Purpose (the aim of the study): Osteoarthritis (OA) exerts a profound impact on quality of life. In the absence of disease-modifying OA drugs (DMOADs), there is a critical need to unravel the molecular drivers of the disease and discern potential variations among individuals. The advent of large-scale, high-throughput omics-related biotechnologies enable us to address this need at an unprecedented scale. The STEpUP OA (Synovial Fluid To Define Molecular Endotypes by Unbiased Proteomics in Osteoarthritis) consortium was established to answer a primary question of whether distinct molecular OA endotypes exist using large-scale proteomics of knee OA synovial fluid (SF). We hypothesised that molecular endotypes may delineate specific patient groups, thereby influencing diagnosis, predicting disease course, and guiding treatment response.

Purpose (the aim of the study): The molecular mechanisms of osteoarthritis (OA) remain largely unexplained. STEpUP OA (Synovial Fluid To Define Molecular Endotypes by Unbiased Proteomics in Osteoarthritis) is an international consortium which has used SomaLogic SomaScan technology to measure over 7000 proteins in the synovial fluid (SF) from >1700 individuals with OA or following joint injury. This has generated an unprecedented molecular and clinical data resource with which to interrogate molecules and pathways associated with disease. As part of this work, we set out to compare the SF proteomic profiles of individuals with advanced and non-advanced radiographic knee OA.

Background Osteoarthritis (OA) has a lifetime risk of over 40%, imposing a huge societal burden. Clinical variability suggests that it could be more than one disease. Synovial fluid To detect Endotypes by Unbiased Proteomics in OA (STEpUP OA) was established to test the hypothesis that there are detectable distinct molecular endotypes in knee OA. Methods OA knee synovial fluid (SF) samples (N=1361) were from pre-existing OA cohorts with cross-sectional clinical (radiographic and pain) data. Samples were divided into Discovery (N = 708) and Replication (N=653) datasets. Proteomic analysis was performed using SomaScan V4.1 assay (6596 proteins). Unsupervised clustering was performed using k-means, assessed using the f(k) metric, with and without adjustments for potential confounders. Regression analyses were used to assess protein associations with radiographic (Kellgren and Lawrence) and knee pain (WOMAC pain), with and without stratification by body mass index (BMI) or biological sex. Adjustments were made for cohort (random intercept) or intracellular protein, using an intracellular protein score (IPS). Analyses were carried out in R according to a pre-published plan. Results No distinct SF molecular endotypes were identified in OA but two indistinct clusters were defined in non-IPS regressed data which were stable across subgroup analyses. Clustering was lost after IPS regression adjustment. Strong, replicable protein associations were observed with radiographic disease severity, which were retained after adjustment for cohort or IPS. Pathway analysis identified a strong epithelial to mesenchymal transition (EMT) pathway, and weaker associations with angiogenesis, complement and coagulation. The latter were variably lost after adjustment for BMI or biological sex. Associations with patient reported pain were weaker. Conclusion These data support knee OA as a biologically continuous disease in which disease severity is associated with a strong, robust, tissue remodelling signature. Subtle differences were found in pathways after stratification by BMI or sex.### Competing Interest StatementTAP, YD, PH, SL, AS, NKA, AJP, DF, MK, BM, AMV and SK declare no conflicts of interest. FW has received consultancy fees from Pfizer. LSL has received consultancy fees from Arthro Therapeutics AB, and is an advisory board member of AstraZeneca. LJD has received consultancy fees from Nightingale Health PLC. TLV has no conflicts to declare with the exception of grant income for STEpUP OA from industry partners (see above). RAM is a shareholder of AstraZeneca. SB and JM are employees and shareholders of Novartis. CTA has received consultancy fees from Novartis, and has received honoraria for educational purposes also from Novartis. TJW is a shareholder of Chondropeptix BV. DAW has received consultancy fees from GlaxoSmithKline plc, AKL Research & Development Limited, Pfizer Ltd, Eli Lilly and Company, Contura International, and AbbVie Inc, has received honoraria for educational purposes from Pfizer Ltd and AbbVie Inc, is a board member (Director) of UKRI and Versus Arthritis Advanced Pain Discovery Platform. ### Funding StatementThe study was supported by Kennedy Trust for Rheumatology Research (grant number: 171806), Versus Arthritis (grant number: 22473), Centre for Osteoarthritis Pathogenesis Versus Arthritis (grant numbers: 21621, 20205), Galapagos, Biosplice, Novartis, Fidia, UCB, Pfizer (non-consortium member) and Somalogic (in kind contributions). The funders Kennedy Trust for Rheumatology Research, Versus Arthritis and Pfizer had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The funders Galapagos, Biosplice, Novartis, Fidia, UCB and SomaLogic were all active consortium members, attending consortium meetings. As such they made contributions to the study design and support of data collection, decision to publish and review and commenting on the manuscript. In addition, SomaLogic, UCB and Novartis were members of the Data Analysis Group.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:University of Oxford Medical Sciences Central University Research Ethics Committee (CUREC) granted ethical approval for the processing, storage and use of samples and linked data for this project on 1st November 2019 (R67029/RE001).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe minimal datasets upon which this data relies and all R code, including the html vignette, are available at https://github.com/ndorms-tperry/STEpUP-OA-Primary-Manuscript. The full STEpUP OA dataset may be made available by application to the Data Access and Publication Group of STEpUP OA (stepupoa@kennedy.ox.ac.uk) once the primary analysis manuscript is published, in accordance with what is stipulated in our Consortium Agreement. This may attract an access fee to cover administrative processing. Neither the minimal dataset nor the full STEpUP OA dataset include patient identifiable data.

