Association between weight gain and knee osteoarthritis: a systematic review.

OBJECTIVE: Although weight loss is recommended to manage knee osteoarthritis (KOA), adults tend to gain weight with age which may affect KOA symptoms and progression. We conducted a systematic review and data synthesis to investigate the association between weight gain and KOA, defined by clinical features, structural progression, and total knee replacement (TKR). DESIGN: MEDLINE and EMBASE were systematically searched for controlled trials and cohort studies of participants with (or at risk of) KOA examining the relationship between weight gain and KOA clinical features (pain, function, quality of life), structural progression, and TKR. Risk of bias was assessed using the ROBINS-I tool. Results were organised by outcome, with meta-analyses performed where appropriate. RESULTS: Twenty-three studies were included. Results showed significant detrimental effects of weight gain on pain (4 of 7 studies), stiffness (2 of 2 studies), function (5 of 6 studies), and the single studies examining quality of life, and clinical and radiographic KOA. Weight gain adversely affected cartilage (6 of 9 studies), bone marrow lesions (1 of 4 studies), meniscal damage (1 of 3 studies) and effusion/synovitis (1 of 1 study). Weight gain significantly increased TKR (3 of 6 studies): meta-analysis of 2 with available data demonstrated significant increases in TKR/5 kg weight gain in women, HR 1.34 (95% CI 1.18-1.51), and in men, HR 1.25 (95% CI 1.16-1.34). CONCLUSIONS: Weight gain in adults is associated with increased clinical and structural KOA and TKR. Prevention of weight gain should be considered to improve outcomes in KOA.

Trajectories of body mass index from early adulthood to late midlife and incidence of total knee arthroplasty for osteoarthritis: findings from a prospective cohort study.

OBJECTIVE: To examine the association between body mass index (BMI) trajectories from early adulthood to late midlife and risk of total knee arthroplasty (TKA) for osteoarthritis. METHODS: 24,368 participants from the Melbourne Collaborative Cohort Study with weight collected during 1990-1994, 1995-1998, and 2003-2007, recalled weight at age 18-21 years, and height measured during 1990-1994 were included. Incident TKA from 2003 to 2007 to December 2018 was determined by linking cohort records to the National Joint Replacement Registry. RESULTS: Using group-based trajectory modelling, six distinct trajectories (TR) of BMI from early adulthood (age 18-21 years) to late midlife (approximately 62 years) were identified: lower normal to normal BMI (TR1; 19.7% population), normal BMI to borderline overweight (TR2; 36.7%), normal BMI to overweight (TR3; 26.8%), overweight to borderline obese (TR4; 3.5%), normal BMI to class 1 obesity (TR5; 10.1%), overweight to class 2 obesity (TR6; 3.2%). Over 12.4 years, 1,328 (5.4%) had TKA. The hazard ratios for TKA increased in all TR compared to TR1 [from TR2: 2.03 (95% CI 1.64-2.52) to TR6: 8.59 (6.44-11.46)]. 28.4% of TKA could be prevented if individuals followed the trajectory one lower, an average weight reduction of 8-12 kg from early adulthood to late midlife, saving $AUS 373 million/year. Most reduction would occur in TR2 (population attributable fraction 37.9%, 95% CI 26.7-47.3%) and TR3 (26.8%, 20.0-31.2%). CONCLUSIONS: Prevention of weight gain from young adulthood to late midlife in order to reduce overweight/obesity has the potential to significantly reduce the cost and burden of TKA.

Prediction of knee pain improvement over two years for knee osteoarthritis using a dynamic nomogram based on MRI-derived radiomics: a proof-of-concept study.

OBJECTIVES: To develop and validate a nomogram to detect improved knee pain in osteoarthritis (OA) by integrating magnetic resonance imaging (MRI) radiomics signature of subchondral bone and clinical characteristics. METHODS: Participants were selected from the Vitamin D Effects on Osteoarthritis (VIDEO) study. The primary outcome was 20% improvement of knee pain score over 2 years in participants administrated either vitamin D or placebo. Radiomics features of subchondral bone and clinical characteristics from 216 participants were extracted and analyzed. The participants were randomly split into the training and validation cohorts at a ratio of 8:2. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and generate radiomics signatures. The optimal radiomics signature and clinical indicators were fitted into a nomogram using multivariable logistic regression model. RESULTS: The nomogram showed favorable discrimination performance [AUCtraining, 0.79 (95% CI: 0.72-0.79), AUCvalidation, 0.83 (95% CI: 0.70-0.96)] as well as a good calibration. Additional contributing value of fusion radiomics signature to the nomogram was statistically significant (NRI, 0.23; IDI, 0.14, P < 0.001 in training cohort and NRI, 0.29; IDI, 0.18, P < 0.05 in validating cohort). Decision curve analysis confirmed the clinical usefulness of nomogram. CONCLUSION: The radiomics-based nomogram comprising the MR radiomics signature and clinical variables achieves a favorable predictive efficacy and accuracy in differentiating improvement in knee pain among OA patients. This proof-of-concept study provides a promising way to predict clinically meaningful outcomes.

Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies.

OBJECTIVE: Osteoarthritis causes significant pain and disability with no approved disease-modifying drugs. We systematically reviewed the evidence from both pre-clinical and human studies for the potential disease-modifying effect of metformin in osteoarthritis. METHODS: Ovid Medline, Embase and CINAHL were searched between inception and June 2021 using MeSH terms and key words to identify studies examining the association between metformin use and outcome measures related to osteoarthritis. Two reviewers performed the risk of bias assessment and 3 reviewers extracted data independently. Qualitative evidence synthesis was performed. This systematic review is registered on PROSPERO (CRD42021261052 and CRD42021261060). RESULTS: Fifteen (10 pre-clinical and 5 human) studies were included. Most studies (10 pre-clinical and 3 human) assessed the effect of metformin using knee osteoarthritis models. In pre-clinical studies, metformin was assessed for the effect on structural outcomes (n = 10); immunomodulation (n = 5); pain (n = 4); and molecular pathways of its effect in osteoarthritis (n = 7). For human studies, metformin was evaluated for the effect on structural progression (n = 3); pain (n = 1); and immunomodulation (n = 1). Overall, pre-clinical studies consistently showed metformin having a chondroprotective, immunomodulatory and analgesic effect in osteoarthritis, predominantly mediated by adenosine monophosphate-activated protein kinase activation. Evidence from human studies, although limited, was consistent with findings in pre-clinical studies. CONCLUSION: We found consistent evidence across pre-clinical and human studies to support a favourable effect of metformin on chondroprotection, immunomodulation and pain reduction in knee osteoarthritis. Further high-quality clinical trials are needed to confirm these findings as metformin could be a novel therapeutic drug for the treatment of osteoarthritis.

Association between osteoarthritis-related serum biochemical markers over 11 years and knee MRI-based imaging biomarkers in middle-aged adults.

OBJECTIVE: To describe the associations between osteoarthritis (OA)-related biochemical markers (COMP, MMP-3, HA) and MRI-based imaging biomarkers in middle-aged adults over 10-13 years. METHODS: Blood serum samples collected during the Childhood Determinants of Adult Health (CDAH)-1 study (year:2004-06; n = 156) and 10-13 year follow-up at CDAH-3 (n = 167) were analysed for COMP, MMP-3, and HA using non-isotopic ELISA. Knee MRI scans obtained during the CDAH-knee study (year:2008-10; n = 313) were assessed for cartilage volume and thickness, subchondral bone area, cartilage defects, and BML. RESULTS: In a multivariable linear regression model describing the association of baseline biochemical markers with MRI-markers (assessed after 4-years), we found a significant negative association of standardised COMP with medial femorotibial compartment cartilage thickness (ß:-0.070; 95%CI:-0.138,-0.001), and standardised MMP-3 with patellar cartilage volume (ß:-141.548; 95%CI:-254.917,-28.179) and total bone area (ß:-0.729; 95%CI:-1.340,-0.118). In multivariable Tobit regression model, there was a significant association of MRI-markers with biochemical markers (assessed after 6-9 years); a significant negative association of patellar cartilage volume (ß:-0.001; 95%CI:-0.002,-0.00004), and total bone area (ß:-0.158; 95%CI-0.307,-0.010) with MMP-3, and total cartilage volume (ß:-0.001; 95%CI:-0.001,-0.0001) and total bone area (ß:-0.373; 95%CI:-0.636,-0.111) with COMP. No significant associations were observed between MRI-based imaging biomarkers and HA. CONCLUSION: COMP and MMP-3 levels were negatively associated with knee cartilage thickness and volume assessed 4-years later, respectively. Knee cartilage volume and bone area were negatively associated with COMP and MMP-3 levels assessed 6-9 years later. These results suggest that OA-related biochemical markers and MRI-markers are interrelated in early OA.

The interactions between MRI-detected osteophytes and bone marrow lesions or effusion-synovitis on knee symptom progression: an exploratory study.

