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Objective: To determine the effect of zoledronic acid (ZA) on the risk of total knee replacement (TKR) in patients with symptomatic knee osteoarthritis and without severe joint space narrowing (JSN)., Methods: We included 222 participants (mean age 62 years, 52% female) from the two-year Zoledronic Acid for Osteoarthritis Knee Pain trial (113 received 5 mg of ZA annually and 109 received placebo) conducted between November 2013 and October 2017. Primary TKR were identified until February 22, 2022. The effect of ZA on TKR risk was evaluated using Cox proportional hazard regression models. Because the treatment effect failed the proportional hazards assumption, a time-varying coefficients analysis for treatment was conducted by splitting the study into two periods (ie, within and after two years of randomization)., Results: Over a mean follow-up of seven years, 39% and 30% of participants had any TKR in the ZA and placebo groups, and 28% and 18% had TKR in the study knee, respectively. Use of ZA was associated with a higher risk of TKR in any knee (hazard ratio [HR] 4.2, 95% confidence interval [CI] 1.2-14.7) and showed a trend in the study knee (HR 6.8, 95%CI 0.9-53.9) during the trial. In the posttrial period, the risk of TKR was similar in the ZA and the placebo groups for any knee (HR 1.2, 95%CI 0.5-1.8) and the study knee (HR 1.4, 95%CI 0.5-2.2)., Conclusion: These results suggest that ZA is not protective against TKR in patients with symptomatic knee osteoarthritis and without severe JSN., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Using a qualitative design this study aimed to (1) explore the experience of people living with osteoarthritis (OA), (2) gain an understanding of their navigation of the health system and, (3) explore their opinions on the role of exercise and joint replacement surgery for the management of OA., Methods: Purposive sampling was used to recruit 26 participants with knee OA, aged 45 years and over, from Tasmania, Australia. Semi-structured interviews were audio-recorded, transcribed, coded, and thematically analysed to document participant understanding and experience of OA and their opinions on the role of exercise and surgery in managing OA., Results: Of the 26 participants, 80% (n = 21) were female with a mean age of 66 years. The main theme identified was that individuals with knee OA were navigating a maze of OA treatments. Three related subthemes were that participants: (i) perceived their general practitioner did not have an ongoing role in their OA care, (ii) self-directed their management and, (iii) sampled from a 'smorgasbord' of treatment options, including low-value care options. Two other major themes were: the role of exercise for OA management, and surgery as a last resort., Conclusion: Our findings suggest that OA patients may not be choosing consistent, high-value care for their OA. This highlights the importance of an evidence-based multi-disciplinary approach to guide patients to self-manage their OA and support their navigation of the health system. Reducing emphasis on the pathway to surgery and streamlining access to conservative management strategies may assist people to receive high-value care., (© 2022 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Background: Curcuma longa (CL) extract is modestly effective for relieving knee symptoms in knee osteoarthritis (OA) patients; however, its mechanism of action is unclear., Purpose: We aimed to determine the effects of CL treatment on serum inflammatory markers over 12 weeks and to explore its potential effects on synovitis assessed by contrast-enhanced magnetic resonance imaging (CE-MRI) of the knee., Methods: Secondary analyses were conducted on the CL for knee OA (CurKOA) trial, which compared CL (n = 36) and placebo (n = 34) over 12 weeks for the treatment of knee OA. Systemic inflammatory markers (TNFα, IL6, and hsCRP) and a cartilage extracellular matrix degradative enzyme (MMP-3) were measured. A subgroup of participants (CL, n = 7; placebo, n = 5) underwent CE-MRI at baseline and a 12-week follow-up., Results: Over 12 weeks, there were no between-group differences in change in hsCRP, IL-6, and TNFα levels. MMP-3 levels decreased in both CL (-1.31 ng/ml [95%CI: -1.89 to -0.73]) and placebo (-2.34 ng/ml [95%CI: -2.95 to -1.73]) groups, with the placebo group having a slightly greater decrease (1.03 ng/ml [95%CI: 0.19 to 1.88]). Most (10 of 12) sub-study participants had normal synovial thickness scores at baseline. One participant had mild synovitis in each of the placebo and CL groups. Synovitis status was stable for all except two participants, one each in the CL and placebo group, whose synovitis score increased., Conclusion: This is the first study that explored the effect of CL treatment on local and systemic inflammation using biochemical markers and CE-MRI outcomes on knee OA patients. Secondary analyses from this pilot study suggest that CL is unlikely to have clinically significant effects on systemic (inflammatory and cartilage) or local synovitis (CE-MRI) biomarkers compared to placebo. The mechanism of action for CL effect on pain remains unclear., Competing Interests: Declaration of Competing Interests All authors have agreed that they have no conflicts of interest related to this study. Natural Remedies Pvt. Ltd. provided the CL and placebo according to the investigators’ standardisation requirements. None of the investigators has any direct association with the company or received any additional support from them. The study's planning, execution, analysis, the writing of the manuscript, and the choice to submit it for publication were all done independently from the funders of the project., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Objective: To evaluate the effect of annual infusions of zoledronic acid (ZA) with or without a single injection of methylprednisolone, compared to placebo, on quantitative magnetic resonance imaging 3-D bone area and bone shape in participants with symptomatic knee osteoarthritis (OA)., Methods: This was a post-hoc analysis of the ZAP2 trial. Active appearance modelling was used to assess bone area (mm 2 ) and femur bone shape (B-score) in 262 participants (mean 61.8 ± 8.0 years, 51% female) at baseline, 6, and 24 months. Radiographic joint space narrowing (JSN) was measured at baseline. An 'OA shape' was defined as a B-score of >1.96., Results: At baseline 65% of participants demonstrated an OA shape. Treatment with ZA plus methylprednisolone but not ZA alone, compared to placebo, was associated with significantly slower expansion in bone area at the medial femoral (-33.9 mm 2 , 95% confidence interval [CI] -61.8 to -6.0) and lateral femoral (-22.0 mm 2 , 95%CI -40.7 to -3.4) compartments over 24 months. B-score increased in all groups, with no significant between-group differences. There were significant interactions of JSN (grade 0 vs grade 1-2) and B-score (≤1.96 vs >1.96) with treatment effect on bone area (p < 0.05), such that ZA plus methylprednisolone slowed the expansion of medial and lateral femoral bone area over 24 months in participants with JSN grade 1-2 or a B-score of >1.96., Conclusions: ZA plus methylprednisolone may retard expansion of bone area over 24 months, but ZA alone may not. Neither ZA with or without methylprednisolone slowed progression of bone shape over 6 or 24 months., Competing Interests: Declaration of Competing Interest LLL reports personal fees from Amgen Pty Ltd, outside the submitted work. MB is an employee of Imorphics Ltd, a company providing measurement of imaging biomarkers, which is wholly owned by Stryker Corp, and MB has share options in that company. PGC has done consultancies or speakers bureaus for AbbVie, Amgen, AstraZeneca, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Novartis, Pfizer, Stryker and UCB. LM has received funding unrelated to this study with grants from Janssen and speaker fees from Pfizer, Abbvie, Lilly. TW reports personal fees from AMGEN, outside the submitted work. GJ reports personal fees from BMS, Roche, AbbVie, Amgen, Lilly, Novartis, Jannsen, and grants from Covance, outside the submitted work. Other authors declare that they have no other conflict of interests., (Copyright © 2022. Published by Elsevier Inc.)