Objectives To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis. Methods Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.1 (>7000 SOMAmers/proteins). An optimised approach to standardisation was developed. Technical confounders and batch-effects were identified and adjusted for. Poorly performing SOMAmers and samples were excluded. Variance in the data was determined by principal component (PC) analysis. Results A synovial fluid standardised protocol was optimised that had good reliability (<20% co-efficient of variation for >80% of SOMAmers in pooled samples) and overall good correlation with immunoassay. 1720 samples and >6290 SOMAmers met inclusion criteria. 48% of data variance (PC1) was strongly correlated with individual SOMAmer signal intensities, particularly with low abundance proteins (median correlation coefficient 0.70), and was enriched for nuclear and non-secreted proteins. We concluded that this component was predominantly intracellular proteins, and could be adjusted for using an ‘intracellular protein score’ (IPS). PC2 (7% variance) was attributable to processing batch and was batch-corrected by ComBat. Lesser effects were attributed to other technical confounders. Data visualisation revealed clustering of injury and OA cases in overlapping but distinguishable areas of high-dimensional proteomic space. Conclusions We have developed a robust method for analysing synovial fluid protein, creating a molecular and clinical dataset of unprecedented scale to explore potential patient subtypes and the molecular pathogenesis of OA. Such methodology underpins the development of new approaches to tackle this disease which remains a huge societal challenge.

Purpose (the aim of the study): The FNIH OA Biomarkers Consortium aims to identify, develop, and qualify biomarkers to support new drug development in OA. Phase I of the project used data from the Osteoarthritis Initiative and sought to determine the predictive ability of biomarkers for the symptomatic and radiographic progression of knee OA; results have been published. Here we present results of the PROGRESS OA study, which aims to validate these biomarkers in the control arms of existing completed OA randomized controlled trials (RCTs).

Purpose: The STEpUP OA consortium (Synovial Fluid To Define Molecular Endotypes by Unbiased Proteomics in Osteoarthritis) was set up with a primary objective to address whether OA is a single disease or made up of multiple distinct molecular endotypes, when examining large scale (SomaLogic) proteomic profiling of synovial fluid (SF) from multiple cohorts. Assay of SF as a discovery matrix using this technology (as opposed to serum/plasma) has not been previously reported other than in small sample numbers and early versions of the array.

