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Objective: General practitioners (GP) are often the first medical professionals to treat musculoskeletal complaints. Yet the impact of COVID-19 on primary care utilisation for musculoskeletal complaints is largely unknown. This study quantifies the impact of the pandemic on primary care utilisation for musculoskeletal complaints and specifically osteoarthritis (OA) in the Netherlands., Design: We extracted data on GP consultations in 2015-2020 from 118,756 patients over 45 years of age and estimated reductions in consultations in 2020 as compared to 5-year average. Outcomes were GP consultations for: any musculoskeletal complaints, knee and hip OA, knee and hip complaints, and newly diagnosed knee and hip OA/complaints., Results: The relative reductions in consultations ranged from 46.7% (95% confidence intervals (CI): 43.9-49.3%) (all musculoskeletal consultations) to 61.6% (95% CI: 44.7-73.3%) (hip complaints) at the peak of the first wave, and from 9.3% (95% CI: 5.7-12.7%) (all musculoskeletal consultations) to 26.6% (95% CI: 11.5-39.1%) (knee OA) at the peak of the second wave. The reductions for new diagnoses were 87.0% (95% CI: 71.5-94.1%) for knee OA/complaints, and 70.5% (95% CI: 37.7-86.0%) for hip OA/complaints at the peak of the first wave, and not statistically significant at the peak of the second wave., Conclusion: We observed 47% reduction in GP consultations for musculoskeletal disorders during the first wave and 9% during the second wave. For hip and knee OA/complaints, the reductions were over 50% during the first, and 10% during the second wave. This disruption may lead to accumulation of patients with severe OA symptoms and more requests for arthroplasty surgery., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the risk of comorbidity following diagnosis of knee or hip osteoarthritis (OA)., Design: A cohort study was conducted using the Integrated Primary Care Information database, containing electronic health records of 2.5 million patients from the Netherlands. Adults at risk for OA were included. Diagnosis of knee or hip OA (=exposure) and 58 long-term comorbidities (=outcome) were defined by diagnostic codes following the International Classification of Primary Care coding system. Time between the start of follow-up and incident diagnosis of OA was defined as unexposed, and between diagnosis of OA and the end of follow-up as exposed. Age and sex adjusted hazard ratios (HRs) comparing comorbidity rates in exposed and unexposed patient time were estimated with 99.9% confidence intervals (CI)., Results: The study population consisted of 1,890,712 patients. For 30 of the 58 studied comorbidities, exposure to knee OA showed a HR larger than 1. Largest positive associations (HR with (99.9% CIs)) were found for obesity 2.55 (2.29-2.84) and fibromyalgia 2.06 (1.53-2.77). For two conditions a HR < 1 was found, other comorbidities showed no association with exposure to knee OA. For 26 comorbidities, exposure to hip OA showed a HR larger than 1. The largest were found for polymyalgia rheumatica 1.81 (1.41-2.32) and fibromyalgia 1.70 (1.10-2.63). All other comorbidities showed no associations with hip OA., Conclusion: This study showed that many comorbidities were diagnosed more often in patients with knee or hip OA. This suggests that the management of OA should consider the risk of other long-term-conditions., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the associations of biomarkers in serum [highsensitivity C-reactive protein (hs-CRP), serum cartilage oligomeric protein (sCOMP), serum propeptide of type I procollagen (sPINP) and serum osteocalcin (sOC)] and urine [urinary type II collagen telopeptide (uCTX-2)] with the extent and progression of nocturnal pain, pain while walking, and fatigue in participants with hip and/or knee pain suspected to be early stage osteoarthritis (OA)., Methods: hs-CRP, uCTX-2, sCOMP, sPINP and sOC were measured at baseline in 1,002 participants of the Cohort Hip and Cohort Knee (CHECK). Nocturnal pain, pain while walking and fatigue were assessed by self-reported questionnaires at baseline and 2-year follow-up. Associations between these biomarkers and symptoms were examined using logistic and linear regression analyses., Results: hs-CRP was significantly associated with mild nocturnal pain (OR 1.18 95% CI 1.01-1.37), with mild and moderate pain while walking (OR 1.17 95% CI 1.01-1.35 and OR 1.56 95% CI 1.29-1.90, respectively) and with progression of nocturnal pain (OR 1.25 95% CI 1.07-1.46). uCTX-2 was associated with mild nocturnal pain (OR 1.40 95% CI 1.05-1.85) and with mild and severe-extreme pain while walking (OR 1.35 95% CI 1.04-1.75 and OR 2.55 95% CI 1.03-6.34, respectively). sPINP was associated with severe-extreme nocturnal pain (OR 0.45 95% CI 0.25-0.82). No significant associations were found for sCOMP and sOC, nor for any of the biomarkers and fatigue., Conclusion: This study of biomarkers in a large cohort of participants with hip and/or knee pain suspected to reflect early stage hip and/or knee OA suggests that inflammation and cartilage matrix degeneration play a role in pain, but not in fatigue., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Ability to assess flares in osteoarthritis (OA) of the knee and hip (KHOA) is important in clinical care and research. Using mixed methods, we developed a self-reported instrument measuring flare and assessed its psychometric properties., Methods: We constructed questionnaire items from semi-structured interviews and a focus group (patients, clinicians) by using a dual-language (English-French) approach. A Delphi consensus method was used to select the most relevant items. Patients with OA from Australia, France and the United States completed the preliminary Flare-OA, HOOS, KOOS and Mini-OAKHQOL questionnaires online. We used a factor analysis and content approach to reduce items and determine structural validity. We tested the resulting questionnaire (score 0-100) for internal consistency, convergent and known-groups validity., Results: Initially, 180 statements were generated and reduced to 33 items in five domains (response 0 = not at all, to 10 = absolutely) by Delphi consensus (50 patients, 116 professionals) and an expert meeting. After 398 patients (mean [SD] age 64 [8.5] years, 70.4% female, 86.7% knee OA) completed the questionnaire, it was reduced to 19 items by factor analysis and a content approach (RMSEA = 0.06; CFI = 0.96; TLI = 0.94). The Cronbach's alpha was >0.9 for the five domains and the whole questionnaire. Correlation coefficients between Flare-OA and other instrument scores were as predicted, supporting construct validity. The difference in Flare-OA score between patients with and without flare (31.8) largely exceeded 2 SEM (10.2)., Conclusion: Flare-OA is a valid and reliable patient-reported instrument for assessing the occurrence and severity of flare in patients with KHOA in clinical research., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Hip and knee osteoarthritis (OA) are leading causes of global disability. Most research to date has focused on the knee, with results often extrapolated to the hip, and this extends to treatment recommendations in clinical guidelines. Extrapolating results from research on knee OA may limit our understanding of disease characteristics specific to hip OA, thereby constraining development and implementation of effective treatments. This review highlights differences between hip and knee OA with respect to prevalence, prognosis, epigenetics, pathophysiology, anatomical and biomechanical factors, clinical presentation, pain and non-surgical treatment recommendations and management., (Copyright © 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To design an automated workflow for hip radiographs focused on joint shape and tests its prognostic value for future hip osteoarthritis., Design: We used baseline and 8-year follow-up data from 1,002 participants of the CHECK-study. The primary outcome was definite radiographic hip osteoarthritis (rHOA) (Kellgren-Lawrence grade ≥2 or joint replacement) at 8-year follow-up. We designed a method to automatically segment the hip joint from radiographs. Subsequently, we applied machine learning algorithms (elastic net with automated parameter optimization) to provide the Shape-Score, a single value describing the risk for future rHOA based solely on joint shape. We built and internally validated prediction models using baseline demographics, physical examination, and radiologists scores and tested the added prognostic value of the Shape-Score using Area-Under-the-Curve (AUC). Missing data was imputed by multiple imputation by chained equations. Only hips with pain in the corresponding leg were included., Results: 84% were female, mean age was 56 (±5.1) years, mean BMI 26.3 (±4.2). Of 1,044 hips with pain at baseline and complete follow-up, 143 showed radiographic osteoarthritis and 42 were replaced. 91.5% of the hips had follow-up data available. The Shape-Score was a significant predictor of rHOA (odds ratio per decimal increase 5.21, 95%-CI (3.74-7.24)). The prediction model using demographics, physical examination, and radiologists scores demonstrated an AUC of 0.795, 95%-CI (0.757-0.834). After addition of the Shape-Score the AUC rose to 0.864, 95%-CI (0.833-0.895)., Conclusions: Our Shape-Score, automatically derived from radiographs using a novel machine learning workflow, may strongly improve risk prediction in hip osteoarthritis., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The aim of this study was to estimate lifetime risk of knee and hip replacement following a GP diagnosis of osteoarthritis and assess how this risk varies with patient characteristics., Methods: Routinely collected data from Catalonia, Spain, covering 2006 to 2015, were used. Study participants had a newly recorded GP diagnosis of knee or hip osteoarthritis. Parametric survival models were specified for risk of knee/hip replacement and death following diagnosis. Survival models were combined using a Markov model and lifetime risk estimated for the average patient profile. The effects of age at diagnosis, sex, comorbidities, socioeconomic status, body mass index (BMI), and smoking on risk were assessed., Results: 48,311 individuals diagnosed with knee osteoarthritis were included, of whom 2,561 underwent knee replacement. 15,105 individuals diagnosed with hip osteoarthritis were included, of whom 1,247 underwent hip replacement. The average participant's lifetime risk for knee replacement was 30% (95% CI: 25-36%) and for hip replacement was 14% (10-19%). Notable patient characteristics influencing lifetime risk were age at diagnosis for knee and hip replacement, sex for hip replacement, and BMI for knee replacement. BMI increasing from 25 to 35 was associated with lifetime risk of knee replacement increasing from 24% (20-28%) to 32% (26-37%) for otherwise average patients., Conclusion: Knee and hip replacement are not inevitable after an osteoarthritis diagnosis, with average lifetime risks of less than a third and a sixth, respectively. Patient characteristics, most notably BMI, influence lifetime risks., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To describe the radiographic and symptomatic course in subjects with hip or knee complaints suspected of early osteoarthritis (OA)., Design: CHECK (Cohort Hip and Cohort Knee) is a multicenter, prospective observational cohort study of 1,002 subjects with first complaints in knee(s) and/or hip(s) (age 56 ± 5 years; 79% female; body mass index (BMI) 26 ± 4 kg/m 2 ). Visits took place at baseline and at 2, 5, 8, and 10 year follow-up. At each visit, questionnaires were administered, physical examination performed, and X-ray images obtained. Clinical OA was defined according to the clinical American College of Rheumatism (ACR) criteria. Radiographic OA (ROA) was defined as Kellgren and Lawrence score (K&L) ≥2., Results: 83% of the subjects reported knee pain, 59% hip pain, and 42% reported both hip and knee pain at baseline. 85% of the subjects completed 10-year follow-up. Pain scores remained rather stable over time, although individual scores fluctuated. A total of 138 subjects never fulfilled the clinical American College of Rheumatology (ACR) criteria. 60% (n = 601) had ROA in one or both knees, and 51% (n = 513) had ROA in one or both hips at 10 years. Only 13.5% of the subjects did not develop ROA after 10 years. Most joint replacements (n = 52 (57%)) took place in subjects with multiple affected joints., Conclusions: The symptomatic course in subjects with hip or knee complaints suspected of OA remained fairly stable on population level, though individual scores fluctuated. The radiological course was progressive, with joint replacements particularly in subjects with both hip and knee OA., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To systematically review the minimal clinically important difference (MCID) and patient acceptable symptom state (PASS) estimates in pain and function measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in patients who underwent primary total knee replacement (TKR) and primary total hip replacement (THR)., Design: The study was carried out following PRISMA recommendations. We searched five electronic databases. Two reviewers independently screened titles, abstracts and full-text papers using a priori inclusion/exclusion criteria. Data were extracted by two independent reviewers. Data were synthesized, with WOMAC values converted to 0-100 scores (0 = best, 100 = worst)., Results: Thirteen studies were included. Research methods used to calculate MCIDs and PASS varied across studies (e.g., using anchor-based or distribution methods, wording of anchor questions within anchor-based methods). Baseline WOMAC scores also varied across studies. Across studies and methods, MCIDs for the WOMAC in patients undergoing TKR ranged from 13.3 to 36.0 for pain and 1.8-33.0 for function; values for WOMAC in THR ranged from 8.3 to 41.0 for pain and from 9.7 to 34.0 for function. PASS cut-offs for TKR ranged from 25.0 to 28.6 for pain and 32.3-36.7 for function, and cut-offs for THR from 15.0 to 30.6 for pain and 28.0-42.0 for function., Conclusion: Although the WOMAC is a commonly used measure for a single condition, the variability in methods used to calculate MCID and PASS estimates results in a range of values across studies making it unclear whether values reported in the literature can be applied with confidence. Future research is needed to refine methods used to calculate MCIDs and PASS., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To explore, using a qualitative approach, reasons for patients' continued willingness or their shift in willingness for total joint replacement (TJR) surgery, following participation in Joint Academy, a Swedish, digital, non-surgical treatment program for osteoarthritis (OA)., Design: Nineteen patients with hip or knee OA were interviewed after finishing their first 6 weeks in the treatment program, using a semi-structured interview guide. The interviews were transcribed verbatim and analyzed using a systematic text condensation method., Results: Analysis of the interview data revealed three main categories of reasons provided for the participants' decisions regarding surgery: 1) Various reasons for participating in Joint Academy with three sub-categories: (a) longstanding pain affects daily life, (b) last chance for improvement and (c) mandatory treatment to be eligible for total joint replacements (TJR); 2) Willingness for TJR following treatment, which included four sub-categories: (a) surgery - the last resort, (b) reduced pain and improved functioning, (c) no perceived improvements after treatment, and (d) trust in healthcare providers; and 3) Expectations of TJR. The shift in willingness towards or away from TJR was mainly due to the perceived success of Joint Academy in improving their functioning., Conclusion: Several patients reconsidered their options and had changed their attitude to TJR after participation in a digital program aimed at reducing OA symptoms and improving functioning. These results highlight the importance of providing patients with adequate information about non-surgical management options to facilitate shared decision-making, and possibly reduce the need for surgery., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: This study was design to examine the diagnostic performance of cartilage oligomeric matrix protein (COMP), C-terminal cross-linking telopeptide of type II collagen (CTX-II), and matrix metalloproteinase-3 (MMP-3) as biomarker for knee and hip OA., Methods: Systematic search on multiple databases was completed in January 2018 using certain keywords. COMP, CTX-II, MMP-3 levels in knee and hip OA patients and healthy individuals were collected and calculated. Differences between subgroups were expressed as standardized mean differences (SMD). Subgroup analyses were performed to compare COMP, CTX-II, and MMP-3 performance between measuring sources, genders, large and small sample size and diagnostic criteria for OA patients., Results: A moderate performance of COMP in distinguishing between knee (SMD: 0.68; 95% confidence intervals (CI): 0.43-0.93; P < 0.0001) or hip (SMD: 0.25; 95% CI, 0.10, 0.40; P = 0.0008) OA patients and controls were found. CTX-II showed a moderated standardised mean differences (SMD) of 0.48 (95% CI, 0.32, 0.64; P < 0.0001) in the detection of knee OA and a large SMD of 0.76 (95% CI, 0.09, 1.42; P = 0.03) in diagnosing hip OA. A small SMD of 0.32 (95% CI, -0.03, 0.67; P = 0.07) was found for MMP-3 performance and the results did not reach statistic significance. Progression study revealed potential effectiveness of serum COMP in predicting OA progression. Subgroup analysis showed that serum COMP and urinary CTX-II performed better in male than female. Study size and diagnostic criteria did not significantly influence the pooled SMD, but they might be the sources of heterogeneity among studies., Conclusion: The overall results indicates that serum COMP and urinary CTX-II can distinguish between knee or hip OA patients and control subjects. Serum COMP is effective in predicting OA progression.Further researches with rigorous study design and a larger sample size are required to validate our findings., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: Long intergenic non-coding RNAs (lincRNAs) are emerging as key regulators in gene expression; however, little is known about the lincRNA expression changes that occur in osteoarthritis (OA). Here we aimed to define a transcriptome of lncRNAs in OA cartilage, specifically comparing the lincRNA transcriptome of knee and hip cartilage., Method: RNA-seq was performed on nucleic acid extracted from hip cartilage from patients undergoing joint replacement surgery because of either OA (n = 10) or because of a neck of femur fracture (NOF; n = 6). After transcript alignment, counts were performed using Salmon and differential expression for ENSEMBL lincRNAs determined using DESeq2. Hip RNA-seq lincRNA expression was compared to a knee dataset (ArrayExpress; E-MTAB-4304). ChIP-seq data from ENCODE