Background: Knee osteoarthritis is the most prevalent chronic musculoskeletal debilitating disease. Current treatments are only symptomatic, and to improve this, we need a robust prediction model to stratify patients at an early stage according to the risk of joint structure disease progression. Some genetic factors, including single nucleotide polymorphism (SNP) genes and mitochondrial (mt)DNA haplogroups/clusters, have been linked to this disease. For the first time, we aim to determine, by using machine learning, whether some SNP genes and mtDNA haplogroups/clusters alone or combined could predict early knee osteoarthritis structural progressors., Methods: Participants (901) were first classified for the probability of being structural progressors. Genotyping included SNP genes TP63, FTO, GNL3, DUS4L, GDF5, SUPT3H, MCF2L, and TGFA; mtDNA haplogroups H, J, T, Uk, and others; and clusters HV, TJ, KU, and C-others. They were considered for prediction with major risk factors of osteoarthritis, namely, age and body mass index (BMI). Seven supervised machine learning methodologies were evaluated. The support vector machine was used to generate gender-based models. The best input combination was assessed using sensitivity and synergy analyses. Validation was performed using tenfold cross-validation and an external cohort (TASOAC)., Results: From 277 models, two were defined. Both used age and BMI in addition for the first one of the SNP genes TP63, DUS4L, GDF5, and FTO with an accuracy of 85.0%; the second profits from the association of mtDNA haplogroups and SNP genes FTO and SUPT3H with 82.5% accuracy. The highest impact was associated with the haplogroup H, the presence of CT alleles for rs8044769 at FTO, and the absence of AA for rs10948172 at SUPT3H. Validation accuracy with the cross-validation (about 95%) and the external cohort (90.5%, 85.7%, respectively) was excellent for both models., Conclusions: This study introduces a novel source of decision support in precision medicine in which, for the first time, two models were developed consisting of (i) age, BMI, TP63, DUS4L, GDF5, and FTO and (ii) the optimum one as it has one less variable: age, BMI, mtDNA haplogroup, FTO, and SUPT3H. Such a framework is translational and would benefit patients at risk of structural progressive knee osteoarthritis., (© 2022. The Author(s).)

Background: There is an unmet need for treatments for knee osteoarthritis (OA). Effusion-synovitis is a common inflammatory phenotype of knee OA and predicts knee pain and structural degradation. Anti-inflammatory therapies, such as diacerein, may be effective for this phenotype. While diacerein is recommended for alleviating pain in OA patients, evidence for its effectiveness is inconsistent, possibly because studies have not targeted patients with an inflammatory phenotype. Therefore, we will conduct a multi-centre, randomised, placebo-controlled double-blind trial to determine the effect of diacerein on changes in knee pain and effusion-synovitis over 24 weeks in patients with knee OA and magnetic resonance imaging (MRI)-defined effusion-synovitis., Methods: We will recruit 260 patients with clinical knee OA, significant knee pain, and MRI-detected effusion-synovitis in Hobart, Melbourne, Adelaide, and Perth, Australia. They will be randomly allocated to receive either diacerein (50mg twice daily) or identical placebo for 24 weeks. MRI of the study knee will be performed at screening and after 24 weeks of intervention. The primary outcome is improvement in knee pain at 24 weeks as assessed by a 100-mm visual analogue scale (VAS). Secondary outcomes include improvement in volumetric (ml) and semi-quantitative (Whole-Organ Magnetic Resonance Imaging Score, 0-3) measurements of effusion-synovitis using MRI over 24 weeks, and improvement in knee pain (VAS) at 4, 8, 12, 16, and 20 weeks. Intention-to-treat analyses of primary and secondary outcomes will be performed as the primary analyses. Per protocol analyses will be performed as the secondary analyses., Discussion: This study will provide high-quality evidence to determine whether diacerein improves pain, changes disease trajectory, and slows disease progression in OA patients with effusion-synovitis. If diacerein proves effective, this has the potential to significantly benefit the substantial proportion (up to 60%) of knee OA patients with an inflammatory phenotype., Trial Registration: Australian and New Zealand Clinical Trial Registry ACTRN12618001656224 . Registered on 08 October 2018., (© 2022. The Author(s).)

Background: A socioeconomic gradient exists in the utilisation of total hip replacements (THR) and total knee replacements (TKR) for osteoarthritis. However, the relations between socioeconomic status (SES) and time to THR or TKR is unknown., Aim: To describe the association between SES and time to THR and TKR., Methods: One thousand and seventy-two older adults residing in Tasmania, Australia, were studied. Incident primary THR and TKR were determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. At baseline, each participant's area-level SES was determined using the Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) from the Australian Bureau of Statistics' 2001 census data. The IRSAD was analysed in two ways: (i) categorised into quartiles, whereby quartile 1 represented the most socioeconomically disadvantaged group; and (ii) the cohort dichotomised at the quartile 1 cut-point., Results: The mean age was 63.0 (±7.5) years and 51% were women. Over the median follow up of 12.9 (interquartile range: 12.2-13.9) years, 56 (5%) participants had a THR and 79 (7%) had a TKR. Compared with the most disadvantaged quartile, less disadvantaged participants were less likely to have a THR (i.e. less disadvantaged participants had a longer time to THR; hazard ratio (HR): 0.56; 95% confidence interval (CI) 0.32, 1.00) but not TKR (HR: 0.90; 95% CI 0.53, 1.54). However, the former became non-significant after adjustment for pain and radiographic osteoarthritis, suggesting that the associations may be mediated by these factors., Conclusions: The present study suggests that time to joint replacement was determined according to the symptoms/need of the participants rather than their SES., (© 2020 Royal Australasian College of Physicians.)

Objective: To describe the association between change in subchondral bone marrow lesions (BMLs) and change in tibiofemoral cartilage volume and knee symptoms in patients with symptomatic knee OA., Methods: In total, 251 participants (mean 61.7 years, 51% female) were included. Tibiofemoral cartilage volume was measured at baseline and 24 months, and BML size at baseline, 6 and 24 months. Knee pain and function scores were evaluated at baseline, 6 and 24 months. Change in total and compartment-specific BML size was categorized according to the Least Significance Criterion. Linear mixed-effects models were used to evaluate the associations of change in BMLs over 6 and 24 months with change in cartilage volume over 24 months and knee symptoms over 6 and 24 months., Results: Total BML size enlarged in 26% of participants, regressed in 31% and remained stable in 43% over 24 months. Compared with stable BMLs in the same compartment, enlarging BMLs over 24 months were associated with greater cartilage loss (difference: -53.0mm3, 95% CI: -100.0, -6.0), and regressing BMLs were not significantly associated with reduced cartilage loss (difference: 32.4mm3, 95% CI: -8.6, 73.3) over 24 months. Neither enlargement nor regression of total BML size over 6 and 24 months was associated with change in knee pain and function over the same time intervals., Conclusions: In subjects with symptomatic knee osteoarthritis and BMLs, enlarging BMLs may lead to greater cartilage loss but regressing lesions are not associated with reduced cartilage loss while neither is associated with change in knee symptoms., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: To describe demographic and clinical factors associated with the presence and incidence of depression and explore the temporal relationship between depression and joint symptoms in patients with symptomatic knee osteoarthritis (OA)., Methods: Three hundred ninety-seven participants were selected from a randomized controlled trial in people with symptomatic knee OA and vitamin D deficiency (age 63.3 ± 7.1 year, 48.6% female). Depression severity and knee joint symptoms were assessed using the patient health questionnaire (PHQ-9) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively, at baseline and 24 months., Results: The presence and incidence of depression was 25.4 and 11.2%, respectively. At baseline, having younger age, a higher body mass index (BMI), greater scores of WOMAC pain (PR: 1.05, 95%CI:1.03, 1.07), dysfunction (PR: 1.02, 95%CI:1.01, 1.02) and stiffness (PR: 1.05, 95%CI: 1.02, 1.09), lower education level, having more than one comorbidity and having two or more painful body sites were significantly associated with a higher presence of depression. Over 24 months, being female, having a higher WOMAC pain (RR: 1.05, 95%CI: 1.02, 1.09) and dysfunction score (RR: 1.02, 95%CI: 1.01, 1.03) at baseline and having two or more painful sites were significantly associated with a higher incidence of depression. In contrast, baseline depression was not associated with changes in knee joint symptoms over 24 months., Conclusion: Knee OA risk factors and joint symptoms, along with co-existing multi-site pain are associated with the presence and development of depression. This suggests that managing common OA risk factors and joint symptoms may be important for prevention and treatment depression in patients with knee OA., Trial Registration: ClinicalTrials.gov identifier: NCT01176344 . Anzctr.org.au identifier: ACTRN12610000495022 .