OBJECTIVES: To investigate the longitudinal association between MRI-detected osteophyte scores and progression of knee symptoms, and whether the association was modified in the presence of bone marrow lesions (BMLs) or effusion-synovitis. METHODS: Data from Vitamin D Effects on Osteoarthritis (VIDEO) study, a randomized, double-blinded and placebo-controlled clinical trial in symptomatic knee osteoarthritis (OA) patients, were analyzed as an exploratory study. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to assess knee symptoms. Osteophytes, BMLs and effusion-synovitis were measured using MRI. RESULTS: 334 participants with MRI information and WOMAC score (baseline and follow-up) were included in the analyses, with 24.3% of them having knee pain increased 2 years later. Statistically significant interactions were found between MRI-detected osteophytes and BMLs or effusion-synovitis on increased knee symptoms. In participants with BMLs, higher baseline scores of MRI-detected osteophytes in most compartments were significantly associated with increased total knee pain, weight-bearing pain, stiffness, and physical dysfunction, after adjustment for age, sex, body mass index, intervention and effusion-synovitis. In participants with effusion-synovitis, higher baseline scores of MRI-detected osteophytes in almost all the compartments were significantly associated with increased total knee pain, weight-bearing pain, stiffness, and physical dysfunction, after adjustment for age, sex, body mass index, intervention and BMLs. In contrast, MRI-detected osteophyte scores were generally not associated with knee symptom progression in participants without baseline BMLs or effusion-synovitis. CONCLUSIONS: MRI-detected OPs are associated with increased total knee pain, weight-bearing knee pain, stiffness and physical dysfunction in participants presenting BMLs or effusion-synovitis, but not in participants lacking BMLs or effusion-synovitis. This suggests they could interact with bone or synovial abnormalities to induce symptoms in knee OA.

Predictors of total hip replacement in community based older adults: a cohort study.

OBJECTIVE: The purpose of this study is to describe predictors of total hip replacement (THR) in community dwelling older adults. A better understanding of predictors of THR can aid in triaging patients and researching preventative strategies. DESIGN: At baseline, participants had assessment of radiographic OA and cam morphology (from pelvic radiographs), shape mode scores and hip bone mineral density (BMD; from dual energy X-ray absorptiometry (DXA)). After 2.6 and 5 years, participants reported hip pain using WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), and had hip structural changes assessed using magnetic resonance imaging (MRI). Risk of THR was analysed using mixed-effect Poisson regression. RESULTS: Incidence of THR for OA over 14 years was 4.6% (37/801). As expected, WOMAC hip pain and hip radiographic OA both predicted risk of THR. Additionally, shape mode 2 score (decreasing acetabular coverage) (RR 1.83/SD; 95% CI 1.1-3.04), shape mode 4 score (non-spherical femoral head) (RR 0.59/SD; 95% CI 0.36-0.96), cam morphology (α > 60°) (RR 2.2/SD; 95% CI 1.33-3.36), neck of femur BMD (RR 2.09/SD, 95% CI 1.48-2.94) and bone marrow lesions (BMLs) increased risk of THR (RR 7.10/unit; 95% CI 1.09-46.29). CONCLUSION: In addition to hip pain and radiographic hip OA, measures of hip shape, cam morphology, BMD and BMLs independently predict risk of THR. This supports the role of hip bone geometry and structure in the pathogenesis of end stage hip OA and has identified factors that can be used to improve prediction models for THR.

Systematic review and meta-analysis of the prevalence of neuropathic-like pain and/or pain sensitization in people with knee and hip osteoarthritis.

OBJECTIVE: To determine the prevalence of neuropathic-like pain (NP) and pain sensitization (PS) defined by self-report questionnaires in knee and hip osteoarthritis, and whether prevalence is potentially explained by disease-severity or affected joint. DESIGN: MEDLINE, EMBASE, CINAHL were systematically searched (1990-April 2020) for studies describing the prevalence of NP and PS in knee and hip osteoarthritis using self-report questionnaires. Random-effects meta-analysis was performed. Statistical heterogeneity between studies and sub-groups (affected joint and population source as a proxy for disease severity) was assessed (I2 statistic and the Chi-squared test). RESULTS: From 2,706 non-duplicated references, 39 studies were included (2011-2020). Thirty-six studies reported on knee pain and six on hip pain. For knee osteoarthritis, the pooled prevalence of NP was: using PainDETECT, possible NP(score ≥13) 40% (95%CI 32-48%); probable NP(score >18) 20% (95%CI 15-24%); using Self-Report Leeds Assessment of Neuropathic Symptoms and Signs, 32% (95%CI 26-38%); using Douleur Neuropathique (DN4) 41% (95% CI 24-59%). The prevalence of PS using Central Sensitization Inventory (CSI) was 36% (95% CI 12-59%). For hip osteoarthritis, the pooled prevalence of NP was: using PainDETECT, possible NP 29% (95%CI 22-37%%); probable NP 9% (95%CI 6-13%); using DN4 22% (95%CI 12-31%) in one study. The prevalence of possible NP pain was higher at the knee (40%) than the hip (29%) (difference 11% (95% CI 0-22%), P = 0.05). CONCLUSIONS: Using self-report questionnaire tools, NP was more prevalent in knee than hip osteoarthritis. The prevalence of NP in knee and hip osteoarthritis were similar for each joint regardless of study population source or tool used. Whether defining NP using self-report questionnaires enables more effective targeted therapy in osteoarthritis requires investigation.