was used to determine whether lincRNAs were associated with promoters (plncRNA) or unidirectional enhancer-like regulatory elements (elncRNAs)., Results: Our analysis of the hip transcriptome identified 1692 expressed Transcripts Per Million (TPM ≥1) Ensembl lincRNAs, of which 198 were significantly (FDR ≤0.05) differentially expressed in OA vs normal (NOF) cartilage. Similar analysis of knee cartilage transcriptome identified 648 Emsembl lincRNAs with 93 significantly (FDR ≤0.05) differentially expressed in intact vs damaged cartilage. In total, 1834 lincRNAs were expressed in both hip and knee cartilage, with a highly significant correlation in expression between the two cartilages., Conclusion: This is the first study to use RNA-seq to map and compare the lincRNA transcriptomes of hip and knee cartilage. We propose that lincRNAs expressed selectively in cartilage, or showing differential expression in OA, will play a role in cartilage homoeostasis., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine factors associated with orthopaedic surgeons' decision to recommend total joint replacement (TJR) in people with knee and hip osteoarthritis (OA)., Design: Cross-sectional study in eleven countries. For consecutive outpatients with definite hip or knee OA consulting an orthopaedic surgeon, the surgeon's indication of TJR was collected, as well as patients' characteristics including comorbidities and social situation, OA symptom duration, pain, stiffness and function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), joint-specific quality of life, Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) radiographic grade (0-4), and surgeons' characteristics. Univariable and multivariable logistic regressions were performed to identify factors associated with the indication of TJR, adjusted by country., Results: In total, 1905 patients were included: mean age was 66.5 (standard deviation [SD], 10.8) years, 1082 (58.0%) were women, mean OA symptom duration was 5.0 (SD 7.0) years. TJR was recommended in 561/1127 (49.8%) knee OA and 542/778 (69.7%) hip OA patients. In multivariable analysis on 516 patients with complete data, the variables associated with TJR indication were radiographic grade (Odds Ratio, OR for one grade increase, for knee and hip OA, respectively: 2.90, 95% confidence interval [1.69-4.97] and 3.30 [2.17-5.03]) and WOMAC total score (OR for 10 points increase: 1.65 [1.32-2.06] and 1.38 [1.15-1.66], respectively). After excluding radiographic grade from the analyses, on 1265 patients, greater WOMAC total score was the main predictor for knee and hip OA; older age was also significant for knee OA., Conclusion: Radiographic severity and patient-reported pain and function play a major role in surgeons' recommendation for TJR., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine the change in walking gait biomechanics after total hip arthroplasty (THA) for osteoarthritis (OA) compared to the pre-operative gait status, and to compare the recovery of gait following THA with healthy individuals., Methods: Systematic review with meta-analysis of studies investigating changes in gait biomechanics after THA compared to (1) preoperative levels and (2) healthy individuals. Data were pooled at commonly reported time points and standardised mean differences (SMDs) were calculated in meta-analyses for spatiotemporal, kinematic and kinetic parameters., Results: Seventy-four studies with a total of 2,477 patients were included. At 6 weeks postoperative, increases were evident for walking speed (SMD: 0.32, 95% confidence intervals (CI) 0.14, 0.50), stride length (SMD: 0.40, 95% CI 0.19, 0.61), step length (SMD: 0.41, 95% CI 0.23, 0.59), and transverse plane hip range of motion (ROM) (SMD: 0.36, 95% CI 0.05, 0.67) compared to pre-operative gait. Sagittal, coronal and transverse hip ROM was significantly increased at 3 months (SMDs: 0.50 to 1.07). At 12 months postoperative, patients demonstrated deficits compared with healthy individuals for walking speed (SMD: -0.59, 95% CI -1.08 to -0.11), stride length (SMD: -1.27, 95% CI -1.63, -0.91), single limb support time (SMD: -0.82, 95% CI -1.23, -0.41) and sagittal plane hip ROM (SMD: -1.16, 95% CI -1.83, -0.49). Risk of bias scores ranged from seven to 24 out of 26., Conclusions: Following THA for OA, early improvements were demonstrated for spatiotemporal and kinematic gait patterns compared to the pre-operative levels. Deficits were still observed in THA patients compared to healthy individuals at 12 months., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To examine the association between ambulatory activity (AA), body composition measures and hip or knee joint replacement (JR) due to osteoarthritis., Design: At baseline, 1082 community-dwelling older-adults aged 50-80 years were studied. AA was measured objectively using pedometer and body composition by dual-energy X-ray absorptiometry. The incidence of primary (first-time) JR was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). Log binomial regression with generalized estimating equations were used to estimate the risk of JR associated with baseline AA and body composition measures, adjusting for age, sex, X-ray disease severity, and pain., Results: Over 13 years of follow-up, 74 (6.8%) participants had a knee replacement (KR) and 50 (4.7%) a hip replacement (HR). AA was associated with a higher risk of KR (RR 1.09/1000 steps/day, 95% CI 1.01, 1.16) and a lower risk of HR (RR 0.90/1000 steps/day, 95% CI 0.81, 0.99). Body mass index (BMI) (RR 1.07/kg/m 2 , 95% CI 1.03, 1.12), total fat mass (RR 1.03/kg, 95% CI 1.01, 1.06), trunk fat mass (RR 1.05/kg, 95% CI 1.00, 1.09), and waist circumference (RR 1.02/cm, 95% CI 1.00, 1.04) were associated with a higher risk of KR. Body composition measures were not associated with HR., Conclusions: An objective measure of AA was associated with a small increased risk of KR and a small reduced risk of HR. Worse body composition profiles were associated with KR, but not HR. Altogether this may suggest different causal pathways for each site with regard to habitual activity and obesity., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors., Design: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786)., Results: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort., Conclusions: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Slipped capital femoral epiphysis (SCFE) in adolescence is associated with increased risk of future osteoarthritis (OA). The purpose of this study was to study clinical and radiographic risk factors for early cartilage degeneration after SCFE., Design: 22 patients (44 hips) (mean age 24 years, range 18-27) treated with in situ fixation (The Hansson hook-pin) for stable SCFE on average 11 years previously were investigated. Cartilage status was assessed with delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC). The alpha angle, reflecting femoroacetabular impingement (FAI), and the original slip angle were measured. Clinical outcome was assessed with the Copenhagen hip and groin outcome score (HAGOS) and clinical examination., Results: The dGEMRIC index was lower in SCFE hips than unaffected hips 456 ms (CI 419-493) vs 521 ms (CI 476-567) (P = 0.03). The difference was larger (mean 21 ms) in anterior than posterior regions of the hip (P = 0.038). The alpha angle was higher in SCFE hips, 61.5° (CI 53.9-69.1) vs 45.6° (CI 43.6-47.6), (P < 0.001). The alpha angle, but not the original slip angle, correlated negatively with the dGEMRIC index (R = -0.40, P = 0.046). There was a positive correlation between HAGOS and the dGEMRIC-index (R = 0.41, P = 0.012)., Conclusions: Early cartilage degeneration after SCFE seems related to persisting FAI in adulthood, rather than the initial slip severity. The correlation between dGEMRIC and HAGOS indicates a clinical relevance of the MRI findings. Our results suggest that FAI after SCFE should be evaluated already after physeal closure in order to predict and possibly prevent future OA development., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: First, to study how markers of matrix metabolism, inflammation markers, and adipokines relate to (superior) cam deformity and (possible) cam impingement of the hip. Second, to investigate whether they can identify subjects with cam deformity that are at risk of future hip osteoarthritis (OA)., Method: In a cohort of 1002 subjects (CHECK), (superior) cam deformity was defined by an alpha angle >60° on anteroposterior pelvic radiographs and (possible) cam impingement by a cam deformity together with internal hip rotation ≤20°. Hip OA at 5-year follow-up was defined by Kellgren and Lawrence grade ≥2 or total hip replacement., Results: Subjects with (superior) cam deformity and (possible) cam impingement showed lower levels of bone turnover markers (uCTX-I, uNTX-I, sPINP, sOC) than those without. Cam deformity was positively associated with future hip OA, but associations were weaker at high levels of bone turnover. sCOMP and sHA levels were higher in subjects with cam deformity, while other cartilage and synovium markers were not. Some markers of inflammation (pLeptin, pAdiponectin, and erythrocyte sedimentation rate) were lower in presence of cam deformity and cam impingement, but high-sensitivity C-reactive protein was not. Most associations depended largely on gender differences., Conclusion: Bone metabolism may be relevant in the pathogenesis of (superior) cam deformity and in the development of (superior) cam deformity into hip OA. Subjects with cam deformity and cam impingement surprisingly showed lower levels of inflammation markers and adipokines. Associations of cartilage turnover markers with cam deformity and cam impingement were less obvious., (Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Imaging of hip in osteoarthritis (OA) has seen considerable progress in the past decade, with the introduction of new techniques that may be more sensitive to structural disease changes. The purpose of this expert opinion, consensus driven recommendation is to provide detail on how to apply hip imaging in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, artifacts associated with various MRI sequences); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, and validity); recommendations for trials; and research recommendations., (Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objectives: To assess associations between uCTX-II or uCIIM and severity of hip pain in patients with mild-moderate hip osteoarthritis (OA) over a 2-year period, and establish whether the level of these biomarkers at baseline could estimate a specific trajectory of hip pain., Design: A cohort study with a 2-year follow-up and 6-monthly measurements of urinary biomarkers (uCTX-II and uCIIM) and symptom severity. Patients were recruited from general practices. The primary outcome was hip pain, measured with the Western Ontario and McMasters University Osteoarthritis Index (WOMAC) subscale and the Visual Analog Scale (VAS). Associations between hip pain and biomarkers were assessed using linear mixed-model analysis for repeated measurements. Five previously identified pain trajectories were used as outcome to investigate whether the level of biomarkers at baseline could estimate membership in one of the trajectories using multinomial regression analysis., Results: LoguCTX-II and loguCIIM were not associated with WOMAC pain or VAS pain during the 2-year follow-up. Patients in the highly progressive pain trajectory and the moderate pain trajectory were more likely to have a higher loguCTX-II at baseline (OR 6.7; 95% CI 1.6-28.2 and OR 4.8; 95% CI 1.0-22.8, respectively) than patients in the mild pain trajectory., Conclusion: This study shows that in patients with mild-moderate hip OA the urinary biochemical markers uCTX-II and uCIIM are not cross-sectionally associated with hip pain during the 2-year follow-up. Because the uCTX-II level estimated a progressive or moderate hip pain trajectory, this correlation needs to be confirmed in additional patients with hip OA., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Hip osteoarthritis (OA) is characterized by cartilage degradation, subchondral bone sclerosis and osteophyte formation. Nowadays, OA is thought to develop via different etiologies that all lead to a similar form of end stage joint degradation. One of these subtypes is related to an abnormal shaped hip joint, like acetabular dysplasia and a cam deformity. These bony abnormalities are highly predictive for development of hip OA, but they are likely to already be present from childhood. This suggests that these deformations induce OA changes in the hip, well before extensive hip degradation becomes present three to four decades later. Accurate detection and successful characterization of these early OA events might lead to better treatment options for hip OA besides nowadays available invasive joint replacement surgery. However, current diagnostic imaging techniques like radiographs or plain magnetic resonance imaging (MRI), are not sensitive enough to detect these subtle early OA changes. Nor are they able to disentangle intertwined and overlapping cascades from different OA subtypes, and neither can they predict OA progression. New and more sensitive imaging techniques might enable us to detect first OA changes on a cellular level, providing us with new opportunities for early intervention. In this respect, shape analysis using radiography, MRI, computed tomography (CT), single photon emission computed tomography (SPECT)/CT, and positron emission tomography (PET) might prove promising techniques and be more suited to detect early pathological changes in the hip joint. A broad application of these techniques might give us more understanding what can be considered physiological adaptation of the hip, or when early OA really starts. With a more clear definition of early OA, more homogenous patient populations can be selected and help with the development of new disease modifying OA interventions., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this review is to describe imaging techniques for evaluation of non-osteochondral structures such as the synovium, menisci in the knee, labrum in the hip, ligaments and muscles and to review the literature from recent clinical and epidemiological studies of OA., Methods: This is a non-systematic narrative review of published literature on imaging of non-osteochondral tissues in OA. PubMed and MEDLINE search for articles published up to 2014, using the keywords osteoarthritis, synovitis, meniscus, labrum, ligaments, plica, muscles, magnetic resonance imaging (MRI), ultrasound, computed tomography (CT), scintigraphy, and positron emission tomography (PET)., Results: Published literature showed imaging of non-osteochondral tissues in OA relies primarily on MRI and ultrasound. The use of semiquantitative and quantitative imaging biomarkers of non-osteochondral tissues in clinical and epidemiological OA studies is reported. We highlight studies that have compared both imaging methodologies directly, and those that have established a relationship between imaging biomarkers and clinical outcomes. We provide recommendations as to which imaging protocols should be used to assess disease-specific changes regarding synovium, meniscus in the knee, labrum in the hip, and ligaments, and highlight potential pitfalls in their usage., Conclusion: MRI and ultrasound are currently the most useful imaging modalities for evaluation of non-osteochondral tissues in OA. MRI evaluation of any tissue needs to be performed using appropriate MR pulse sequences. Ultrasound may be particularly useful for evaluation of small joints of the hand. Nuclear medicine and CT play a limited role in imaging of non-osteochondral tissues in OA., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To calculate inter-observer reliability between four different trained readers and an experienced reader on early radiographic osteoarthritis (OA) features in our early OA cohort hip and cohort knee (CHECK) cohort., Methods: Four readers were trained by a radiologist and experienced reader to score radiographic OA features. After this training they scored the CHECK cohort. Of the 1002 participants, 38 were scored by all readers. Five different angle radiographs (three for the knee, two for the hip) at three different time points were scored and compared. Inter-observer reliability was evaluated between each of the four trained readers and the experienced reader. Separate radiographic OA features and of overall Kellgren & Lawrence (K&L) scores. In addition, reliability of progression of radiographic was determined in K&L scores and joint space narrowing (JSN)., Results: For hip and knee there was substantial inter-observer reliability on overall K&L scores. In the knee, JSN was scored with fair to moderate reliability, osteophytes with moderate to nearly perfect reliability, and other features with fair to substantial reliability. In the hip, reliability ranged from substantial to nearly perfect. Moderate inter-observer reliability was found for progression of OA in both knee and hip, with slightly better reliability for progression based on K&L scores than on separate features., Conclusion: Good inter-observer reliability can be achieved between trained readers and an experienced reader. Although JSN in the knee is scored with lower inter-observer reliability than osteophytes, this does not seem to influence overall K&L scoring. In the hip all features showed good reliability., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Hip arthroplasty and revision surgery is growing exponentially in OECD countries, but rates vary between countries., Methods: We extracted economic data and utilization rates data about hip arthroplasty done in OECD countries between 1990 and 2011. Absolute number of implantations and compound annual growth rates were computed per 100,000 population and for patients aged 65 years old and over and for patients aged 64 years and younger., Results: In the majority of OECD countries, there has been a significant increase in the utilization of total hip arthroplasty in the last 10 years, but rates vary to a great extent: In the United States, Switzerland, and Germany the utilization rate exceeds 200/100,000 population whereas in Spain and Mexico rates are 102 and 8, respectively. There is a strong correlation between gross domestic product (GDP) and health care expenditures per capita with utilization rate. Utilization rates in all age groups have continued to rise up to present day. A seven fold higher growth rate was seen in patients aged 64 years and younger as compared to older patients., Conclusion: We observed a 38-fold variation in the utilization of hip arthroplasty among OECD countries, correlating with GDP and health care expenditures. Over recent years, there has been an increase in the utilization rate in most countries. This was particularly evident in the younger patients. Due to increasing life expectancy and the disproportionally high use of arthroplasty in younger patients we expect an exponential increase of revision rate in the future., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