Background: Current pharmacologic therapies for patients with osteoarthritis are suboptimal., Objective: To determine the efficacy of Curcuma longa extract (CL) for reducing knee symptoms and effusion-synovitis in patients with symptomatic knee osteoarthritis and knee effusion-synovitis., Design: Randomized, double-blind, placebo-controlled trial. (Australian New Zealand Clinical Trials Registry: ACTRN12618000080224)., Setting: Single-center study with patients from southern Tasmania, Australia., Participants: 70 participants with symptomatic knee osteoarthritis and ultrasonography-defined effusion-synovitis., Intervention: 2 capsules of CL ( n  = 36) or matched placebo ( n  = 34) per day for 12 weeks., Measurements: The 2 primary outcomes were changes in knee pain on a visual analogue scale (VAS) and effusion-synovitis volume on magnetic resonance imaging (MRI). The key secondary outcomes were change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and cartilage composition values. Outcomes were assessed over 12 weeks., Results: CL improved VAS pain compared with placebo by -9.1 mm (95% CI, -17.8 to -0.4 mm [ P  = 0.039]) but did not change effusion-synovitis volume (3.2 mL [CI, -0.3 to 6.8 mL]). CL also improved WOMAC knee pain (-47.2 mm [CI, -81.2 to -13.2 mm]; P  = 0.006) but not lateral femoral cartilage T2 relaxation time (-0.4 ms [CI, -1.1 to 0.3 ms]). The incidence of adverse events was similar in the CL ( n  = 14 [39%]) and placebo ( n  = 18 [53%]) groups ( P  = 0.16); 2 events in the CL group and 5 in the placebo group may have been treatment related., Limitation: Modest sample size and short duration., Conclusion: CL was more effective than placebo for knee pain but did not affect knee effusion-synovitis or cartilage composition. Multicenter trials with larger sample sizes are needed to assess the clinical significance of these findings., Primary Funding Source: University of Tasmania and Natural Remedies Private Limited.

Aims: To describe the associations between interindividual (between-person) and intraindividual (within-person) variability in physical activity (PA) and knee pain and functional limitation among older adults. We also investigated the potential bidirectional association of between-person and within-person variability in knee pain and functional limitation with PA., Method: Participants (N = 1064; 51% women; mean age 63 ± 7.4 years) were measured at baseline, 2.5, and 5 years. PA was measured using pedometers. Knee pain and functional limitation were assessed using the WOMAC scale. A two-part hurdle model, with adjustment for confounders, estimated the association of between-person and within-person variability in PA with knee pain/functional limitation (as the outcome). Linear mixed effect regression models described the association of between-person and within-person variability in knee pain and functional limitation with PA (as the outcome)., Results: Between-person effects showed that participants with a higher 5-year average PA had lower average WOMAC scores (β= -1.17, 95% CI: -1.82, -0.51). Within-person effects showed that at time-points when participants had a higher PA level than average, they also had lower WOMAC scores (β= -0.85, 95% CI: -1.36, -0.35). Conversely, both between-person (β= -15.6, 95% CI: -22.5, -8.8) and within-person increase (β= -7.4, 95% CI: -13.5, -1.4) in WOMAC scores were associated with lower PA., Conclusion: These findings suggest that PA and knee pain/dysfunctional contribute to the development of one another. Pain can lead to changes in inter- and intraindividual PA levels, but the reverse is also possible - changes in PA results in changes in inter- and intraindividual pain/dysfunctional levels., Competing Interests: Declaration of Competing Interest All authors listed on this manuscript certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Hip effusion-synovitis may be relevant to osteoarthritis (OA) but is of uncertain etiology. The aim of this study was to describe the cross-sectional and longitudinal associations of hip effusion-synovitis with clinical and structural risk factors of OA in older adults., Methods: One hundred ninety-six subjects from the Tasmanian Older Adult Cohort (TASOAC) study with a right hip STIR (Short T1 Inversion Recovery) Magnetic Resonance Imaging (MRI) on two occasions were included. Hip effusion-synovitis CSA (cm 2 ) was assessed quantitatively. Hip pain was determined by WOMAC (Western Ontario and McMaster Universities Osteoarthritis) while hip bone marrow lesions (BMLs), cartilage defects (femoral and/or acetabular) and high cartilage signal were assessed on MRI. Joint space narrowing (0-3) and osteophytes (0-3) were measured on x-ray using Altman's atlas., Results: Of 196 subjects, 32% (n = 63) had no or a small hip effusion-synovitis while 68% (n = 133) subjects had a moderate or large hip effusion-synovitis. Both groups were similar but those with moderate or large hip effusion-synovitis were older, had higher BMI and more hip pain. Cross-sectionally, hip effusion-synovitis at multiple sites was associated with presence of hip pain [Prevalence ratio (PR):1.42 95%CI:1.05,1.93], but not with severity of hip pain. Furthermore, hip effusion-synovitis size associated with femoral defect (βeta:0.32 95%CI:0.08,0.56). Longitudinally, and incident hip cartilage defect (PR: 2.23 95%CI:1.00, 4.97) were associated with an increase in hip effusion-synovitis CSA. Furthermore, independent of presence of effusion-synovitis, hip BMLs predicted incident (PR: 1.62 95%CI: 1.13, 2.34) and worsening of hip cartilage defects (PR: 1.50 95%CI: 1.20, 1.86). While hip cartilage defect predicted incident (PR: 1.11 95%CI: 1.03, 1.20) and worsening hip BMLs (PR: 1.16 95%CI: 1.04, 1.30)., Conclusions: Hip effusion-synovitis at multiple sites (presumably reflecting extent) may be associated with hip pain. Hip BMLs and hip cartilage defects are co-dependent and predict worsening hip effusion-synovitis, indicating causal pathways between defects, BMLs and effusion-synovitis.