ObjectiveThe effect of physical activity on the risk of developing knee osteoarthritis (OA) is unclear. We undertook this study to examine the relationship between recreational physical activity and incident knee OA outcomes using comparable physical activity and OA definitions.MethodsData were acquired from 6 global, community‐based cohorts of participants with and those without knee OA. Eligible participants had no evidence of knee OA or rheumatoid arthritis at baseline. Participants were followed up for 5–12 years for incident outcomes including the following: 1) radiographic knee OA (Kellgren‐Lawrence [K/L] grade ≥2), 2) painful radiographic knee OA (radiographic OA with knee pain), and 3) OA‐related knee pain. Self‐reported recreational physical activity included sports and walking/cycling activities and was quantified at baseline as metabolic equivalents of task (METs) in days per week. Risk ratios (RRs) were calculated and pooled using individual participant data meta‐analysis. Secondary analysis assessed the association between physical activity, defined as time (hours per week) spent in recreational physical activity and incident knee OA outcomes.ResultsBased on a total of 5,065 participants, pooled RR estimates for the association of MET days per week with painful radiographic OA (RR 1.02 [95% confidence interval (95% CI) 0.93–1.12]), radiographic OA (RR 1.00 [95% CI 0.94–1.07]), and OA‐related knee pain (RR 1.00 [95% CI 0.96–1.04]) were not significant. Similarly, the analysis of hours per week spent in physical activity also showed no significant associations with all outcomes.ConclusionOur findings suggest that whole‐body, physiologic energy expenditure during recreational activities and time spent in physical activity were not associated with incident knee OA outcomes.

Purpose: Several numerical patient-reported outcome measures (PROMs) have been used for measuring knee pain.Each aims to measure the participant's experience of pain, but may address different pain characteristics.There is increasing need for pooling pain data from studies using different PROMs and implementing such techniques as Individual Patient Data (IPD) analyses.Harmonised data should give the same numerical value for pain severity, irrespective of the host PROM.Our recent meta-analysis of data taken from different patient groups (Georgopoulos et al., OARSI 2021,

In this narrative review article, we critically assess the current state of the osteoarthritis (OA) drug development pipeline. We discuss the current state-of-the-art in relation to the development and evaluation of candidate disease-modifying OA drugs (DMOADs) and the limitations associated with the tools and methodologies that are used to assess outcomes in OA clinical trials. We focus on the definition of DMOADs, highlight the need for an updated definition in the form of a consensus statement from all the major stakeholders, including academia, industry, regulatory agencies, and patient organizations, and provide a summary of the results of recent clinical trials of novel DMOAD candidates. We propose that DMOADs should be more appropriately targeted and investigated according to the emerging clinical phenotypes and molecular endotypes of OA. Based on the findings from recent clinical trials, we propose key topics and directions for the development of future DMOADs.

Objective: Cryoneurolysis, cold-induced reversible conduction block of peripheral nerves, is an effective treatment for reducing knee osteoarthritis (OA) symptoms and opioid use following knee arthroplasty. There are however, limited data concerning its use for ankle OA. Our aim was to assess clinically significant long-term symptomatic relief of ankle OA with cryoneurolysis. Method: This single-center, open-label trial included participants aged >18 years with radiographic tibiotalar OA, unilateral ankle pain ≥5/10 on Numerical Rating Scale (NRS), and with no ankle surgery within 6-months of screening. Following ultrasound-guided cryoneurolysis of nerves in the participant's pain distribution (sural, saphenous, superficial and/or deep fibular nerves), outcomes were assessed at clinic visits (6, 12 and 24-weeks) and by telephone interview (3, 9, 18-weeks). The primary endpoint was change in Foot and Ankle Outcome Score (FAOS) (pain subscale) at 12-weeks. Change in quality of life (FAOS-QoL), activities of daily living (FAOS-ADL), NRS-pain, and physical performance measures were also assessed. Longitudinal mixed models were constructed to evaluate changes from baseline at 6, 12- and 24-weeks post-treatment. Results: Forty participants enrolled (50% female, mean ​± ​SD age 63.0 ​± ​12.8 years). At 12-weeks post treatment, FAOS-pain (20.8, p ​< ​0.0001), ADL (18.1, p ​= ​0.0003), QoL (19.9, p ​= ​0.0003) and NRS-pain (−2.6, p ​< ​0.0001) were significantly improved from baseline. No difference in 40-m fast-paced walking test was detected at 12-weeks post-treatment (−1.2sec, p ​= ​0.59). For all outcomes, similar findings were observed at 6- and 24-week visits. Conclusion: Cryoneurolysis resulted in statistically significant improvements in ankle pain, physical function and QoL for up to 24-weeks in participants with unilateral, symptomatic ankle OA.