The association between incident vertebral deformities, health-related quality of life and functional impairment: a 10.7-year cohort study.

We aimed to describe longitudinal changes in health-related quality of life (HRQoL) measures associated with incident vertebral deformities (VDs) over 10.7 years. Incident VDs are associated with clinically significant functional impairment in men, and reduction in overall HRQoL in older women. Increasing severity and number of incident VDs are associated with clinically meaningful functional impairment in men, but not women. INTRODUCTION: To describe associations between incident VD and changes in HRQoL and functional ability in older adults over 10.7 years. METHODS: Participants (n = 780) underwent whole-body dual-energy X-ray absorptiometry (DXA) scans at baseline, 2.5, 5.1 and 10.7 years later. VD was defined as ≥ 25% reduction in anterior height relative to posterior height of vertebrae from T4 to L4. An incident VD was defined as a new VD at any follow-up visit. Assessment of Quality of Life (AQoL-4D) questionnaire and Health Assessment Questionnaire-Disability Index (HAQ-DI) were used to assess HRQoL and functional impairment. Changes in AQoL and HAQ-DI associated with incident VD were analysed using multilevel mixed-effects linear regression. Log binomial regression was used to examine clinically relevant changes and effects of severity and number of VD. RESULTS: The incidence of VD was 37% over 10.7 years. In women, incident VDs were associated with annual reduction in AQoL utility score (ß = -0.005, 95% CI -0.008 to -0.002). Men had increased risk of clinically significant reduction in HAQ-DI (IRR = 1.76, 95% CI 1.07-2.89). Men had increased risk of clinically important functional impairment with increasing severity (IRR 1.76, 95% CI 1.04-2.95 for mild vs IRR 1.98, 95% CI 1.13-3.47 for moderate to severe VD) as well as number of incident VD (IRR 1.85, 95% CI 1.17-2.93 for one vs IRR 1.88, 95% CI 0.94-3.78 for ≥ 2 VDs). Such associations were not observed in women. CONCLUSIONS: Incident VDs are associated with clinically significant functional impairment in men, and reduction in overall HRQoL in older women. Increasing severity and number of incident VDs are associated with clinically meaningful functional impairment in men, but not women.

The cross-sectional and longitudinal associations of dietary patterns with knee symptoms and MRI detected structure in patients with knee osteoarthritis.

OBJECTIVES: To examine the cross-sectional and longitudinal associations of dietary patterns with knee symptoms and structures in patients with knee osteoarthritis (OA). METHODS: Participants with symptomatic knee OA were recruited from a randomised, placebo-controlled trial conducted in Tasmania (N = 259) and Victoria (N = 133). Diet was assessed by the Anti-Cancer Council of Victoria food frequency questionnaire. Factor analysis was used to identify dietary patterns. Knee symptoms were assessed using Western Ontario and McMaster Universities Arthritis Index (WOMAC) and structures using MRI. Multivariable linear regressions were used to examine associations. RESULTS: Three dietary patterns ("high-fat", "healthy" and "mixed") were identified in whole sample. Participants with higher "healthy pattern" score had lower total WOMAC, pain, function and stiffness scores at baseline but the associations were not significant over 24 months. Three ("western", "vegetable and meat" and "mediterranean") and two ("processed" and "vegetable") patterns were identified in Tasmania and Victoria, respectively. Cross-sectionally, only "mediterranean pattern" and "vegetable pattern" scores were significantly and negatively associated with total WOMAC or function scores. Longitudinally, participants with higher "western pattern" had worsening function (ß: 0.35, 95%CI: 0.03, 0.67) and total WOMAC (ß: 0.40, 95%CI: 0.07, 0.72) scores; furthermore, "vegetable pattern" was associated with decreased WOMAC stiffness score (ß: -0.47, 95%CI: -0.93, -0.02). In contrast, dietary patterns were largely not associated with structural changes. CONCLUSION: Some healthy dietary patterns were associated with reduced joint symptoms but dietary patterns were not associated with joint structure in this sample with knee OA. Further studies are required to confirm these findings.