In 2010, in Osteoarthritis and Cartilage, we published a comprehensive systematic review applying the consensus BIPED criteria (Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic) criteria on serum and urinary biochemical markers for knee and hip osteoarthritis (OA) using publications that were available at that time. It appeared that none of the biochemical markers at that time were sufficiently discriminating to allow diagnosis and prognosis of OA in individual or limited numbers of patients, nor performed so consistently that they could function as primary outcome parameters in clinical trials. Also at present, almost 3 years later, this ultimate goal has not been reached (yet). Frankly, it might be questioned whether we are making the most adequate steps ahead and maybe we have to take a step back to reconsider our approaches. Some reflections are made and discussed: A critical review of molecular metabolism in OA and validation of currently investigated marker molecules in this may be vital and may lead to new and better markers. Creating cohorts in which synovial fluid (SF) is obtained in a systematic way, together with serum and urine, may also bring the field a further step ahead. Thirdly, better understanding of different phenotypes (subtypes) of OA may facilitate identification and validation of biochemical markers. Finally, the systems biology approach as discussed in the last years OA in review on biomarkers, although very complex, might provide steps forward. Looking ahead, we are optimistic but realistic in our expectations, we believe that the field can be brought forward by critically and cautiously reconsidering our approaches, and making changes forward, one step at a time., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the measurement properties of an Internet-based self-administered questionnaire in ascertaining cases of hip and knee osteoarthritis (OA)., Methods: Questionnaire data from 4269 Canadian subjects aged 45-85 were collected on hip and knee joint health including self-reported items on medically-diagnosed hip and knee OA and joint replacement. A sub-cohort of 100 subjects was recruited for clinical examination. The self-reported outcomes were evaluated using the American College of Rheumatology clinical classification criteria for hip and knee OA as the gold standard for clinical verification. Analysis was at the joint level (200 knees, 200 hips). Validity was examined using sensitivity, specificity, and predictive values; to account for correlated joints of the same subject, bootstrapping was performed to yield valid 95% confidence interval (CI's)., Results: Self-reported measures for a medical diagnosis of knee OA had a positive predictive value of 86%, negative predictive value 91%, sensitivity 73% and specificity 96% for correctly identifying clinical knee OA. For hip OA, the values were 61%, 98%, 81% and 94% respectively., Conclusion: Internet self-report of medically-diagnosed hip and knee OA in metro Vancouver residents correctly identified most cases and non-cases of clinical OA when compared with the ACR clinical classification criteria gold standard. In particular, specificity was very high, important in risk factor studies due to the profound effect of even small losses in specificity on the measure of association. The findings provide evidence that these questionnaire case definitions have utility for identifying hip and knee OA in community and population-based studies when the purpose is to link potential risk factors with knee and hip health., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate cross-sectional and predictive associations of plasma adipokines with biochemical markers of systemic joint metabolism and radiographic signs of early-stage knee osteoarthritis (OA)., Design: The adipokines pLeptin, pAdiponectin, and pResistin, the cartilage markers C-terminal telopeptide of type II collagen (uCTX-II), N-terminal propeptide of type IIA procollagen (sPIIANP), chondroitin sulfate 846 (sCS846), and cartilage oligomeric matrix protein (sCOMP), and the synovial markers hyaluronic acid (sHA) and N-terminal propeptide of type III procollagen (sPIIINP) were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of Cohort Hip and Cohort Knee (CHECK), a cohort of 1002 subjects with early-stage symptomatic knee and/or hip OA. Knee radiographs were obtained at baseline and after 2 and 5 years and scored according to Kellgren & Lawrence., Results: pLeptin showed positive associations with uCTX-II, sCOMP, sPIIANP, sHA, and sPIIINP, and with presence and progression of radiographic knee OA. Associations expectedly disappeared after adjustment for body mass index. pResistin showed positive associations with sPIIINP and present and incident radiographic knee OA that were largely independent of BMI. pAdiponectin showed positive associations with uCTX-II and sCOMP. Furthermore, pAdiponectin did not show associations with radiographic knee OA on itself, but associations of pResistin with present radiographic knee OA were stronger in higher pAdiponectin tertiles (P = 0.024 for interaction between pAdiponectin and pResistin). Although statistically significant, all associations were weak., Conclusions: Adipokines may have aggravating, although may be minor, structural effects in early-stage knee OA., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess a wide spectrum of biochemical markers (biomarkers) in a large cohort of individuals with (very) early symptomatic knee and/or hip osteoarthritis (OA). Secondly, to investigate associations between biomarkers and between biomarkers and demographics to demonstrate validity of the obtained dataset and further investigate the involvement and/or role of these biomarkers in OA., Design: Fourteen biomarkers (uCTX-II, uCTX-I, uNTX-I, sCOMP, sPIIANP, sCS846, sC1,2C, sOC, sPINP, sHA, sPIIINP, pLeptin, pAdiponectin, pResistin) were assessed by ELISA or RIA in CHECK (Cohort Hip and Cohort Knee), a 10-year prospective cohort of 1,002 individuals with early symptomatic knee and/or hip OA., Results: Quality controls revealed that gathered data were technically reliable. The majority of biomarkers showed relevant associations with demographic variables, which were expectedly different between genders and/or menopausal status for some. Principal component analysis enabled identification of five clusters, consecutively designated as 'bone-CTX-II', 'inflammation', 'synovium', 'C1,2C-adipokines', and 'cartilage synthesis' cluster. Notably, uCTX-II clustered with biomarkers of bone metabolism, while sCOMP clustered with biomarkers of synovial activity., Conclusions: The identified clusters extended knowledge on individual biomarkers from mostly smaller studies as did the observed associations between biomarker levels and demographics, from which validity of our data was deduced. uCTX-II may not only reflect articular cartilage but also bone metabolism and sCOMP may reflect synovial rather than cartilage metabolism. Major involvement of adipokines in joint metabolism was not identified., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: This study investigates sulphated glycosaminoglycans (sGAG) content changes in early osteoarthritis (OA), and whether contrast-enhanced magnetic resonance imaging (MRI) of cartilage in vitro may identify early event of OA pathology., Method: Osteochondral plugs from patients with hip OA or femoral neck fracture (reference group) were collected and analysed by 1.5 T MRI with ΔR1 as a measure of cartilage contrast concentration. Cartilage hydration, contents of sGAG, cartilage oligomeric matrix protein (COMP), hydroxyproline, denatured collagen, and aggrecan TEGE(392) neoepitope were determined and histological grading was performed., Results: sGAG content correlated to ΔR1, although no difference in either of these parameters was detectable between OA and reference cartilage at 4 h of contrast equilibration. In contrast, biochemical analysis of other cartilage matrix constituents showed distinct alterations typical for early cartilage degradation in OA cartilage and with clear evidence for increased aggrecan turnover., Conclusion: In the present in vitro study, cartilage sGAG content could not distinguish between early OA cartilage and reference cartilage. Given, that delayed gadolinium enhanced MRI of cartilage (dGEMRIC) indicates early events in the pathogenesis of OA in vivo, our results from the in vitro studies imply other, additional factors than cartilage sGAG content, e.g., alterations in diffusion or increased supply of contrast agent in the diseased joint. Alternatively, an altered dGEMRIC reflects later stages of OA, when sGAG content decreases. Further investigations are warranted, to understand variations in sGAG content in pathology, an essential background for interpreting dGEMRIC measurements., (Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To develop a semiquantitative MRI-based scoring system (HOAMS) of hip osteoarthritis (OA) and test its reliability and validity., Design: Fifty-two patients with chronic hip pain were included. 1.5T magnetic resonance imaging (MRI) was performed on all patients. Pelvic radiographs were scored according to the Kellgren-Lawrence (KL) system. Clinical outcomes were assessed by the hip osteoarthritis outcome score (HOOS). MRIs were analyzed using a novel whole-joint MRI score that incorporated 13 articular features. Reliability was determined on a random subset of 15 cases. Weighted-kappa statistics and overall agreement were used as a measure of intra- and inter-observer reliability. Associations between MRI features and radiographic OA severity were calculated using Cochran-Armitage test for trend. Ordinal logistic regression was used to assess associations between MRI features and severity of pain and functional limitation., Results: Distribution of radiographic grading was: KL 0=12 (27%), KL 1=11 (25%), KL 2=14 (32%), KL 3=5 (11%) and KL 4=2 (5%). Intra-reader reliability for the different features ranged from 0.18 (cysts) to 0.85 (cartilage). Inter-reader reliability ranged between 0.15 (cysts) and 0.85 (BMLs). Low kappas were due to low frequencies of some features as overall percent agreement was good to excellent (83.8% and 83.1%). There was a strong association between MRI-detected lesions and radiographic severity (P=0.002). Non-significant trends were observed between MRI features and clinical outcomes., Conclusion: MRI-based semiquantitative assessment of the hip shows adequate reliability. Presence of more severe MRI-detected intraarticular pathology shows a strong association with radiographic OA. The results suggest possible associations between MRI-detected pathology and clinical symptoms., (Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: Despite a growing body of Magnetic Resonance Imaging (MRI) literature in osteoarthritis (OA), there is little uniformity in its diagnostic application. We envisage in the first instance the definition requiring further validation and testing in the research setting before considering implementation/feasibility testing in the clinical setting. The objective of our research was to develop an MRI definition of structural OA., Methods: We undertook a multistage process consisting of a number of different steps. The intent was to develop testable definitions of OA (knee, hip and/or hand) on MRI. This was an evidence driven approach with results of a systematic review provided to the group prior to a Delphi exercise. Each participant of the steering group was allowed to submit independently up to five propositions related to key aspects in MRI diagnosis of knee OA. The steering group then participated in a Delphi exercise to reach consensus on which propositions we would recommend for a definition of structural OA on MRI. For each round of voting, ≥60% votes led to include and ≤20% votes led to exclude a proposition. After developing the proposition one of the definitions developed was tested for its validity against radiographic OA in an extant database., Results: For the systematic review we identified 25 studies which met all of our inclusion criteria and contained relevant diagnostic measure and performance data. At the completion of the Delphi voting exercise 11 propositions were accepted for definition of structural OA on MRI. We assessed the diagnostic performance of the tibiofemoral MRI definition against a radiographic reference standard. The diagnostic performance for individual features was: osteophyte C statistic=0.61, for cartilage loss C statistic=0.73, for bone marrow lesions C statistic=0.72 and for meniscus tear in any region C statistic=0.78. The overall composite model for these four features was a C statistic=0.59. We detected good specificity (1) but less optimal sensitivity (0.46) likely due to detection of disease earlier on MRI., Conclusion: We have developed MRI definition of knee OA that requires further formal testing with regards their diagnostic performance (especially in datasets of persons with early disease), before they are more widely used. Our current analysis suggests that further testing should focus on comparisons other than the radiograph, that may capture later stage disease and thus nullify the potential for detecting early disease that MRI may afford. The propositions are not to detract from, nor to discourage the use of traditional means of diagnosing OA., (Copyright © 2011 Osteoarthritis Research Society International. All rights reserved.)