Objectives: To identify subgroups of community-dwelling older adults and to assess their longitudinal associations with long-term osteoarthritis (OA) outcomes., Methods: 1046 older adults aged 50-80 years were studied. At baseline, body mass index (BMI), pedometer-measured ambulatory activity (AA), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) determined knee pain and information on comorbidities were obtained. Tibial cartilage volume and bone-marrow lesions (BMLs) were assessed using MRI at baseline and 10 years and total knee replacements (TKR) by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Latent class analysis was used to determine participant subgroups, considering baseline BMI, AA, pain and comorbidities, and linear mixed-effects or log-binomial models were used to assess the associations., Results: Three subgroups/classes were identified: subgroup 1 (43%): Normal/overweight participants with higher AA, lower pain and lower comorbidities; subgroup 2 (32%): Overweight participants with lower AA, mild pain and higher comorbidities; subgroup 3 (25%): Obese participants with lower AA, mild pain and higher comorbidities. Subgroup 3 had greater cartilage volume loss (β - 60.56 mm 3 , 95% CI - 105.91, - 15.21) and a higher risk of TKR (RR 3.19, 95% CI 1.75, 5.81), compared to subgroup 1. Subgroup 2 was not associated with cartilage volume change (β 13.06 mm 3 , 95% CI - 30.87, 57.00) or risk of TKR (RR 1.16, 95% CI 0.56, 2.36), compared to subgroup 1. Subgroup membership was not associated with worsening BMLs., Conclusions: Our findings suggest the existence of homogeneous subgroups of participants and support the utility of identifying patterns of characteristics/risk factors that may cluster together and using them to identify subgroups of people who may be at a higher risk of developing and/or progressing OA. Key Points • Complex interplay among characteristics/factors leads to conflicting evidence between ambulatory activity and knee osteoarthritis. • Distinct subgroups are identifiable based on ambulatory activity, body mass index, knee pain, and comorbidities. • Identifying subgroups can be used to determine those who are at risk of developing/progressing osteoarthritis.

Importance: A proof-of-principle study suggested that intravenous zoledronic acid may reduce knee pain and the size of bone marrow lesions in people with knee osteoarthritis, but data from large trials are lacking., Objective: To determine the effects of intravenous zoledronic acid on knee cartilage volume loss in patients with symptomatic knee osteoarthritis and bone marrow lesions., Design, Setting, and Participants: A 24-month multicenter, double-blind placebo-controlled randomized clinical trial conducted at 4 sites in Australia (1 research center and 3 hospitals). Adults aged 50 years or older with symptomatic knee osteoarthritis and subchondral bone marrow lesions detected by magnetic resonance imaging (MRI) were enrolled from November 2013 through September 2015. The final date of follow-up was October 9, 2017., Interventions: Intravenous infusion with either 5 mg of zoledronic acid in a 100-mL saline solution (n = 113) or a placebo saline solution (n = 110) at baseline and 12 months., Main Outcomes and Measures: The primary outcome was absolute change in tibiofemoral cartilage volume assessed using MRI over 24 months (the minimum clinically important difference [MCID] has not been established). Three prespecified secondary outcomes were change in knee pain assessed by a visual analog scale (0 [no pain] to 100 [unbearable pain]; MCID, 15) and the Western Ontario and McMaster Universities Osteoarthritis Index (0 [no pain] to 500 [unbearable pain]; MCID, 75) over 3, 6, 12, 18, and 24 months and change in bone marrow lesion size over 6 and 24 months (the MCID has not been established)., Results: Of 223 participants enrolled (mean age, 62.0 years [SD, 8.0 years]; 52% were female), 190 (85%) completed the trial. Change in tibiofemoral cartilage volume was not significantly different between the zoledronic acid group and the placebo group over 24 months (-878 mm3 vs -919 mm3; between-group difference, 41 mm3 [95% CI, -79 to 161 mm3]; P = .50). No significant between-group differences were found for any of the prespecified secondary outcomes, including changes in knee pain assessed by a visual analog scale (-11.5 in the zoledronic acid group vs -16.8 in the placebo group; between-group difference, 5.2 [95% CI, -2.3 to 12.8]; P = .17), changes in knee pain assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (-37.5 vs -58.0, respectively; between-group difference, 20.5 [95% CI, -11.2 to 52.2]; P = .21), and changes in bone marrow lesion size (-33 mm2 vs -6 mm2; between-group difference, -27 mm2 [95% CI, -127 to 73 mm2]; P = .60) over 24 months. Adverse events were more common with zoledronic acid than with placebo (96% vs 83%, respectively) and consisted mainly of acute reactions (defined as symptoms within 3 days of administration of infusion; 87% vs 56%)., Conclusions and Relevance: Among patients with symptomatic knee osteoarthritis and bone marrow lesions, yearly zoledronic acid infusions, compared with placebo, did not significantly reduce cartilage volume loss over 24 months. These findings do not support the use of zoledronic acid in the treatment of knee osteoarthritis., Trial Registration: anzctr.org.au Identifier: ACTRN12613000039785.

Objectives: To determine the effect of vitamin D supplementation and maintaining sufficient serum vitamin D on depressive symptoms in patients with knee osteoarthritis (OA) and vitamin D deficiency., Design: A prespecified secondary analysis of a multicentre, randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive oral vitamin D 3 (50,000 IU, n = 209) or placebo (n = 204) monthly for 24 months. In addition, participants who completed the trial were classified into 2 groups according to their serum 25(OH)D levels at month 3 and 24 as follows: not consistently sufficient (serum 25(OH)D ≤ 50 nmol/L at month 3 and/or 24), and consistently sufficient (serum 25(OH)D > 50 nmol/L at both month 3 and 24). Multilevel mixed-effect models were used to compare differences of change in PHQ-9 scores between groups., Setting and Participants: This clinical trial was conducted in participants with symptomatic knee OA and vitamin D deficiency from June 2010 to December 2013 in Tasmania and Victoria, Australia., Measures: The primary outcome was the depressive symptoms change over 24 months, which was measured using the Patient Health Questionnaire (PHQ-9, 0-27)., Results: Of 599 participants who were screened for eligibility, 413 participants were enrolled (mean age: 63.2 years; 50.3% female) and 340 participants (intervention n = 181, placebo n = 159, 82.3% retention rate) completed the study. The baseline prevalence of depression (PHQ-9 score ≥5) was 25.4%. Depressive symptoms improved more in the vitamin D supplementation group compared to the placebo group [β: -0.66, 95% confidence interval (CI): -1.22 to -0.11, P for difference = .02] and in the participants who maintained vitamin D sufficiency compared to those who did not (β: -0.73, 95% CI: -1.41 to -0.05, P for difference = .04) over 24 months., Conclusions/implications: These findings suggest that vitamin D supplementation and maintaining adequate vitamin D levels over 24 months may be beneficial for depressive symptoms in patients with knee OA., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Resistin acts as an endogenous ligand of Toll-like receptor (TLR)-4 that triggers major inflammatory pathways and mediates inflammatory processes. The role of resistin in osteoarthritis (OA) pathogenesis is unclear. The aim of this study is to describe the longitudinal associations of serum levels of resistin with knee synovitis measures and structural abnormalities in patients with knee OA., Design: A prospective cohort study., Setting and Participants: Patients (n = 200) with symptomatic knee OA (mean age 63.1 years, range 49-79; female 46.5%) participated., Measures: All measures were performed at baseline and 2 years later. Serum resistin was measured using enzyme-linked immunosorbent assay. Infrapatellar fat pad (IPFP) high signal intensity alteration and effusion synovitis were measured from magnetic resonance imaging (MRI). Knee structures including cartilage volume, cartilage defects, and bone marrow lesions (BMLs) were also assessed by MRI semiquantitatively or quantitatively. Linear or logistic mixed effects regression analyses were used in longitudinal analyses., Results: Serum resistin was positively associated with high signal intensity alteration measures of IPFP as well as the presence [relative risk = 1.06, 95% confidence interval (CI) 1.02, 1.10] and volume (β = 0.77, 95% CI 0.01, 1.53) of effusion synovitis in multivariable analyses. Serum levels of resistin were also positively associated with higher tibiofemoral cartilage defect (β = 1.98, 95% CI 0.34, 3.57) and BML scores (β = 3.18, 95% CI 0.99, 5.37) after adjustment for covariates., Conclusion and Implications: Higher serum levels of resistin are associated with knee synovitis surrogate measures and structural abnormalities, suggesting that obesity may promote OA not only by increasing weight loading on joints but also by triggering 1 or more inflammatory pathways., (Copyright © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