Shoe-stiffening inserts for first metatarsophalangeal joint osteoarthritis: a randomised trial.

OBJECTIVE: To evaluate the efficacy of carbon-fibre shoe-stiffening inserts in individuals with first metatarsophalangeal joint osteoarthritis. DESIGN: This was a randomised, sham-controlled, participant- and assessor-blinded trial. One hundred participants with first metatarsophalangeal joint osteoarthritis received rehabilitation therapy and were randomised to receive either carbon fibre shoe-stiffening inserts (n = 49) or sham inserts (n = 51). The primary outcome measure was the Foot Health Status Questionnaire (FHSQ) pain domain assessed at 12 weeks. RESULTS: All 100 randomised participants (mean age 57.5 (SD 10.3) years; 55 (55%) women) were included in the analysis of the primary outcome. At the 12 week primary endpoint, there were 13 drop-outs (7 in the sham insert group and 6 in the shoe-stiffening insert group), giving completion rates of 86 and 88%, respectively. Both groups demonstrated improvements in the FHSQ pain domain score at each follow-up period, and there was a significant between-group difference in favour of the shoe-stiffening insert group (adjusted mean difference of 6.66 points, 95% CI 0.65 to 12.67, P = 0.030). There were no between-group differences for the secondary outcomes, although global improvement was more common in the shoe-stiffening insert group compared to the sham insert group (61 vs 34%, RR 1.73, 95% CI 1.05 to 2.88, P = 0.033; number needed to treat 4, 95% CI 2 to 16). CONCLUSION: Carbon-fibre shoe-stiffening inserts were more effective at reducing foot pain than sham inserts at 12 weeks. These results support the use of shoe-stiffening inserts for the management of this condition, although due to the uncertainty around the effect on the primary outcome, some individuals may not experience a clinically worthwhile improvement.

Does preoperative neuropathic-like pain and central sensitisation affect the post-operative outcome of knee joint replacement for osteoarthritis? A systematic review and meta analysis.

BACKGROUND: Almost a third of those undergoing knee replacement for osteoarthritis have poor outcomes despite technically successful surgery. Preoperative neuropathic-like pain and/or pain sensitisation may increase the risk of pain following joint replacement. OBJECTIVE: To examine whether preoperative neuropathic-like pain and pain sensitisation predicts pain, function and satisfaction following joint replacement for knee osteoarthritis. DESIGN: Systematic review with meta-analysis. METHODS: Medline, EMBASE and CINAHL were systematically searched until March 2020. Studies detecting neuropathic-like pain and/or sensitisation using self-report questionnaires prior to knee replacement for osteoarthritis, and relating this to post-operative outcomes were identified. Data extraction, risk of bias assessment and meta-analysis were performed, where appropriate. RESULTS: Five manuscripts, including one preprint, examining six cohorts were included: four used painDETECT or modified painDETECT, one the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs, and another the Central Sensitisation Inventory to identify preoperative characteristics. Three studies showed preoperative neuropathic-like pain or sensitisation was associated with more intense post-operative pain. All four studies examining the risk of significant pain after knee replacement suggested it was increased after >3 months. The only study examining patient satisfaction and function found reduced satisfaction, but no difference in function in those with preoperative sensitisation. Meta-analysis found the relative risk of increased pain following knee replacement in those with neuropathic-like pain (painDETECT ≥13) to be 2.05 (95% confidence intervals 1.51, 2.79). CONCLUSION: These results provide consistent but limited evidence that self-report tools detecting neuropathic-like pain and/or pain sensitisation, predict patients at higher risk of pain following knee replacement.

Comparison of radiographic and MRI osteoarthritis definitions and their combination for prediction of tibial cartilage loss, knee symptoms and total knee replacement: a longitudinal study.