Objective: There is ongoing debate on whether an association between radiographic and clinical osteoarthritis (OA) exists. We hypothesized that the inconsistency in the detection of an association might be caused by different definitions of OA, by different radiographic protocols, and by scoring methods for radiographic damage and symptoms. The goal of this study was to evaluate which methodological criteria are important to detect an association between radiographic and clinical OA of hip and knee., Methods: A literature search was performed with the keywords 'OA', 'hip', 'knee', 'radiographic', and 'clinical' and results were screened for relevant studies. Quality criteria for study characteristics and methodology were developed. Studies were classified according to these criteria and the presence of an association between radiographic and clinical OA was scored. The importance of methodological quality and patient characteristics on the presence of an association was evaluated., Results: The literature search resulted in 39 studies describing an association between radiographic and clinical OA. The frequency of an association between radiographic and clinical OA outcome measures diminished when less quality criteria were fulfilled. Specifically the criterion for standardized outcome measures appeared important in the detection of an association. The association was not influenced by patient characteristics. Only four studies were identified that fulfilled all quality criteria and in these studies an association was found for the knee joint and an inconsistent association was found for the hip joint., Conclusion: Methodological quality criteria are of importance to reveal an association between radiographic and clinical OA., (Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Context: Molecules that are released into biological fluids during matrix metabolism of articular cartilage, subchondral bone, and synovial tissue could serve as biochemical markers of the process of osteoarthritis (OA). Unfortunately, actual breakthroughs in the biochemical OA marker field are limited so far., Objective: By reviewing the status of commercially available biochemical OA markers according to the "Burden of disease, Investigative, Prognostic, Efficacy of intervention, and Diagnostic" ("BIPED") classification, future use of this "BIPED" classification is encouraged and more efficient biochemical OA marker research stimulated., Data Sources: Three electronic databases [PubMed, Scopus, EMBASE (1997-May 2009)] were searched for publications on blood and urinary biochemical markers in human primary knee and hip-OA., Study Selection: Stepwise selection of original English publications describing human studies on blood or urinary biochemical markers in primary knee or hip-OA was performed. Selected articles were fully read to determine whether biochemical markers were investigated on performance within any of the "BIPED" categories. Eighty-four relevant publications were identified., Data Extraction: Data from relevant publications were tabulated according to the "BIPED" classification. Individual analyses within a publication were summarized in general "BIPED" scores., Data Synthesis: An uneven distribution of scores on biochemical marker performance and heterogeneity among the publications complicated direct comparison of individual biochemical markers. Comparison of categories of biochemical markers was therefore performed instead. In general, biochemical markers of cartilage degradation were investigated most extensively and performed well in comparison with other categories of biochemical markers. Biochemical markers of bone metabolism performed less adequately. Biochemical markers of synovial tissue metabolism were not investigated extensively, but performed quite well., Conclusions: Specific biochemical markers and categories of biochemical markers as well as their nature, origin and metabolism, need further investigation. International standardization of future investigations should be pursued to obtain more high-quality, homogenous data on the full spectrum of biochemical OA markers., (Copyright 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Aim: To conduct a multi-language translation and cross-cultural adaptation of the Intermittent and Constant OsteoArthritis Pain (ICOAP) questionnaire for hip and knee osteoarthritis (OA)., Methods: The questionnaires were translated and cross-culturally adapted in parallel, using a common protocol, into the following languages: Czech, Dutch, French (France), German, Italian, Norwegian, Spanish (Castillan), North and Central American Spanish, Swedish. The process was conducted following five steps: (1)--independent translation into the target language by two or three persons; (2)--consensus meeting to obtain a single preliminary translated version; (3)--backward translation by an independent bilingual native English speaker, blinded to the English original version; (4)--final version produced by a multidisciplinary consensus committee; (5)--pre-testing of the final version with 10-20 target-language-native hip and knee OA patients., Results: The process could be followed and completed in all countries. Only slight differences were identified in the structure of the sentences between the original and the translated versions. A large majority of the patients felt that the questionnaire was easy to understand and complete. Only a few minor criticisms were expressed. Moreover, a majority of patients found the concepts of constant pain and pain that comes and goes to be of a great pertinence and were very happy with the distinction., Conclusion: The ICOAP questionnaire is now available for multi-center international studies.