To identify serum biomarker(s) for predicting knee cartilage volume loss over time, we studied 139 knee osteoarthritis (OA) patients from a previous 24-month clinical trial cohort. Targeted metabolomic profiling was performed on serum collected at baseline. The pairwise metabolite ratios as proxies for enzymatic reaction were calculated and used in the analysis. Cartilage volume loss between baseline and 24 months was assessed quantitatively by magnetic resonance imaging (MRI). Data revealed an association between the serum ratio of lysophosphatidylcholine 18:2 (lysoPC 18:2) to phosphatidylcholine 44:3 (PC44:3) and the cartilage volume loss in the lateral compartment (β = -0.21 ± 0.04, p = 8.53*10 -7 ) and with joint degradation markers, COMP (r = 0.32, p = 0.0002) and MMP1 (r = 0.26, p = 0.002). The significance remained after adjustment for age, sex, BMI, diabetes, hypertension, dyslipidemia, and the treatment taken in the original study. As the ratio indicated the over activation of the conversion pathway of PC to lysoPC catalyzed by phospholipase A 2 (PLA 2 ), we assessed and found that a specific PLA 2 , PLA 2 G5, was significantly increased in human OA cartilage and synovial membrane (85% and 19% respectively, both p < 0.04) compared to controls, and its overexpression correlated with IL-6 (r = 0.63, p = 0.0008). Our data suggest that the serum lysoPC 18:2 to PC44:3 ratio is highly associated with a greater risk of cartilage volume loss of the knee and warrants further investigation in an independent cohort.

Objective: To describe the cross-sectional and longitudinal associations between quantitative measures of infrapatellar fat pad (IPFP) signal-intensity alteration and knee structural abnormalities in patients with symptomatic knee osteoarthritis (OA)., Methods: A total of 261 patients (mean ± SD age 63.0 ± 7.2 years) with symptomatic knee OA were selected from a randomized controlled trial with a follow-up of 2 years. IPFP signal-intensity alterations at baseline were quantitatively measured on T2-weighted fat-saturated magnetic resonance imaging using MATLAB. These quantitative measures included the SD of whole IPFP signal intensity measurement, the upper quartile value of high signal intensity (UQ H ), the ratio of volume of high signal-intensity alteration to volume of whole IPFP (percentage H ), and the clustering effect of high signal intensity (clustering-factor H ). Cartilage volume and defects and bone marrow lesions (BMLs) were assessed using validated measures., Results: Higher baseline SD of the IPFP, UQ H , and clustering-factor H were associated with greater loss of tibial cartilage volume and larger increases in tibiofemoral cartilage defects over 2 years. Patients with high and medium tertiles of clustering-factor H had greater loss of cartilage volume per annum compared with those with a low tertile (for high 4.9%, for medium 4.6%, and for low 3.3% annually). Baseline percentage H and clustering-factor H were positively and significantly associated with increases in tibiofemoral BMLs over 2 years. Cross-sectional associations between IPFP measures and knee structures were similar but more consistent., Conclusion: Quantitative measures of increased signal intensity in the IPFP were associated with knee structural abnormalities in the tibiofemoral compartment, suggesting that these measurements could be used as an additional entry criterion to enrich studies for faster progressors of knee OA., (© 2018, American College of Rheumatology.)

Objective: To identify and validate knee pain phenotypes in an older population across different pain-related domains over 10.7 years., Methods: A total of 963 participants (mean age 63 years) from a population-based older adult cohort study were studied at baseline and followed up at 2.6 (n = 875), 5.1 (n = 768) and 10.7 years (n = 563). Baseline demographic, psychological, lifestyle and comorbidities data were obtained and MRI was performed to measure knee structural pathology. WOMAC pain and pain at multiple sites were assessed by questionnaires at each time-point. Latent class analysis was used to identify knee pain phenotypes, considering sex, BMI, emotional problems, education level, comorbidities, number of painful sites and knee structural pathology., Results: Three pain phenotypes were identified: Class 1: high prevalence of emotional problems and low prevalence of structural damage (25%); Class 2: high prevalence of structural damage and low prevalence of emotional problems (20%); Class 3: low prevalence of emotional problems and low prevalence of structural damage (55%). Participants within Class 1 and 2 had greater BMI, more comorbidities, a higher prevalence of radiographic knee OA and knee structural pathology compared with Class 3. Furthermore, compared with Class 2 and 3, WOMAC pain and number of painful sites were consistently greater at each time-point over 10.7 years in Class 1. Results were similar when the analyses were restricted to participants with radiographic knee OA., Conclusion: Psychological and structural factors interact with each other to exacerbate pain perception, suggesting that tailored treatment approaches for older people with knee pain in clinical practice are needed.

Background: Bisphosphonates are a class of drugs that slow bone loss and are a promising candidate to treat knee osteoarthritis (OA) patients. In a pilot study, we demonstrated that zoledronic acid reduced knee pain and size of subchondral bone marrow lesions (BMLs) over 6 months in knee OA patients with significant knee pain and BMLs. A longer, larger study is required to assess whether decreases in BML size will translate to reductions in cartilage loss over time. We are currently conducting a multicentre, randomised, double-blind, placebo-controlled trial over 24 months that aims to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change (assessed using magnetic resonance imaging (MRI)) and knee pain in knee OA patients., Methods: Two hundred sixty-four patients with clinical knee OA, significant knee pain and subchondral BMLs present on MRI will be recruited in Hobart, Melbourne, Sydney and Adelaide. They will be randomly allocated to the two arms of the study, receiving an annual identical intravenous infusion of either 100 mL of fluid containing zoledronic acid (5 mg/100 mL) or placebo (0.9% NaCl 100 mL), at baseline and 1 year later. MRI of the study knee will be performed at screening, month 6 and 24. Knee structure, symptoms and function will be assessed using validated methods. The primary outcome is absolute change in tibiofemoral cartilage volume (mm 3 ) over 24 months. Secondary outcomes include improvement in knee pain over 3, 6, 12, 18, and 24 months and reductions in BML size over 6 and 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses will be performed as the secondary analyses., Discussion: This study will provide high-quality evidence to assess whether zoledronic acid has a novel disease modifying effect in OA by slowing cartilage loss and reducing pain. If zoledronic acid proves effective, it suggests great potential for cost savings through a delay or reduced need for joint replacement surgery, and potential for great improvements in quality of life for OA suffers., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12613000039785 , registered on 14 January 2013.

