daily living (ADL) such as stair ambulation. The Levitation “Tri-Compartment Offloader” (TCO) knee brace was designed to reduce pain in individuals with multicompartment KOA. This brace uses novel spring technology to reduce tibiofemoral and patellofemoral forces via reduced quadriceps forces. Information on brace utility during stair ambulation is limited. This study evaluated the effect of the TCO during stair descent in patients with multicompartment KOA by assessing knee flexion moments (KFM), quadriceps activity and pain. Nine participants (6 male, age 61.4±8.1 yrs; BMI 30.4±4.0 kg/m2) were tested following informed consent. Participants had medial tibiofemoral and patellofemoral OA (Kellgren-Lawrence grades two to four) diagnosed by an orthopaedic surgeon. Joint kinetics and muscle activity were evaluated during stair descent to compare three bracing conditions: 1) without brace (OFF); 2) brace in low power (LOW); and 3) brace in high power (HIGH). The brace spring engages from 60° to 120° and 15° to 120° knee flexion in LOW and HIGH, respectively. Individual brace size and fit were adjusted by a trained researcher. Participants performed three trials of step-over-step stair descent for each bracing condition. Three-dimensional kinematics were acquired using an 8-camera motion capture system. Forty-one spherical reflective markers were attached to the skin (on each leg and pelvis segment) and 8 markers on the brace. Ground reaction forces and surface EMG from the vastus medialis (VM) and vastus lateralis (VL) were collected for the braced leg. Participants rated knee pain intensity performing the task following each bracing condition on a 10cm Visual Analog Scale ranging from “no pain” (0) to “worst imaginable pain” (100). Resultant brace and knee flexion angles and KFM were analysed during stair contact for the braced leg. The brace moment was determined using brace torque-angle curves and was subtracted from the calculated KFM. Resultant moments were normalized to bodyweight and height. Peak KFMs were calculated for the loading response (Peak1) and push-off (Peak2) phases of support. EMG signals were normalized and analysed during stair contact using wavelet analysis. Signal intensities were summed across wavelets and time to determine muscle power. Results were averaged across all 3 trials for each participant. Paired T-tests were used to determine differences between bracing conditions with a Bonferroni adjustment for multiple comparisons (α=0.025). Peak KFM was significantly lower compared to OFF with the brace worn in HIGH during the push-off phase (p Table 1: Average peak knee flexion moments, quadriceps muscle power and knee pain during stair descent in 3 brace conditions (n=9). Quadriceps activity, knee flexion moments and pain were significantly reduced with TCO brace wear during stair descent in KOA patients. These findings suggest that the TCO assists the quadriceps to reduce KFM and knee pain during stair descent. This is the first biomechanical evidence to support use of the TCO to reduce pain during an ADL that produces especially high knee forces and flexion moments. For any figures or tables, please contact the authors directly

Summary Statement. OA knee with subchondral cyst formation presented differential microstructure and mechanical competence of trabecular bone. This finding sheds light on the pivot role of subchondral cyst in OA bone pathophysiology. Introduction. Subchondral bone cyst (SBC) is a major radiological finding in knee osteoarthritis (OA), together with joint space narrowing, osteophyte and sclerotic bone formation. There is mounting evidence showing that SBC originates in the same region as bone marrow lesions (BMLs). The presence of subchondral bone cyst (SBCs), in conjunction with BMLs, was associated with the severity of pain, and was able to predict tibial cartilage lolume loss and risk of joint replacement surgery in knee OA patient. It is speculated that the presence of SBCs might increase intraosseous pressure of subchondral bone, and trigger active remodeling and high turnover of surrounding trabecular bone. Yet the exact effect of SBC on the structural and mechanical properties trabecular bone, which provides the support to overlying articular cartilage, remains to be elucidated. Therefore, this study aimed to investiate the microstructure and mechanical competence of trabecular bone of knee OA in presence or absence of SBC. Patients & Methods. A total of 20 postmenopausal women (54–87 years old) with the late-stage of primary knee OA were recruited in this study. Tibial plateau specimens were collected during joint replacement surgery. The samples were grouped for comparison according to presence or absences of SBC in micro-CT images. For micro-CT examination, a cylindrical volume of region of interest (VOI) of 10mm in diameter and 1mm in height was used to cover the trabecular bone region surrounding SBC, and then a cubic VOI of 3.5×3.5×3.5mm. 3. was applied in different anatomic locations of tibial plateau, such as medial, intermediate and lateral part, for the analyses of trabecular bone microstructure. Subsequently, two cylinders of subchondral bone specimens were drilled for each sample with micro-CT guidance from lateral portion of cystic wall along the direction of physiological loading of knee joint. The specimens were processed for micro-CT and mechanical testing using MTS 858 Mini Bionix sequentially. Each specimen was compressed in a longitudinal direction at a speed of 1mm/minute; the ultimate strength and modulus of the specimens were generated. Comparisons of microstructure and mechanical properties of trabecular bone were performed between two groups using student t test. The structure-mechanics relationship was also investigated using Pearson correlation. Results. The bone volume fraction (BV/TV, %) was significantly higher in knee OA specimens in presence of SBC (32±7%) in comparison with those in absence of SBC (16±5%, p<0.001). Meanwhile there were more plate-like trabecular bone surrounding SBC (0.78±0.61) than those without SBC (1.81±0.28, p<0.001), which was indicated by structure model index (0∼3). Furthermore, the trend in conversion of rod-like (close to 3) towards plate-like trabeculae was noticed in different locations of knee OA specimens with SBC formation. Trabecular bone around SBC presented higher modulus (73±22MPa) compared with those without SBC (45±29MPa, p=0.034). The stiffer trabecular bone in presence of SBC correlated with its plate-like morphology (r=0.696, p<0.001) as well as bone volume fraction (r=0.578, p=0.004). Conclusion. Presence of SBC was associated with conversion of trabeculae towards plate-like morphology together with the increase of mechanical competence in advanced knee OA