Ankle arthroplasty, commonly known as ankle replacement, is a surgical procedure for treating end-stage ankle osteoarthritis. Whilst evidence shows good clinical results after surgery, little is known of the long-term survival of ankle replacements and the need for ankle revision. Using more recent implant data and long-term data, there is now opportunity to examine at a population-level the survival rate for ankle implants, to examine between-country differences in ankle revision surgery, and to compare temporal trends in revision rates between countries. Four national joint registries from Australia, New Zealand, Norway and Sweden provided the necessary data on revision outcome following primary ankle replacement, for various periods of observation – the earliest starting in 1993 up to the end of 2019. Data were either acquired from published, online annual reports or were provided from direct contact with the joint registries. The key information extracted were Kaplan-Meier estimates to plot survival probability curves following primary ankle replacement. The survival rates varied between countries. At 2 years, across all registries, survival rates all exceeded 0.9 (range 0.91 to 0.97). The variation widened at 5 years (range 0.80 to 0.91), at 10 years (range 0.66 to 0.84) and further at 15-years follow-up (0.56 to 0.78). At each time point, implant survival was greater in Australia and New Zealand with lower rates in Sweden and Norway. We observed variation in primary ankle replacement survival rates across these national registries, although even after 5 years, these population derived data show an 80% revision free survival. These data raise a number of hypotheses concerning the reasons for between-country differences in revision-free survival which will require access to primary data for analysis.

Abstract Objective Use of specific medications may accelerate the progression of radiographic knee OA (RKOA). Our aim was to examine the effect of medication use on the progression of RKOA. Methods We used longitudinal data from the Osteoarthritis Initiative (OAI), an observational study of risk factors for knee OA. At baseline, we selected participants with RKOA (Kellgren–Lawrence grade ≥2) and excluded those with a history of knee-related injury/surgery and other musculoskeletal disorders. Current medication use (use/non-use in the previous 30 days) and radiographic medial minimum joint space width (mJSW) data were available at baseline and annually up to 96 months follow-up. We used random effects, panel regression to assess the association between current medication use (non-users as reference group) and change in mJSW. Results Of 2054 eligible participants, 2003 participants with baseline mJSW data were included [55.7% female, mean age 63.3 (s.d. 8.98) years]. Of seven medication classes, at baseline NSAIDs were the most frequently used analgesia (14.7%), anti-histamine (10.4%) use was frequent and the following comorbidity medications were used most frequently: statins (27.4%), anti-hypertensives (up to 15.0%), anti-depressant/anxiolytics/psychotropics (14.0%), osteoporosis-related medication (10.9%) and diabetes-related medication (6.9%). Compared with current non-users, current use of NSAIDs was associated with a loss of mJSW (b = −0.042, 95% CI −0.08, −0.0004). No other associations were observed. Conclusions In current users of NSAIDs, mJSW loss was increased compared with current non-users in participants with RKOA. Clinical trials are required to assess the potential disease-modifying effects of these medications.

Objectives Synovitis in symptomatic knee OA (KOA) is common and is associated with joint symptoms. Optimal synovial measurement on MRI is, however, unclear. Our aims were to examine the relationship between MRI measures of synovitis and knee symptoms in symptomatic KOA. Methods Data from a randomized, multicentre, placebo-controlled trial (UK-VIDEO) of vitamin-D therapy in symptomatic KOA were utilized. Participants reported knee symptoms using WOMAC at baseline and annually. On contrast-enhanced (CE) MRI, synovial thickness was measured using established, semi-quantitative methods whilst synovial tissue volume (STV) was assessed as absolute STV (aSTV) and relative to the width of femoral condyle (rSTV). STV of the infrapatellar region was also assessed. Associations between synovial measures and symptoms were analysed using multiple linear regression modelling. Results No linear association was observed between knee symptoms and synovitis thickness scores. Whole-joint aSTV (0.88, 95% CI: 0.17, 1.59) and infrapatellar aSTV (5.96, 95% CI: 1.22, 10.7) were positively associated with knee pain. Whole-joint rSTV had a stronger association with pain (7.96, 95% CI: 2.60, 13.33) and total scores (5.63, 95% CI: 0.32, 10.94). Even stronger associations were found for infrapatellar rSTV with pain (55.47, 95% CI: 19.99, 90.96), function (38.59, 95% CI: 2.1, 75.07) and total scores (41.64, 95% CI: 6.56, 76.72). Conclusions Whole-joint and site-specific infrapatellar STV measures on CE-MRI were associated with knee pain, respectively. Volumes relative to the size of the femoral condyle may be promising outcome measures in KOA trials.