The aim of this study was to determine whether vitamin D supplementation and maintaining vitamin D sufficiency are associated with changes in inflammatory and metabolic biomarkers in patients with knee osteoarthritis (OA) and vitamin D deficiency. A total of 413 participants with symptomatic knee OA and vitamin D deficiency were enrolled in a randomised, placebo-controlled trial and received 1·25 mg vitamin D3 or placebo monthly for 24 months across two sites. In this post hoc analysis, 200 participants from one site (ninety-four from the placebo group and 106 from the vitamin D group; mean age 63·1 (sd 7·3) years, 53·3 % women) were randomly selected for measurement of serum levels of inflammatory and metabolic biomarkers at baseline and 24 months using immunoassays. In addition, participants were classified into two groups according to serum 25-hydroxyvitamin D (25(OH)D) levels at months 3 and 24: (1) not consistently sufficient (25(OH)D≤50 nmol/l at either month 3 or 24, n 61), and (2) consistently sufficient (25(OH)D>50 nmol/l at both months 3 and 24, n 139). Compared with placebo, vitamin D supplementation had no significant effect on change in serum high-sensitive C-reactive protein, IL-6, IL-8, IL-10, leptin, adiponectin, resistin, adipsin and apelin. Being consistently vitamin D sufficient over 2 years was also not associated with changes in these biomarkers compared with not being consistently sufficient. Vitamin D supplementation and maintaining vitamin D sufficiency did not alter serum levels of inflammatory and metabolic biomarkers over 2 years in knee OA patients who were vitamin D insufficient, suggesting that they may not affect systemic inflammation in knee OA patients.

The objective of this study was to investigate the associations of knee structural abnormalities with different patterns of pain. A total of 891 participants (average age 63 years; range 50 to 80 years) participated in this study. Presence of pain at the neck, back, hands, shoulders, hips, knees, and feet was assessed by questionnaire. Participants were categorized as having no pain at any site (no pain), pain only at the knee (KP), pain at other sites but not the knee (OP), and pain at the knee and other sites (KOP). T1-weighted or T2-weighted MRI of the right knee was performed to measure cartilage defects, bone marrow lesions (BMLs), and effusion-synovitis. Osteophytes and joint space narrowing were assessed by X-ray. KP, KOP, and OP were, respectively, present in 3, 43, and 42% of the participants. In multivariable analyses, KOP was associated with the presence of cartilage defects, BMLs, and osteophytes (OR 3.57 (95% CI 1.78 to 7.14), 2.37 (1.27 to 4.43), and 2.87 (1.10 to 7.51), respectively) in those with radiographic knee OA. KP was also associated with presence of these structural abnormalities as well as effusion-synovitis, and these associations were much stronger. The associations between structural abnormalities and KOP were weaker than those with KP in those with radiographic knee OA. This suggests that mechanisms mediating the association between structural pathology, localized, and generalized pain may be different, and central sensitization is possibly involved in generalized pain. Pain at other sites needs to be considered in the management and treatment of OA-related pain.

Background: The aim of this study was to describe whether maintaining sufficient serum vitamin D levels in people with knee osteoarthritis and baseline vitamin D insufficiency has an association with change in knee structures and symptoms over 2 years., Methods: Participants (n = 413, mean age 63.2 years) with symptomatic knee osteoarthritis and vitamin D insufficiency were enrolled in a clinical trial. In all, 340 participants (82.3%) completed the study, with 25-hydroxyvitamin D [25(OH)D] measurements at baseline and months 3 and 24. Participants were classified as consistently insufficient [serum 25(OH)D ≤50 nmol/L at months 3 and 24, n = 45], fluctuating [25(OH)D >50 nmol/L at either point, n = 68), and consistently sufficient [25(OH)D >50 nmol/L at months 3 and 24, n = 226] groups. Knee cartilage volume, cartilage defects, bone marrow lesions, and effusion-synovitis volume were assessed using MRI at baseline and month 24. Knee symptoms were assessed at baseline and months 3, 6, 12, and 24 using the Western Ontario and McMaster Universities Arthritis Index., Results: The consistently sufficient group had significantly less loss of tibial cartilage volume (β 2.1%; 95% confidence interval [CI], 0.3%, 3.9%), less increase in effusion-synovitis volume (β -2.5 mL; 95 CI%, -4.7, -0.2 mL), and less loss of Western Ontario and McMaster Universities Arthritis Index physical function (β -94.2; 95% CI, -183.8, -4.5) compared with the consistently insufficient group in multivariable analyses. In contrast, there were no significant differences in these outcomes between the fluctuating and consistently insufficient groups. Changes in cartilage defects, bone marrow lesions, and knee pain were similar between groups., Conclusion: This post hoc analysis suggests beneficial effects of maintaining vitamin D sufficiency on cartilage loss, effusion-synovitis, and physical function in people with knee osteoarthritis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: There are few clinical and epidemiological studies reporting the association between abnormal changes within the IPFP and knee osteoarthritic changes. This study aims to describe the associations between hypointense signals in the infrapatellar fat pad (IPFP) and knee structural change and symptoms in older adults., Methods: Participants (n = 874) were selected randomly from local community and followed up 2.7 years later (range 2.6-3.3 years). T1- or T2-weighted fat-suppressed magnetic resonance imaging (MRI) was assessed for IPFP hypointense signal, cartilage volume, cartilage defects, and bone marrow lesions (BMLs). Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index (WOMAC) questionnaire. Radiographic osteoarthritis was assessed using the OARSI atlas., Results: Cross-sectionally, hypointense signals in the IPFP were significantly associated with a higher risk of knee cartilage defects at all sites, tibiofemoral BMLs and knee pain in multivariable analyses. Longitudinally, baseline signal abnormalities were significantly and positively associated with increases in knee cartilage defects (OR: 2.27, 95 % CI: 1.61-3.21), BMLs (OR: 1.91, 95 % CI: 1.39-2.62), and knee pain (OR: 1.36, 95 % CI: 1.05-1.76) in multivariable analyses. The associations with cartilage defects remained significant after adjustment for BMLs, but the associations with BMLs and knee pain decreased in magnitude or became non-significant after further adjustment for cartilage defects., Conclusions: Hypointense signals in the IPFP were associated primarily with increased knee cartilage defects and also with BMLs and knee symptoms in cross-sectional and longitudinal analyses, suggesting the abnormality represented by this signal has a potentially important role in osteoarthritis progression.