Summary. The quantification of T1Rho relaxation times is not related with internal loading. Improvements in modeling and imaging techniques might lead to better understanding of the pathomechanics of the knee. Introduction. The onset and progression of knee osteoarthritis has been associated with an increased external knee adduction moment (EKAM). However, this external measure has no direct relationship with internal loading of the knee. For a better understanding of the pathomechanics of the knee musculoskeletal models could be used to relate external and internal knee loading. Consequently, high internal loading might cause cartilage degeneration in patients with OA. T1RhoMRI can detect changes in proteoglycan content and is therefore a non-invasive measure of cartilage degeneration in knee OA. The purpose of this study was to relate internal loading of the knee simulated by musculoskeletal models with cartilage health using T1rhoMRI. Patients & Methods. Preliminary results showed data of seven women (50–65yrs), four healthy and three OA. Subjects underwent 3D gait analysis (VICON Nexus) at comfortable walking speed, EKAM was calculated. Simulations of multi-body musculoskeletal models were driven based on the motion capture data, in order to calculate internal medial-lateral knee forces (MLforce). Besides a T1RhoMRI scan of the knee (Phillips 3T) provided cartilage health of the midsection of the medial condyle according to Pedersen et al, 2011 [4]. Differences between healthy and OA were tested with a one sided T-test, correlations between EKAM and MLforce were calculated. Results. Anthropometrics and walking speed showed no significantly different between OA patients and healthy controls. OA patients had significant larger EKAM and MLforce (p<0.05). T1Rho values were not significantly different between the groups. EKAM was positively correlated with MLforce (R. 2. =0.91, p<0.05) in healthy subjects, no association was found in knee OA patients (R. 2. < 0.01). Discussion / Conclusion. The current study demonstrates that external loading of the knee does not predict internal loading in knee OA patients. We did not find a significant effect of knee OA on cartilage quality assessed by T1Rho MRI. However a non-significant increase was visible at the posterior region of the femoral condyle in OA patients. This elevated T1Rho relaxation is in line with expectations and could be related to an increased cartilage degeneration

Osteoarthritis is one of the major causes of immobility. Most commonly, osteoarthritis manifests at the knee joint. Prevalence of knee osteoarthritis (KNOA) increases with age. Another important risk factor for KNOA is obesity. Research has shown that obese subjects have almost four times the risk of developing KNOA, which may be explained by both an increased knee loading. In medial compartment KNOA, the knee adduction moment (KAM) during gait is considered a marker for disease severity. KAM is dependent of the magnitude of the ground reaction force and its moment arm relative to the knee joint centre. In addition, obesity has been reported to augment KAM during gait. However, after removal of the direct contributions of body weight, KAM parameters may be different due to obesity-related gait adaptations to limit knee loading. While KAM has been thoroughly investigated during gait, little is known about KAM during stair negotiation, during which knee loads are higher compared to gait. The aim of the current study is therefore to compare normalized KAM during the stance phase of stair negotiation between lean KNOA patients, obese KNOA patients, and healthy controls. This case control study included 20 lean controls, 14 lean KNOA patients, and 16 obese KNOA patients. All subjects ascended and descended a two-step staircase at a self-selected, comfortable speed. Radiographic imaging and MRI were used to evaluate knee cartilage and KNOA status. Motion analysis was performed with a three-dimensional motion capture system. Kinetic data were obtained by one force platform. The parameters of study included: stance phase duration, toe-out angle, KAM peaks and KAM impulse. During stair ascent obese KNOA patients showed a longer stance phase than healthy controls (P 0.050). Despite high between-subject variability, KAM impulse was found 45% higher in the obese KNOA group during stair descent, when compared to healthy controls (P =0.012). The absence of a significant effect of groups on the normalized KAM during stair negotiation may be explained by a lower ambulatory speed in the obese KNOA group, that effectively lowers GRFz. Decreasing ambulatory speed may be an effective strategy to lower KAM during stair negotiation