OBJECTIVE: To describe the value of radiographic- and magnetic resonance imaging (MRI)-defined tibiofemoral osteoarthritis (ROA and MRI-OA, respectively) and in combination for predicting tibial cartilage loss, knee pain and disability and total knee replacement (TKR) in a population-based cohort. DESIGN: A radiograph and 1.5T MRI of the right knee was performed. ROA and MRI-OA at baseline were defined according to the Osteoarthritis Research Society International atlas and a published Delphi exercise, respectively. Tibial cartilage volume was measured over 2.6 and 10.7 years. Knee pain and disability were assessed at baseline, 2.6, 5.1 and 10.7 years. Right-sided TKRs were assessed over 13.5 years. RESULTS: Of 574 participants (mean 62 years, 49% female), 8% had ROA alone, 15% had MRI-OA alone, 13% had both ROA and MRI-OA. Having ROA (vs. no ROA) and MRI-OA (vs. no MRI-OA) predicted greater tibial cartilage loss over 2.6 years (-75.9 and -86.4 mm3/year) and higher risk of TKR over 13.5 years (Risk Ratio [RR]: 15.0 and 10.9). Only MRI-OA predicted tibial cartilage loss over 10.7 years (-7.1 mm3/year) and only ROA predicted onset and progression of knee symptoms (RR: 1.32-1.88). In participants with both MRI-OA and ROA, tibial cartilage loss was the greatest (over 2.6 years: -116.1 mm3/year; over 10.7 years: -11.2 mm3/year), and the onset and progression of knee symptoms (RR: 1.75-2.89) and risk of TKR (RR: 50.9) were the highest. CONCLUSIONS: The Delphi definition of MRI-OA is not superior to ROA for predicting structural or symptomatic OA progression but, combining MRI-OA and ROA has much stronger predictive validity.

The association of subchondral and systemic bone mineral density with osteoarthritis-related joint replacements in older adults.

OBJECTIVE: To describe the association of subchondral and systemic bone mineral density (BMD) with knee and hip replacements (KR and HR, respectively) due to osteoarthritis. DESIGN: 1,095 participants (mean age 63 years, 51% female) were included. At baseline, subchondral BMD of the medial and lateral tibia in three regions of interest (ROI) for the right knee, and systemic BMD of the lumbar spine, femoral neck, total hip and whole-body, were measured using dual-energy X-ray absorptiometry. Subchondral BMD of the hip was not measured. Competing risk regression models were used to estimate sub-distribution hazard ratios (SHRs) of KR/HR per one standard deviation (SD) higher in BMD measures, with adjustment of potential confounders. RESULTS: Over 12.2 years, 79 (7.2%) participants underwent a KR and 56 (5.1%) an HR due to osteoarthritis. For the right side, medial subchondral BMD in ROI-3 was associated with an increased risk of KR (SHR 1.95 per SD; 95% Confidence Interval [CI], 1.57 to 2.43). In contrast, systemic BMD was not associated with the risk of KR, but higher BMD at the lumbar spine (1.42, 1.07 to 1.88) and whole-body (1.29, 1.00 to 1.66) were associated with an increased risk of HR at both sides. CONCLUSIONS: Subchondral BMD is positively associated with an increased risk of KR and systemic BMD with an increased risk of HR, suggesting a role of BMD in the progression of osteoarthritis.

KARAOKE: Krill oil versus placebo in the treatment of knee osteoarthritis: protocol for a randomised controlled trial.

BACKGROUND: Knee osteoarthritis (OA) is a common and important cause of pain and disability, but interventions aimed at modifying structures visible on imaging have been disappointing. While OA affects the whole joint, synovitis and effusion have been recognised as having a role in the pathogenesis of OA. Krill oil reduces knee pain and systemic inflammation and could be used for targeting inflammatory mechanisms of OA. METHODS/DESIGN: We will recruit 260 patients with clinical knee OA, significant knee pain and effusion-synovitis present on MRI in five Australian cities (Hobart, Melbourne, Sydney, Adelaide and Perth). These patients will be randomly allocated to the two arms of the study, receiving 2 g/day krill oil or inert placebo daily for 6 months. MRI of the study knee will be performed at screening and after 6 months. Knee symptoms, function and MRI structural abnormalities will be assessed using validated methods. Safety data will be recorded. Primary outcomes are absolute change in knee pain (assessed by visual analog score) and change in size of knee effusion-synovitis over 24 weeks. Secondary outcomes include improvement in knee pain over 4, 8, 12, 16 and 20 weeks. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses adjusting for missing data and for treatment compliance will be performed as the secondary analyses. DISCUSSION: This study will provide high-quality evidence to assess whether krill oil 2 g/day reduces pain and effusion-synovitis size in older adults with clinical knee OA and knee effusion-synovitis. If krill oil is effective and confirmed to be safe, we will provide compelling evidence that krill oil improves pain and function, changes disease trajectory and slows disease progression in OA. Given the lack of approved therapies for slowing disease progression in OA, and moderate cost of krill oil, these findings will be readily translated into clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000726459. Registered on 02 June 2016. Universal Trial Number (UTN) U1111-1181-7087.