Objective: To determine the association between changes in serum levels of cartilage oligomeric matrix protein (COMP) and serum N-telopeptide crosslinks (NTX) over a 6-year interval with the development and progression of radiographically apparent hip osteoarthritis (RHOA) in a community sample of elderly women over 8.3 years of follow-up., Methods: Pelvic radiographs were obtained a mean of 8.3 years apart in Caucasian women > or =65 years of age enrolled in the Study of Osteoporotic Fractures. From a cohort of 5928 subjects, we randomly sampled study subjects ( approximately 170 per group) to perform two nested case-control studies, one of RHOA incidence and the other of RHOA progression. Baseline and year 6 serum COMP and serum NTX levels were measured by enzyme linked immunosorbent assay in duplicate and percentage change in serum levels was calculated. Odds ratios (ORs) and 95% confidence intervals (CIs) for 1 standard deviation (SD) change in the serum COMP and NTX level differences were calculated using logistic regression analysis and used to predict the development or progression of RHOA, adjusting for potential covariates., Results: The percentage change in the level of serum COMP from baseline to year 6 was found to be a risk factor for the development of incident RHOA [adjusted OR of 1.58 per 1 SD increase (95% CI: 1.19-2.09)], and reduction of progression of RHOA [adjusted OR of 0.74 per 1 SD increase (95% CI: 0.58-0.96)]. Quartile analysis of serum COMP changes revealed that the three highest quartiles of change in serum COMP were associated with (1) a five-fold greater risk of developing incident RHOA [adjusted OR=5.42 (95% CI: 2.80-10.60)], and (2) a 50% decreased risk of developing progression of RHOA [adjusted OR=0.48 (95% CI: 0.30-0.80)]. No significant association was found between changes in serum NTX levels from baseline to year 6 with either incident RHOA or the progression of existing RHOA., Conclusion: Measurement of serum COMP at two distinct timepoints may be a method of identifying patients at risk for developing incident RHOA and those with baseline RHOA that will not rapidly progress.