Permanent patellar subluxation is treated with surgeries such as proximal realignment and distal realignment, however, it is difficult to cure this condition by using any methods. We performed mobile-bearing total knee arthroplasty (TKA) in a case of severe knee osteoarthritis complicated with permanent patellar subluxation since childhood, and obtained good results without performing any additional procedures. The patient was an 82-year-old woman with severe pain in the left knee. During the initial examination, the range of motion of the left knee joint was -10°of extension to 140°of flexion, and the Japanese Orthopaedic Association (JOA) score for knee osteoarthritis was 40 points (maximum score: 100). Preoperative radiographs showed a varus deformity in the left lower extremity with a femorotibial angle (FTA) of 188°, the axial view showed luxation of the patella. We performed TKA using a mobile-bearing implant. Intraoperative findings revealed that the central articular surface of the distal femur had disappeared, and that the patellar articular surface was concave and dome-shaped. The lateral patellofemoral ligament was released; this procedure was identical to that performed in conventional TKA. Postoperative radiographs showed good alignment, with an FTA of 173°. In the axial view, the patella was located in a reduced position at any angle of knee joint flexion. The postoperative range of motion of the left knee joint was 0°of extension to 130°of flexion. The patient was able to walk without the support of a T-shaped cane. There are many surgical treatments for permanent patellar subluxation. The appropriate treatment is selected according to the type and seriousness of the dislocation and the age of the patient. From the findings of the present case, we believe that in a case of knee osteoarthritis complicated with permanent patellar subluxation, surgery performed using a mobile-bearing implant would eliminate the necessity of performing additional proximal realignment and distal realignment

Valgus unloader knee braces are a conservative treatment option for medial compartment knee osteoarthritis (OA). These braces are designed to reduce painful, and potentially injurious compressive loading on the damaged medial side of the joint through application of a frontal-plane abduction moment. While some patients experience improvements in pain, function, and joint loading, others see little to no benefit from bracing [1]. Previous biomechanical studies investigating the mechanical effectiveness of bracing have been limited in either their musculoskeletal detail [2] or incorporation of altered external joint moments and forces [3]. The first objective was to model the relative contributions of gait dynamics, muscle forces, and the external brace abduction moment to reducing medial compartment knee loads. The second objective was to determine what factors predict the effectiveness of the valgus unloading brace. Seventeen people with knee OA (8 Female age 54.4 +/− 4.2, BMI 30.00 +/− 4.0 kg/m. 2. , Kellgren-Lawrence range of 1–4 with med. = 3) and 20 healthy age-matched controls participated in this study which was approved by the institutional ethics review board. Subjects walked across a 20m walkway with and without a Donjoy OA Assist knee brace while marker trajectories, ground reaction forces, and lower limb electromyography were recorded. The external moment applied by the brace was estimated by multiplying the brace deformation by is pre-determined brace-stiffness. For each subject, a representative stride was selected for each brace condition. A generic musculokeletal model with two legs, a torso, and 96 muscles was modified to include subject-specific frontal plane alignment and medial and lateral contact locations [4]. Muscle forces, and tibiofemoral contact forces were estimated using static optimization [4]. We defined brace effectiveness as the difference in the peak medial contact force between the braced and the unbraced conditions. A stepwise regression analysis was performed to predict brace effectiveness based on: X-ray frontal plane alignment, medial joint space, KL grade, mass, WOMAC scores, unbraced walking speed, trunk, hip and knee joint angles and moments. The OA Assist brace reduced medial joint loading by approximately 0.1 to 0.2 BW or roughly 10%, during stance. This decrease was primarily due to the external brace abduction moment, and not changes in gait dynamics, or muscle forces. The brace effectiveness could be predicted (R. 2. =0.77) by the KL grade, and the magnitude of the hip adduction moment in early stance (unbraced). The brace was more effective for those that had larger hip adduction moments and for those with more severe OA. The valgus knee brace was found to reduce the medial joint contact force by approximately 10% as estimated using a musculoskeletal model. Bracing resulted in a greater reduction in joint contact force for those who had more severe OA while still maintaining a hip adduction moment similar to that of healthy controls