Metabolic syndrome and trajectory of knee pain in older adults.

OBJECTIVES: To examine the association of metabolic syndrome (MetS) and its components with knee pain severity trajectories. METHODS: Data from a population-based cohort study were utilised. Baseline blood pressure, glucose, triglycerides and high-density lipoprotein (HDL) cholesterol were measured. MetS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III criteria. Radiographic knee osteoarthritis (ROA) was assessed by X-ray. Pain severity was measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain questionnaire at each time-point. Group-based trajectory modelling was used to identify pain trajectories and multi-nominal logistic regression was used for analysis. Mediation analysis was performed to assess whether body mass index (BMI)/central obesity mediated the association between MetS, its components and pain trajectories. RESULTS: Among 985 participants (Mean ± SD age: 62.9 ± 7.4, 50% female), 32% had MetS and 60% had ROA. Three pain trajectories were identified: 'Minimal pain' (52%), 'Mild pain' (33%) and 'Moderate pain' (15%). After adjustment for potential confounders, central obesity increased risk of belonging to both 'Mild pain' and 'Moderate pain' trajectories as compared to the 'Minimal pain' trajectory group, but MetS [relative risk ratio (RRR): 2.26, 95%CI 1.50-3.39], hypertriglyceridemia (RRR: 1.75, 95%CI 1.16-2.62) and low HDL (RRR: 1.67, 95%CI 1.10-2.52) were only associated with 'Moderate pain' trajectory. BMI/central obesity explained 37-70% of these associations. Results were similar in those with ROA. CONCLUSION: MetS and its components are predominantly associated with worse pain trajectories through central obesity, suggesting that the development and maintenance of worse pain trajectories may be caused by MetS.

Promoting mobility and healthy aging in men: a narrative review.

Maintaining mobility is an important aspect of health and well-being in older men. This literature review describes several modifiable and nonmodifiable risk factors impacting bone, muscle, and joint health. Exercise and nutritional interventions may help to prevent the progressive deterioration in bones, muscles, and joints impacting mobility in later life. Limitations in mobility are increasingly recognized as a major public health problem due to an aging population and growing number of older individuals affected by disabling comorbidities. Despite increasing numbers and debilitating consequences, there are no guidelines providing recommendations on strategies to maintain mobility for healthy aging among older men. This narrative review aims to fill this literature gap. PubMed, Scopus, and Google Scholar databases were searched using predefined search terms. Primary studies, exploratory analyses, cross-sectional surveys, meta-analyses, evidence-based clinical reviews, and guidelines from nationally recognized societies focusing on mobility in older men and key elements including bone, muscle and joint health, and balance were selected. Several modifiable and nonmodifiable risk factors have been reported in the literature that impact bone, muscle, and joint health and predispose older men to falls and fractures. The most common conditions impacting bones, muscles, and joints are osteoporosis, sarcopenia, and osteoarthritis, respectively. In addition to being key contributors to disability in the elderly, these conditions are all associated with a higher mortality risk. Although more studies are required, current evidence supports the use of various nonpharmacological (mainly exercise and nutrition) and/or pharmacological treatment modalities to help prevent and/or reverse these conditions. Incorporating lifestyle interventions involving exercise and nutrition at a younger age can help prevent the age-related, progressive deterioration in bones, muscles, and joints that can reduce mobility in later life. Established barriers to physical activities (e.g., poor health, social isolation) in men are important to consider for optimizing outcomes.

Bone marrow lesions in knee osteoarthritis: regional differences in tibial subchondral bone microstructure and their association with cartilage degeneration.