Objective: To describe the associations between infrapatellar fat pad (IPFP) signal intensity alteration at baseline and knee symptoms and structural changes in older adults., Methods: A total of 874 subjects (mean 62.1 years, 50.1% female) selected randomly from local community were studied at baseline and 770 were followed up (only 357 had MRI at follow-up) over 2.6 years. T1-weighted or T2-weighted fat suppressed MRI was used to assess IPFP signal intensity alteration (0-3), cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and 2.6 years later. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index questionnaire. Radiographic osteoarthritis (OA) was assessed., Results: In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with total knee pain as well as knee cartilage defects, BMLs and knee radiographic OA and negatively associated with patellar cartilage volume after adjustment for age, sex, body mass index and/or radiographic OA. Longitudinally, baseline signal intensity alteration within IPFP was significantly and positively associated with increases in knee pain when going upstairs/downstairs as well as increases in tibiofemoral cartilage defects and BMLs, and negatively associated with change in lateral tibial cartilage volume in multivariable analyses., Conclusions: IPFP signal intensity alteration at baseline was associated with knee structural abnormalities and clinical symptoms cross-sectionally and longitudinally in older adults, suggesting that it may serve as an important imaging biomarker in knee OA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To identify novel biomarker(s) for predicting advanced knee OA., Methods: Study participants were derived from the Newfoundland Osteoarthritis Study and the Tasmania Older Adult Cohort Study. All knee OA cases were patients who underwent total knee replacement (TKR) due to primary OA. Metabolic profiling was performed on fasting plasma. Four thousand and eighteen plasma metabolite ratios that were highly correlated with that in SF in our previous study were generated as surrogates for joint metabolism., Results: The discovery cohort included 64 TKR cases and 45 controls and the replication cohorts included a cross-sectional cohort of 72 TKR cases and 76 controls and a longitudinal cohort of 158 subjects, of whom 36 underwent TKR during the 10-year follow-up period. We confirmed the previously reported association of the branched chain amino acids to histidine ratio with advanced knee OA (P = 9.3 × 10(-7)) and identified a novel metabolic marker-the lysophosphatidylcholines (lysoPCs) to phosphatidylcholines (PCs) ratio-that was associated with advanced knee OA (P = 1.5 × 10(-7)) after adjustment for age, sex and BMI. When the subjects of the longitudinal cohort were categorized into two groups based on the optimal cut-off of the ratio of 0.09, we found the subjects with the ratio ⩾0.09 were 2.3 times more likely to undergo TKR than those with the ratio <0.09 during the 10-year follow-up (95% CI: 1.2, 4.3, P = 0.02)., Conclusion: We identified the ratio of lysoPCs to PCs as a novel metabolic marker for predicting advanced knee OA. Further studies are required to examine whether this ratio can predict early OA change., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: The aim of this study was to describe the correlation between changes in structural abnormalities assessed on magnetic resonance imaging (MRI) and change in radiographic osteoarthritis (OA) over 10 years in a midlife cohort., Methods: A total of 211 participants (mean age 45 years [range 26-61 years], 57% female) were studied at baseline, 2 years, and 10 years. Approximately one-half were adult offspring of subjects who had undergone knee replacement for OA and the remainders were randomly selected controls. Joint space narrowing (JSN) and osteophytes were assessed from radiographs, while cartilage volume, cartilage defects, and meniscal tears/extrusion were assessed from MRI. Spearman ranked correlation analysis was used to describe the correlation between structural changes assessed on MRI and radiographs. Only medial tibiofemoral compartment results are presented, as the lateral compartment had limited change., Results: Over 10 years, change in meniscal tears showed a moderate independent correlation with change in both JSN (ρ = +0.37, P < 0.01) and osteophytes (ρ = +0.31, P < 0.01) in the adjusted analysis. Meniscal extrusion (ρ = +0.22, P < 0.01) and cartilage defects (ρ = +0.16, P < 0.04) showed a slightly weaker independent correlation with JSN in the adjusted analysis, whereas cartilage volume loss showed no significant correlation with either of the 2 radiographic outcomes., Conclusion: Change in JSN is correlated with change in meniscal tears and, to a lesser extent, with meniscal extrusion and cartilage defects. In this sample, change in JSN is a composite measure that does not reflect cartilage volume loss, prompting the review of the use of JSN as an outcome measure in chondro-protective drug trials., (© 2016, American College of Rheumatology.)

Background: The aim of this study was to examine whether cartilage volume as measured by MRI and radiographic osteoarthritis (OA) at baseline predict cartilage volume loss over ten years independent of each other and other structural co-pathologies., Methods: 219 participants [mean-age 45(26-61); 57 % female] were studied at baseline and ten years. Approximately half were the adult offspring of subjects who underwent knee replacement for OA and the remainder were randomly selected controls. Joint space narrowing (JSN) and osteophytes were assessed on radiographs and cartilage volume (tibiofemoral), cartilage defects, bone marrow lesions and meniscal tears/extrusion were assessed on MRI., Results: Mean absolute and percentage per annum cartilage volume loss was 1284 mm(3) and 1.91 % respectively in the medial compartment and 1007 mm(3) and 1.38 % respectively in the lateral compartment. Higher baseline tibiofemoral cartilage volume was independently associated with greater absolute cartilage volume loss in both medial (β(95 % CI) = -300 (-399,-200)) and lateral (β = -338 (-443,-233)) compartments and percentage per annum loss in the lateral compartment(β = -0.15 (-0.29, -0.01)). Baseline JSN and osteophytes were associated with cartilage volume loss in the univariable analysis, however these associations did not persist after adjustment for other structural co-pathologies., Conclusion: Cross-sectional cartilage volume measurement independently predicts cartilage volume loss over 10 years and can be used to identify fast progressors in clinical trials. Radiographic JSN and osteophytes on the other hand are a reflection of other co-pathologies assessed on MRI and do not independently predict cartilage volume loss over 10 years.

Objectives: To determine whether high-dose fish oil is superior to low-dose supplementation for symptomatic and structural outcomes in knee osteoarthritis (OA)., Methods: A randomised, double-blind, multicentre trial enrolled 202 patients with knee OA and regular knee pain. They were randomised 1:1 to high-dose fish oil (4.5 g omega-3 fatty acids) 15 mL/day or (2) low-dose fish oil (blend of fish oil and sunola oil; ratio of 1:9, 0.45 g omega-3 fatty acids) 15 mL/day. The primary endpoints were Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score at 3, 6, 12 and 24 months, and change in cartilage volume at 24 months. Secondary outcomes included WOMAC function, quality of life, analgesic and non-steroidal anti-inflammatory drug use and bone marrow lesion score., Results: Although there was improvement in both groups, the low-dose fish oil group had greater improvement in WOMAC pain and function scores at 2 years compared with the high-dose group, whereas between-group differences at 1 year did not reach statistical significance. There was no difference between the two groups in cartilage volume loss at 2 years. For other secondary endpoints, there was no difference between the two groups at 2 years., Conclusions: In people with symptomatic knee OA, there was no additional benefit of a high-dose fish oil compared with low-dose fish oil. The combination comparator oil appeared to have better efficacy in reducing pain at 2 years, suggesting that this requires further investigation., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN 12607000415404)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objectives: To investigate cross-sectional and longitudinal associations between systemic bone mineral density (BMD), subchondral BMD (sBMD) and knee cartilage thickness in older adults with or without radiographic osteoarthritis (ROA)., Methods: A prospective cohort of 158 randomly selected subjects (mean 63 years, 48% women) including 69 non-ROA and 89 ROA subjects were studied at baseline and 2.7 years later. Knee cartilage thickness was semi-automatically determined from T1-weighted fat-suppressed MRI. Knee cartilage volume was measured from MRI. Systemic BMD and sBMD were measured by dual-energy X-ray absorptiometry (DXA)., Results: Cross-sectionally, total body, total hip, spine BMD and/or lateral tibial sBMD were significantly and positively associated with femoral, lateral tibial and/or patellar cartilage thickness in subjects with ROA after adjustment for potential confounders. Longitudinally, a high total body BMD was associated with an increase in femoral cartilage thickness (β: 0.33 mm/g/cm(2), 95% CI 0.13 to 0.53); a high spine BMD was associated with increases in femoral and lateral tibial cartilage thickness (β: 0.25 mm/g/cm(2), 95% CI 0.10 to 0.41; and β: 0.18 mm/g/cm(2), 95% CI: 0.01 to 0.34, respectively) and a high medial tibial sBMD was associated with an increase in medial tibial cartilage thickness (β: 0.45 mm/g/cm(2), 95% CI 0.02 to 0.89) in subjects with ROA. In contrast, there were no significant associations between baseline systemic BMD, sBMD and cartilage volume loss, nor were there associations between BMD and cartilage thickness in subjects without ROA., Conclusions: Both systemic and subchondral BMD are positively associated with increased cartilage thickness in subjects with ROA, suggesting BMD may play a protective role against cartilage loss in knee OA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To compare the responsiveness of magnetic resonance imaging (MRI)-derived measures of knee osteoarthritis over 2.7 years., Methods: There were 430 community-based participants (mean age 63.0 yrs, range 51-79 yrs; 51% female) measured at baseline and 2.7 years later. MRI of the right knee at both timepoints was performed to assess cartilage volume, cartilage defects, bone marrow lesions (BML), meniscal pathology, and tibial bone area. Global measurements were calculated as the sum of tibial and femoral measures. Standardized response mean (SRM) was calculated as the mean of change divided by the SD of change., Results: Global tibiofemoral cartilage volume and cartilage defects had the best SRM of -0.80 and 0.62, respectively. Site-specific measurements were lower (SRM range for cartilage volume -0.48 to -0.54 and cartilage defects 0.33 to 0.49). The SRM for BML was 0.12, meniscal pathology 0.39, and tibial bone area -0.09. Cartilage volume and/or defects tended to be more responsive in those with knee pain, those who were obese, those who were older, and those with radiographic osteoarthritis., Conclusion: Global cartilage volume demonstrated the best sensitivity to change, suggesting that if we relied solely on SRM to optimize clinical trial design, then cartilage volume would be the best outcome measure. However, clinical trials have shown that cartilage volume may be less responsive to treatment compared to other measures that have lower SRM (such as BML). Therefore, although one can optimize trial efficiency by finding more responsive endpoints, both sensitivity to change and magnitude of benefit should be considered.