Objective: Early detection of cartilage disorder in dysplastic hips is important in predicting subsequent progression of osteoarthritis and determining the appropriate timing of osteotomy surgery. We assessed the feasibility of T2 assessment using magnetic resonance (MR) imaging at 3T for evaluating early changes in the acetabular and femoral cartilages for patients with hip dysplasia., Methods: Sagittal T2 maps of the hip were obtained using 3T MR imaging in 10 normal volunteers (14 hips) and in 23 patients (26 hips) with hip dysplasia at pre-arthritic stage (without osteoarthritis) or early-arthritic stage (with osteoarthritis at the Kellgren-Lawrence system of grade 1 or 2). T2 values and the visual appearance of T2 mapping, including gradient T2, low T2, and high T2 patterns, were compared at the superior zones of the acetabular and femoral cartilages among the normal, pre-arthritic, and early-arthritic groups., Results: There were no significant differences in T2 values for both cartilages among the three groups. Regarding the visual appearance of T2 mapping for the acetabular cartilage, all hips in the normal group showed a gradient T2 pattern, while the pre-arthritic groups included six hips (43%) with a low T2 pattern, and the early-arthritic group showed either a low T2 pattern (33%) or a high T2 pattern (67%). The frequency of the gradient T2 pattern was significantly lower for dysplastic hips than for normal hips, in the acetabular and femoral cartilages (P<0.05)., Conclusions: This preliminary study demonstrated the clinical feasibility of T2 assessment of hip cartilage using 3T MR imaging. T2 mapping classification may enable the early detection of osteoarthritic degeneration and the detection of developmental disorders of cartilage matrix in patients with hip dysplasia.