To investigate the association between markers of synovial inflammation and matrix turnover (MRI-based and serum biomarkers) and knee symptoms in established knee osteoarthritis (KOA). This cross-sectional study utilised data from a randomised, multicentre placebo-controlled trial (UK-VIDEO) of vitamin D therapy in symptomatic KOA. Data on serum biomarkers, type III collagen degradation (C3M), metabolite of C-reactive protein (CRPM) and cartilage oligomeric matrix protein (COMP), were available at baseline whilst contrast-enhanced (CE) MRI data were acquired in a subsample at baseline and annually. Knee symptoms were assessed using WOMAC at all visits. We examined the cross-sectional association between knee symptoms and three MRI-based and three serum markers of synovitis and matrix turnover, respectively. A total of 447 participants were included in the serum and 136 participants in the MRI analyses. MRI-defined medial perimeniscal synovitis was positively associated with knee pain and, suprapatellar and medial perimeniscal synovitis with knee function in multivariate analysis. We observed a statistically significant, negative association between a higher concentration of serum C3M and CRPM and knee pain, respectively. Furthermore, the highest CRPM quartile was negatively associated with knee function. Our findings suggest that, in established painful radiographic KOA, MRI-defined medial perimeniscal and suprapatellar synovitis were positively associated with knee symptoms. Serum-based C3M and CRPM markers were negatively associated with knee symptoms. Pain fluctuations are common in KOA and a better understanding of the relationship between markers of synovitis and matrix turnover and knee symptoms would facilitate a more accurate assessment of temporal changes in disease progression.

Our aims were to examine the effects of heeled shoes on incident knee osteoarthritis (OA) and joint pain. We used longitudinal data from the Chingford 1000 Women Study (Chingford Study), a prospective cohort of women aged 50 years or older. Participants with musculoskeletal disorders and/or a history of knee-related injury/surgery were excluded. Participants were followed for up to 5 years for incident outcomes including 1 ) radiographic knee OA (RKOA) and 2 ) joint pain (feet, knees, hips, and back). Footwear data, including ever worn heels of 2 inches or more and daytime/evening hours (per week) spent wearing heeled shoes over five decades (ages <20 years, 20-30 years, 30-40 years, and >50 years), were available at Year 10 whereas knee radiographs and joint symptom data were also collected at Year 15. Cumulative time spent wearing heeled shoes was calculated for women reporting ever-use of heeled shoes (≥2 inches). Multiple logistic regression was used to examine the relationship between exposures and outcomes (from Year 10 to Year 15). A total of 356 women were eligible at Year 10 with a median (interquartile range) age of 60 (56-65) years. Compared with non-use, ever-use of heeled shoes (≥2 inches) was not associated with incident RKOA (1.35; 95% confidence interval: 0.56-3.27). No associations were observed between increasing cumulative time spent wearing heels and incident outcomes. Compared with the non-use of heeled shoes, ever-use of heels (≥2 inches) was not associated with incident RKOA and incident joint symptoms. Further, increasing cumulative time spent wearing heels was not associated with any of our outcomes.