Introduction: There is increasing evidence to suggest that bone marrow lesions (BMLs) play a key role in the pathogenesis of osteoarthritis (OA). However, there is a lack of long term data. The aim of this study was to describe the natural history of knee BMLs, their association with knee pain and examine predictors of BML change over eight years., Methods: A total of 198 subjects (109 adult offspring of subjects who had a knee replacement and 89 community-based controls) were studied. Knee pain and BML size were assessed at two and ten year visits., Results: At the two year visit, 64% of participants (n = 127) had 229 BMLs (34% patella, 26% femoral and 40% tibial). Over eight years, 24% (55/229) increased in size, 55% (125/229) remained stable and 21% (49/229) decreased in size or resolved completely. Of the participants without BMLs at baseline, 52% (37/71) developed incident BMLs., Conclusion: In this midlife cohort, the proportion of BMLs increasing in size was similar to those decreasing in size with the majority remaining stable. Change in BMLs was predicted by BMI and strenuous activity. An increase in BML size or a new BML resulted in an increase in pain especially in males and those with a family history of OA.

Introduction: Recent studies regarding the infrapatellar fat pad (IPFP) mainly focus on the roles of the cells derived from the IPFP. There have been few clinical or epidemiological studies reporting on the association between the IPFP and knee osteoarthritis (OA). Our objective is to generate hypotheses regarding the associations between IPFP maximum area and knee OA measures in older adults., Methods: A total of 977 subjects between 50 and 80 years of age (mean, 62.4 years) participated in the study. Radiographic knee osteophyte and joint space narrowing (JSN) were assessed using the Osteoarthritis Research Society International atlas. T1- or T2-weighted fat suppressed magnetic resonance imaging (MRI) was utilized to assess IPFP maximum area, cartilage volume, cartilage defects, and bone marrow lesions (BMLs). Knee pain was assessed by self-administered Western Ontario McMaster Osteoarthritis Index (WOMAC) questionnaire., Results: After adjustment for potential confounders, IPFP maximum area was significantly associated with joint space narrowing (odds ratio (OR): 0.75, 95% confidence interval (CI): 0.62 to 0.91 (medial), 0.77, 95% CI: 0.62 to 0.96 (lateral)) and medial osteophytes (OR: 0.52, 95% CI: 0.35 to 0.76), knee tibial and patellar cartilage volume (β: 56.9 to 164.9 mm3/cm2, all P <0.001), tibial cartilage defects (OR: 0.58, 95% CI: 0.41 to 0.81 (medial), 0.53, 95% CI: 0.40-0.71 (lateral)), any BMLs (OR: 0.77, 95% CI: 0.63 to 0.94), and knee pain on a flat surface (OR: 0.79, 95% CI: 0.63 to 0.98). IPFP maximum area was negatively, but not significantly, associated with femoral cartilage defects, lateral tibiofemoral BMLs, and total knee pain or other knee pain subscales., Conclusion: IPFP maximum area is beneficially associated with radiographic OA, MRI structural pathology and knee pain on a flat surface suggesting a protective role for IPFP possibly through shock absorption. Consequently, we must pay special attention to IPFP in the clinical settings, avoiding resection of normal IPFP in knee surgery.

The objective of this study was to describe the cross-sectional and longitudinal relationship between hip bone marrow lesions (BMLs), high cartilage signal, and hip and knee pain. One hundred ninety-eight participants in the Tasmanian Older Adult Cohort Study with right hip MRI conducted at two time points, approx. 2.3 years apart, were included. Short T1 Inversion Recovery MR images were used to quantitatively measure hip BML size and determine high cartilage signal presence. Hip and knee pain were individually assessed using the Western Ontario and McMaster Universities Osteoarthritis index pain score. Fifty-five participants (28%) had either femoral and/or acetabular BMLs. Cross-sectionally, the presence of large femoral, acetabular, or any hip BMLs was associated with higher odds of hip pain (OR = 4.42, 95% CI = 1.37-19.7; OR = 5.23, 95% CI = 1.17-22.9; OR = 4.43, 95% CI = 1.46-13.2, respectively). High cartilage signal was strongly associated with hip BMLs (OR = 6.45, 95% CI = 3.37-12.6), but not with pain. Longitudinally, incident acetabular (Mean diff = +5.90, 95% CI = +3.78 to +8.15) and femoral BMLs (Mean diff = +1.18, 95% CI = 0.23-1.94) were associated with worsening hip pain, while resolving femoral BMLs were associated with a decrease in knee pain (Mean diff = -3.18, 95% CI = -5.99 to -0.50). The evidence is consistent for hip, but not knee pain, and strongly suggests that large hip BMLs are associated with hip pain. Furthermore, high cartilage signal is asymptomatic, but strongly associated with hip BMLs. These findings suggest that hip BMLs play an important role in hip osteoarthritis.

Objective: Cartilage loss is a key pathological feature of OA and can be assessed indirectly using radiography or directly through MRI. A number of cross-sectional studies have suggested that primary generalized osteoarthritis (PGOA) may be a distinct disease, but despite the high frequency of involvement of the hip and the knee joints in OA, very few studies have looked at the radiographic association between these two joints, and none has done so using MRI. The aim of this study was to examine the association of hip and knee cartilage measured by both radiography and MRI., Methods: We studied 151 participants from the Tasmanian Older Adult Cohort (TASOAC) study, who were selected randomly from the southern Tasmanian electoral rolls. MRI was used to assess hip and knee cartilage volume and radiography was used to assess joint space narrowing (JSN). Correlation analyses were used to compare cartilage volume measurements and JSN., Results: In adjusted analysis, there was a consistent, positive association between knee and hip cartilage volume that was best for total knee cartilage volume (r = 0.16-0.40, all P < 0.05). In contrast, there was at best a weak correlation, depending on the site, between hip and knee JSN (r = -0.01 to 0.21)., Conclusion: Hip and knee cartilage volume are more strongly associated than hip and knee JSN, suggesting a commonality of cartilage volume at different anatomic sites. The weaker radiographic association may reflect less measurement error with MRI or the contribution of multiple structures to joint space in the knee.