Objective: The purpose of this study was to develop a precise and efficient method for estimating the thickness of the articular cartilage in the hip joint and hence three different stereologic methods were tested based on Magnetic Resonance Imaging., Design: Twenty two females and four males with hip dysplasia underwent MRI. The thickness of the femoral and acetabular cartilage was estimated., Results: The results for all three methods showed that the observed total variance on cartilage thickness is small. The mean thickness of the acetabular cartilage measured by the three different methods ranged between 1.15 mm and 1.46 mm. The mean thickness for the femoral cartilage measured by the three different methods ranged between 1.18 mm and 1.78 mm. The measurements took 15-20 min per hip to carry out., Conclusion: Methods 1 and 3 are as precise but we favour method 3 because the measurements are done on images obtained through the center of the femoral head which means that the cartilage surface is intersected perpendicular and partial volume effect avoided. We suggest that this method can be advantageous for assessing the progression of osteoarthritis in dysplastic hips after periacetabular osteotomy.

Objective: The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is applied extensively to patients with osteoarthritis of the hip or knee. Previous work has challenged the validity of its physical function scale however an extensive evaluation of its pain scale has not been reported. Our purpose was to estimate internal consistency, factorial validity, test-retest reliability, and the standard error of measurement (SEM) of the WOMAC LK 3.1 pain scale., Method: Four hundred and seventy-four patients with osteoarthritis of the hip or knee awaiting arthroplasty were administered the WOMAC. Estimates of internal consistency (coefficient alpha), factorial validity (confirmatory factor analysis), and the SEM based on internal consistency (SEM(IC)) were obtained. Test-retest reliability [Type 2,1 intraclass correlation coefficients (ICC)] and a corresponding SEM(TRT) were estimated on a subsample of 36 patients., Results: Our estimates were: internal consistency alpha=0.84; SEM(IC)=1.48; Type 2,1 ICC=0.77; SEM(TRT)=1.69. Confirmatory factor analysis failed to support a single factor structure of the pain scale with uncorrelated error terms. Two comparable models provided excellent fit: (1) a model with correlated error terms between the walking and stairs items, and between night and sit items (chi2=0.18, P=0.98); (2) a two factor model with walking and stairs items loading on one factor, night and sit items loading on a second factor, and the standing item loading on both factors (chi2=0.18, P=0.98)., Conclusion: Our examination of the factorial structure of the WOMAC pain scale failed to support a single factor and internal consistency analysis yielded a coefficient less than optimal for individual patient use. An alternate strategy to summing the five-item responses when considering individual patient application would be to interpret item responses separately or to sum only those items which display homogeneity.

Introduction: The Hip disability and Osteoarthritis Outcome Score (HOOS) was constructed in Sweden; this questionnaire has proved to be valid for persons with hip disability with or without hip osteoarthritis (OA) and with high demands of physical function., Objective: The objective of this study was to evaluate the internal consistency, reliability, construct validity, and floor and ceiling effects of the Dutch version of the HOOS questionnaire., Patients and Methods: After translation with a forward/backward protocol, 74 hip arthroplasty patients and 88 hip OA patients filled in the Dutch HOOS, as well as a Short Form-36 (SF-36), an Oxford Hip Score (OHS) and a VAS-pain questionnaire., Results: The Dutch version of the HOOS questionnaire achieved excellent scores in all of the clinimetric properties., Conclusion: The Dutch HOOS questionnaire has a good internal consistency and reliability. Moreover, the construct validity is good and no floor and ceiling effects were found. The HOOS is a good instrument for patients with different stadia of hip OA.

Objective: To assess the measurement properties of the Lequesne index of severity for osteoarthritis of the hip (LISOH) together with its overall usefulness with reference to the original stated aims., Method: Postal questionnaire was sent to a random sample of 5500 Oxfordshire residents, aged 65 and above. Respondents with hip symptoms at baseline (but without verification of a diagnosis) were sent an identical follow-up questionnaire 12 months later. The questionnaire included a general health section, including the Short Form-36 survey, and a hip section which began with a screening question about hip pain. Respondents who reported having a prolonged episode of hip pain were asked to complete the LISOH., Results: At baseline, response rate of 66.3% (3341/5039) was obtained from eligible participants; 19.2% (610/3175) of respondents reported having hip pain. Internal reliability (Cronbach's alpha) was 0.84 (95% CI: 0.81-0.86) for all 11 items of the LISOH; however, factor analysis identified two factors (sub-scales): "function and mobility" and "pain and discomfort". Rasch analysis revealed that the two factors were only unidimensional when applied to sub-groups of respondents. Convergent validity of the LISOH was questionable, as the "function and mobility" factor was more highly correlated with SF-36 bodily pain score than was the "pain and discomfort" factor. The assessment of sensitivity over time was problematic due to changing patterns of symptomatic weight-bearing joints over time., Conclusions: The current study identifies major limitations with the LISOH--particularly if used as a single composite measure.

Objective: To use the surgical samples of patients with femoro-acetabular impingement due to a nonspherical head to analyze tissue morphology and early cartilage changes in a mechanical model of hip osteoarthritis (OA)., Design: An aberrant nonspherical shape of the femoral head has been assumed to cause an abutment conflict (impingement mechanism) of the hip with subsequent cartilage lesions of the acetabular rim and surface alterations of the nonspherical portion of the head. In this study, 22 samples of the nonspherical portions of the head have been obtained during hip surgery from young adults (mean 30.4 years, range 19-45 years) with an impingement conflict. The samples were first compared with tissue from the same area obtained from six age-matched deceased persons (control group) with normal hip morphology and second with cartilage from 14 older patients with advanced OA. All samples were characterized histologically and hyaline cartilage was graded according to the Mankin criteria. They were further subjected to examination on a molecular basis by immunohistology for cartilage oligomeric matrix protein (COMP), tenascin-C and a collagenase cleavage product (COL2-3/4C(long)) and by in situ hybridization for collagen type I and collagen type II., Results: All samples from the patient group revealed hyaline cartilage with degenerative signs. According to the Mankin criteria, the cartilage alterations were significantly different when compared with the control group (p=0.007) but were less distinct when compared with cartilage from patients with advanced OA (p=0.014). Positive staining and distribution pattern for COMP, tenascin-C and COL2-3/4C(long) showed similarities between the samples from the impingement group and osteoarthritic cartilage but they were distinctly different when compared with healthy cartilage. Levels of collagen I and II transcripts were upregulated in 6 and 10, respectively, of the 14 samples with OA and in 9 and 12, respectively, of the 22 samples from the impingement group. None of the samples from the control group showed upregulation of Collagen I and II mRNA., Conclusions: The aberrant nonspherical portion of the femoral head in young patients with an impingement conflict consists of hyaline cartilage which shows clear degenerative signs similar to the findings in osteoarthritic cartilage. The tissue alterations are distinctly different when compared with a control group, which substantiates an impingement conflict as an early mechanism for degeneration at the hip joint periphery.

Objectives: The objective of this study was to link the Western Ontario and McMaster Universities (WOMAC) and Lequesne-Algofunctional indices to the ICF on the basis of linking rules developed specifically to accomplish this aim. The linking process enables the understanding of the relationship between health-status measures and the ICF., Methods: Since the fifth World Health Organisation/International Liege Against Rheumatism (WHO/ILAR) Task Force and the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group recommend the use of WOMAC and the Lequesne-Algofunctional indices in patients with osteoarthritis of the hip and knee in clinical trials, these two health-status measures have been used in this study. Both health-status measures were linked to the ICF separately by two trained health professionals. Consensus between health professionals was used to decide which ICF category should be linked to each item/concept of the two questionnaires. To resolve disagreements between the two health professionals, a third person trained in the linking rules was consulted., Results: Except for the concept of 'morning stiffness', both health professionals agreed on the ICF category chosen to link all the items/concepts of both questionnaires. Altogether, 29 different ICF categories have been linked. Five ICF categories belong to the ICF component 'body functions', 23 categories to the component 'activities and participation', and one category to 'environmental factors'. Both questionnaires have 10 ICF categories in common., Conclusions: The results of the linking process reflect both the structure of the two questionnaires studied and the relationship between them, showing that the ICF classification can become the cardinal reference for existing health-status measures.