OBJECTIVE: The aim of this study was to investigate how bone microstructure within bone marrow lesions (BMLs) relates to the bone and cartilage across the whole human tibial plateau. DESIGN: Thirty-two tibial plateaus from patients with osteoarthritis (OA) at total knee arthroplasty and eleven age-matched non-OA controls, were scanned ex vivo by MRI to identify BMLs and by micro CT to quantitate the subchondral (plate and trabecular) bone microstructure. For cartilage evaluation, specimens were processed histologically. RESULTS: BMLs were detected in 75% of the OA samples (OA-BML), located predominantly in the anterior-medial (AM) region. In contrast to non-OA control and OA-no BML, in OA-BML differences in microstructure were significantly more evident between subregions. In OA-BML, the AM region contained the most prominent structural alterations. Between-group comparisons showed that the AM region of the OA-BML group had significantly higher histological degeneration (OARSI grade) (P < .0001, P < .05), thicker subchondral plate (P < .05, P < .05), trabeculae that are more anisotropic (P < .0001, P < .05), well connected (P < .05, P = n.s), and more plate-like (P < 0.05, P < 0.05), compared to controls and OA-no BML at this site. Compared to controls, OA-no BML had significantly higher OARSI grade (P < .0001), and lower trabecular number (P < .05). CONCLUSION: In established knee OA, both the extent of cartilage damage and microstructural degeneration of the subchondral bone were dependent on the presence of a BML. In OA-no BML, bone microstructural alterations are consistent with a bone attrition phase of the disease. Thus, the use of BMLs as MRI image-based biomarkers appear to inform on the degenerative state within the osteochondral unit.

Ambulatory activity interacts with common risk factors for osteoarthritis to modify increases in MRI-detected osteophytes.

OBJECTIVE: To investigate the longitudinal association between objectively measured ambulatory activity (AA) and knee MRI-detected osteophytes (OPs), and to test whether this relationship was modified by common risk factors for OA including sex, obesity, disease severity and knee injury history. METHODS: 408 community-dwelling adults aged 51-81 years were assessed at baseline and 2.7 years. T1-weighted fat-suppressed MRI was used to evaluate knee OPs at both time points. AA was assessed at baseline by pedometers and categorized as: less active (≤7499 steps per day), moderately active (7500-9999 steps per day) and highly active (≥10,000 steps per day). RESULTS: Statistically significant interactions were detected between knee OA risk factors and AA on increases in MRI-detected OPs (all P < 0.05). In stratified analyses, being moderately active, compared to being less active, was protective against an increase in MRI-detected OPs (score change of ≥1) in females (relative risk (RR) = 0.42, 95%CI, 0.25-0.70, P < 0.01), those who were obese (RR = 0.50, 95%CI, 0.30-0.83, P < 0.01), those with radiographic OA (ROA) (RR = 0.68, 95%CI, 0.47-0.97, P = 0.02) and those with a history of knee injury (RR = 0.27, 95%CI, 0.08-0.88, P = 0.02) in almost every knee compartment, after adjustment for confounders. No statistically significant associations were found in males, non-obese, non-ROA or non-injury groups. CONCLUSIONS: Being moderately active is protective against an increase in MRI-detected OPs in females, those with ROA, those who are obese and those with a history of knee injury. These findings suggest that being moderately active is beneficial for individuals who are at higher risk of knee OA.

Relationship of weight and obesity with the risk of knee and hip arthroplasty for osteoarthritis across different levels of physical performance: a prospective cohort study.

OBJECTIVE: To examine the association between obesity and knee and hip arthroplasty for osteoarthritis across a range of physical performance. METHOD: The body mass index and physical performance (on the 36-item Short Form Health Survey) of 9135 Australian Diabetes, Obesity and Lifestyle Study participants were measured in 1999-2000. The incidence of knee and hip arthroplasty during 2002-2011 was determined by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. RESULTS: Over 9.1 ± 2.3 years (mean ± sd)) of follow-up, 317 participants had knee and 202 had hip arthroplasty for osteoarthritis. Using those with neither obesity nor significantly impaired physical performance as the reference group, participants with both obesity and significantly impaired physical performance had a higher knee arthroplasty risk [hazard ratio (HR) = 5.25, 95% confidence interval (CI) 3.85-7.14] than those with obesity alone (HR = 2.49, 95% CI 1.81-3.44) or impaired physical performance alone (HR = 2.19, 95% CI 1.59-3.02). Similar results were observed for hip arthroplasty (obesity and impaired physical performance: HR = 2.67, 95% CI 1.72-4.15; obesity alone: HR = 1.65, 95% CI 1.08-2.51; impaired physical performance alone: HR = 1.83, 95% CI 1.26-2.66). Among overweight/obese patients, 5 kg greater baseline weight increased the knee arthroplasty risk across all levels of physical performance, and hip arthroplasty risk in those with the highest level of physical performance. CONCLUSION: Although impaired physical performance is an independent risk factor for knee and hip arthroplasty, greater weight increased knee arthroplasty for overweight/obese participants at all levels of physical performance, but hip arthroplasty only in those with good physical performance. Targeting weight loss has the potential to reduce the risk of knee arthroplasty and improve patient outcomes, even in those with poor physical performance.