Objectives: To examine whether foot and/or ankle pain increases the risk of knee OA. Design: We utilised longitudinal data from the Multicentre Osteoarthritis Study (MOST); a community-based cohort of risk factors for knee OA. Participants without frequent knee pain (clinic visit only) and radiographic knee OA (RKOA) at baseline and, with no evidence of inflammatory musculoskeletal disease and a history of knee-related surgery were followed for up to 84-months for incident outcomes; i) RKOA (Kellgren-Lawrence (KL) ≥2), ii) symptomatic RKOA (RKOA and frequent pain in the same knee) and iii) frequent knee pain only. At baseline, ankle and foot symptoms were assessed, with knee radiographs and symptoms also assessed at 30, 60 and 84-months. Our exposures included baseline ankle, foot, and ankle and foot pain (participant-level). Associations between foot and/or ankle pain and incident outcomes were assessed using multiple logistic regression, with adjustment for participant characteristics and ankle/foot pain. Results: No statistically significant associations were observed between ankle, foot and, ankle and foot pain and incident RKOA, respectively. Ankle pain with (2.30, 95% CI 1.13 to 4.66) and without foot pain (OR: 2.53, 95% CI 1.34 to 4.80) were associated with increased odds of incident symptomatic RKOA and frequent knee pain. No statistically significant associations were observed between foot pain and these outcomes. Conclusions: Ankle pain should be a focus point, more so than foot pain, in the management of knee OA. Future studies should include additional ankle joint-specific symptom questions to better elucidate the knee OA biomechanical pathway.

Background: Over the past decade, there has been a growth in the use of ankle replacements. Data from national joint registries have shown between-country differences in the utilization of ankle replacement. The reasons for these differences are, however, not well understood. Our aims were to describe and compare the annual incidence of primary ankle replacement between countries and, to examine potential reasons for variation over time. Methods: We used aggregate data and summary statistics on ankle replacements for the period 1993 to 2019 from national joint replacement registries in Australia, Finland, New Zealand, Norway, Sweden and the United Kingdom. From the annual recorded counts of procedures, demographic data were extracted on age, sex distribution, and indication(s) for primary ankle replacement. Registry-level summary results were also obtained on data completeness, counts of hospitals/units, and health care providers performing ankle replacements annually and data collection processes (mandatory vs voluntary). Annual ankle replacement incidence for all diagnoses and, by indication categories (osteoarthritis [OA] and rheumatoid arthritis [RA]), were calculated per 100 000 residential population aged ≥18 years. Results: For the period with data from all 6 countries (2010-2015), New Zealand had the largest annual incidence (mean ± SD) of 3.3 ± 0.2 ankle replacement procedures per 100 000 population whereas Finland had the lowest incidence (0.92 replacements). There were no common temporal trends in the utilization of ankle replacements. Over the years studied, OA was the predominant diagnosis in the United Kingdom, Australia, and New Zealand, whereas RA was the most common indication in Scandinavia. Conclusion: In these 6 countries, we found marked differences in the utilization of ankle replacements. Registry-related factors including data completeness and the number of hospitals/surgeons performing ankle replacements are likely to contribute to the observed between-country differences and need to be carefully considered when interpreting comparisons for this less common site for joint replacement surgery. Level of Evidence: Level III, retrospective study.

To examine whether knee subchondral cysts, measured on magnetic resonance imaging (MRI), are associated with incident knee osteoarthritis (OA) outcomes.

Objective To assess the association between occupational exposures and knee osteoarthritis (OA). Methods We systematically searched for observational studies that examined the relationship between occupational exposures and knee OA and total knee replacement. Four databases were searched up to October 1, 2019. Two reviewers independently assessed study quality using the Newcastle-Ottawa Scale and evidence quality using the Grading of Recommendations Assessment, Development and Evaluation approach. Subgroup meta-analyses were conducted for important study characteristics and each type of occupational exposure. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for the meta-analysis using random-effects models. Results Eighty eligible studies were identified including 25 case-control (n = 20,505 total participants), 36 cross-sectional (n = 139,463 total participants), and 19 cohort studies (n = 16,824,492 total participants). A synthesis of 71 studies suggested increased odds of knee OA (OR 1.52 [95% CI 1.37-1.69]) by combining different physically demanding jobs and occupational activities as compared to sedentary occupations and/or low-exposure groups. Odds of knee OA were greater in males and in industry-based studies and studies assessing lifetime occupational exposures. There were 9 specific job titles that were associated with knee OA, including farmer, builder, metal worker, and floor layer. Occupational lifting, kneeling, climbing, squatting, and standing were all associated with higher odds of knee OA as compared to the odds of knee OA in sedentary workers. Conclusion Strenuous, physically demanding occupations and occupational activities were associated with increased odds of knee OA as supported by moderate-quality evidence. Specifically, agricultural and construction sectors, which typically involve heavy lifting, frequent climbing, prolonged kneeling, squatting, and standing, carried increased odds of knee OA.