Objective: To assess the reliability and validity of the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) as an outcome measure in Asian patients with knee or hip osteoarthritis (OA) in Singapore., Design: The WOMAC was administered twice 7 days apart to 66 consecutive English-speaking Chinese, Malay or Indian inpatients and outpatients with knee or hip OA seen at a tertiary referral centre through a structured interview, which also assessed demographic and other characteristics. Internal consistency was assessed using Cronbach's alpha, reliability using Spearman's correlations, intraclass correlations and repeatability coefficients, and relationships between WOMAC domains and known determinants of function using Spearman's correlations and the Mann-Whitney U-test., Results: The WOMAC showed good internal consistency (alpha=0.70 to 0.93) and good reliability, with intraclass correlations of 0.83 to 0.90 and mean test-retest score differences of 0.02 to 0.13 points (possible range 4 points). Results of Likert scoring assessment supported the validity of the WOMAC when interpreted in the context of the close association between pain and physical function. Eight of nine a priori hypotheses relating WOMAC Pain and Physical Function scores to known determinants of function were present, supporting construct validity of this scale., Conclusion: The WOMAC is a valid and reliable outcome measure in Asian patients with OA in Singapore.

Objective: To determine the predictive value of serum levels of TIMP-1 and hyaluronic acid in a 1 year prospective study in hip osteoarthritis (OA)., Methods: Twenty-nine patients with OA of the hip were enrolled in a 1-year prospective study (median follow-up, 13 months). Biochemical analysis was used to assess TIMP-1 and hyaluronic acid at entry and at the end of the study. Radiographic evaluation with an assisted computed program was performed to calculate progression of joint space narrowing. Statistical tests served to determine correlations between observed serum levels and radiograph joint space narrowing., Results: Among the 29 patients, 10 showed joint space narrowing greater than 0.6 mm per year. The initial concentration of TIMP-1 as well as delta value of variation in serum levels of TIMP-1 (difference between TIMP-1 concentration at entry and at the end) correlated with the progression of joint space narrowing. A cut-off value of 600 ng/ml of TIMP-1 allowed the patients who progressed slowly from those who progressed more rapidly. Hyaluronic acid serum level was not predictive of evolution., Conclusion: TIMP-1 serum level may serve to predict the evolution of patients with hip OA., (Copyright 2001 OsteoArthritis Research Society International.)

Objective: A new micro-histological method of assessing the sulfated glycosaminoglycan (S-GAG) content in unstained histological sections of articular cartilage was developed and used to study the effects of orally administered Diacerhein (DIA) on joint cartilage in an ovine model of osteoarthritis (OA)., Methods: Twenty adult, age-matched Merino wethers were subjected to bilateral lateral meniscectomy, while 10 served as non-operated controls (NOC groups). Half of the operated sheep (N=10) remained untreated (MEN groups), while the other 10 animals were given DIA (25 mg/kg orally) daily for 3 months, then 50 mg/kg daily for a further 6 months (DIA groups). Five animals each of the DIA, MEN and NOC groups, respectively, were sacrificed at 3 months post-operatively, and the remainder 6 months later. For the present study only one knee joint of each animal was used for histological processing. The tissues studied were from the lateral femoral condyles (LFC) and lateral tibial plateaux (LTP). Each of these joint regions was further subdivided into inner (I), middle (M), and outer (O) zones. Unstained histological sections from these AC regions and zones were then analysed for S-GAG content using the following procedure. Images of each section of 6 microm thickness were acquired using a flatbed scanner and the area determined with an image analysis software program. The sections were then transferred to wells of a microtiter plate, digested with papain and the S-GAG content quantitated using a modification of the 1,9-dimethylmethylene blue dye binding assay. The data was represented as microg S-GAG/mm(3)of each tissue section. These data were also compared with toluidine blue stained sections from the same paraffin blocks., Results: The results obtained showed that the area of histological sections could be very accurately determined by computer assisted image analysis using a 10 mmx10 mm calibration grid. Cartilage sections of areas ranging from 1 mm(2)up to 25 mm(2)were analysed for S-GAG content with this simple technique. There was a linear relationship between section thickness (2-10 microm) and S-GAG content per unit area (R(2)=0.993). Sections of 6 microm thickness were found to be optimal. S-GAG analyses of serial sections from tibial and femoral articular cartilage (I, M and O zones) revealed an average coefficient of variation of 7.0+/-2.3% (range 4.9-10.2%) confirming the accuracy and reproducibility of this assay method. A separate experiment showed that no significant losses of S-GAG occurred during the histological sample processing. The different regions and zones of the knee joint AC in the six experimental groups revealed variable levels of S-GAG which did not necessarily correlate with the histochemical distribution of toluidine blue staining. The major S-GAG changes occurred in the middle (lesion zone) and outer zones (hypertrophic zone) of both the LFC and LTP of the MEN groups. In the lesion (M) zone the S-GAG content was reduced while in the O zone levels were increased at both 3 and 6 months post-surgery. In animals receiving Diacerhein S-GAG levels in the M zone were lower than or equivalent to those of non-drug treated OA or non-operated controls for both joint regions at 3 and 6 months. While the hypertrophic response in the outer zone of the LFC, as assessed by S-GAG content, was enhanced by drug treatment, the cartilage of the outer zones of the LTP was not affected by drug treatment., Conclusion: The results of this study have demonstrated that the S-GAG (and therefore proteoglycan [PG]) content in different cartilage zones of OA joints can be readily quantitated by direct biochemical analysis of unstained histological sections. By this means subtle changes in PG distribution in different cartilage zones, which were not evident using traditional histochemical staining methods, could be readily detected.

Objective: To investigate whether any of 14 serum and urine molecular markers (MMs) used to monitor osteoarthritis (OA) would be associated with particular clinical end-points., Design: Thirty-nine OA patients were bled and urine collected at five time points: at baseline visit and at visits 1, 3, 6 and 12 months later. Twelve clinical measurements were made and the concentrations of each of 14 MMs were determined. Principal component analysis, stepwise linear regression with backward elimination, and logistic regression were used to determine the correlations between MMs and clinical measures., Results: Principal component analysis was used to reduce the 12 clinical measurements into three independent clinical clusters: baseline clinical assessments, changes in clinical assessments and signal joint measurements. The 14 MMs were similarly reduced to five MM clusters. Each of the three clinical clusters was correlated with a single but different MM cluster. Baseline clinical assessments were correlated with bone markers typified by hydroxylysyl pyridinoline (HP) crosslinks, swelling of the signal joint was correlated with inflammation markers, especially CRP, and the change in clinical assessments over the 1 year evaluation was correlated with TGFbeta1. There was no correlation between any of the skeletal markers and the clinical measures, a situation which draws attention to the need for a direct assessment of cartilage damage in OA to validate the use of cartilage markers., Conclusions: This study demonstrates statistical methodology for analysis of clinical trials using multiple MMs and clinical end-points. The patient numbers are sufficient to test hypotheses of relationships of single MMs such as CRP, TGFbeta1 and HP to clinical measures, but larger clinical trials are needed to validate hypotheses., (Copyright 2001 OsteoArthritis Research Society International.)

Objective: To investigate the relationships between serum and urinary molecular markers (MM) used to monitor osteoarthritis., Design: Forty osteoarthritis patients had blood and urine collected at baseline and 1, 3, 6 and 12 months later. Specimens from 20 controls were obtained twice at a one month interval. The concentration of 14 different markers was determined at each time point and the data were analyzed by statistical methodology., Results: The markers could be divided by the method of principal components analysis into five clusters of related markers: inflammation markers (C-reactive protein, tumor necrosis receptor type I and tumor necrosis receptor type II, interleukin 6, eosinophilic cationic protein), bone markers (bone sialoprotein, hydroxylysyl pyridinoline, lysyl pyridinoline), putative markers of cartilage anabolism (carboxypropeptide of type II procollagen, hyaluronan, epitope 846) and catabolism (keratan sulfate, cartilage oligomeric matrix protein), and transforming growth factor beta. Three markers (tumor necrosis factor receptor II, cartilage oligomeric matrix protein and epitope 846) from independent clusters discriminated osteoarthritis patients from controls. Inflammation was not a confounding factor in measurement, but a recognizable distinguishing factor in osteoarthritis., Conclusions: The markers separated into rational groups on the basis of their covariance, a finding with independent biochemical support. The covariance of markers from the same cluster suggests the use of a representative marker from the cluster to reflect changes in osteoarthritis. If multiple markers are being measured within a single cluster, then the use of a weighted cluster 'factor' may be preferable to the separate use of individual markers.