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The aim of this study was to evaluate the effect of zoledronic acid (ZA) and denosumab on low back pain (LBP) and Modic change (MC) over 6 months. Adults aged ≥40 years with significant LBP for at least 6 months duration and MC (type 1, 2, or mixed) were randomized to receive ZA (5 mg/100 mL), denosumab (60 mg), or placebo. LBP was measured monthly by visual analogue scale (VAS) and the LBP Rating Scale (RS). MC was measured from MRIs of T12 -S1 vertebrae at screening and 6 months. A total of 103 participants with moderate/severe LBP (mean VAS = 57 mm; mean RS = 18) and median total MC area 538 mm2 were enrolled. Compared to placebo, LBP reduced significantly at 6 months in the ZA group for RS (-3.3; 95% CI, -5.9 to -0.7) but not VAS (-8.2; 95% CI, -18.8 to +2.4) with similar findings for denosumab (RS, -3.0; 95% CI, -5.7 to -0.3; VAS, -10.7; 95% CI, -21.7 to +0.2). There was little change in areal MC size overall and no difference between groups with the exception of denosumab in those with type 1 Modic change (-22.1 mm2 ; 95% CI, -41.5 to -2.7). In post hoc analyses, both medications significantly reduced VAS LBP in participants with milder disc degeneration and non-neuropathic pain, and denosumab reduced VAS LBP in those with type 1 MC over 6 months, compared to placebo. Adverse events were more frequent in the ZA group. These results suggests a potential therapeutic role for ZA and denosumab in MC-associated LBP.

Background/AimThe clinical relevance of MRI knee abnormalities in athletes is unclear. This study aimed to determine the prevalence of MRI knee abnormalities in Australian Rules Football (ARF) players and describe their associations with pain, function, past and incident injury and surgery history.Methods75 male players (mean age 21, range 16–30) from the Tasmanian State Football League were examined early in the playing season (baseline). History of knee injury/surgery and knee pain and function were assessed. Players underwent MRI scans of both knees at baseline. Clinical measurements and MRI scans were repeated at the end of the season, and incident knee injuries during the season were recorded.ResultsMRI knee abnormalities were common at baseline (67% bone marrow lesions, 16% meniscal tear/extrusion, 43% cartilage defects, 67% effusion synovitis). Meniscal tears/extrusion and synovial fluid volume were positively associated with knee symptoms, but these associations were small in magnitude and did not persist after further accounting for injury history. Players with a history of injury were at a greater risk of having meniscal tears/extrusion, effusion synovitis and greater synovial fluid volume. In contrast, players with a history of surgery were at a greater risk of having cartilage defects and meniscal tears/extrusion. Incident injuries were significantly associated with worsening symptoms, BML development and incident meniscal damage.ConclusionsMRI abnormalities are common in ARF players, are linked to a previous knee injury and surgery history, as well as incident injury but do not dictate clinical symptomatology.

Objective Hip morphology plays a significant role in the incidence and progression of hip osteoarthritis (OA). We hypothesized that hip shape would also be associated with other key factors and tested this in a longitudinal community-based cohort combining radiographic, magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and clinical data. Methods Baseline DXA images of the left hip of 831 subjects from the Tasmanian Older Adult Cohort were analyzed using an 85-point statistical shape model. Hip pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index, and muscle strength was measured using a dynamometer. Hip structural changes were assessed using MRI and radiographic OA using plain radiographs. Results Six shape modes accounted for 68% of shape variation. At baseline, modes 1, 2, 4, and 6 were associated with radiographic hip OA; modes 1, 3, 4, and 6 were correlated with hip cartilage volume; and all except mode 2 were correlated with muscle strength. Higher mode 1 and lower mode 3 and mode 6 scores at baseline predicted hip pain at followup and higher mode 1 and mode 2 scores were associated with hip effusion-synovitis. Higher scores for mode 2 (decreasing acetabular coverage) and lower scores for mode 4 (nonspherical femoral head) at baseline predicted 10-year total hip replacement (THR), while mode 4 alone was correlated with bone marrow lesions (BMLs), effusion-synovitis, and increased cartilage signal. Conclusion Hip shape is associated with radiographic OA, THR, hip pain, effusion-synovitis, BMLs, muscle strength, and hip structural changes. These data suggest that different shape modes reflect multiple facets of hip OA.

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.

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.

Background: Quantitative and semi-quantitative measurement of structural changes on MRI have been widely adopted in knee osteoarthritis (OA) research. However, few long-term studies describe the independent association of these structural factors and total knee replacement (TKR) in older adults. Objectives: To describe whether cartilage defects, bone marrow lesions (BMLs), effusion-synovitis, and meniscal pathologies at baseline are associated with TKR over 13 years and to estimate the additive effect of these measures for risk prediction of TKR. Methods: 1082 participants (mean age 62.8 years, 50% female) were randomly recruited from Tasmania and followed over 13.3 years. A 1.5T MRI scan of the right knee was acquired at baseline (n=930). Cartilage defects (grade 0-4), BMLs (grade 0-3), effusion-synovitis (grade 0-3), meniscal tears (grade 0-3) and meniscal extrusion (grade 0-2) was scored at baseline using T1-weighted and T2-weighted MRI. WOMAC knee pain was recorded from questionnaires and radiographic OA (ROA) was assessed by OARSI scale. The incidence of primary (first-time) TKR was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). Log binomial regression were used to estimate the risk of TKR associated with baseline MRI measures, adjusting for age, sex, BMI, ROA, and pain. Receiver operating characteristic (ROC) analyses were used and area under the curves (AUCs) were compared. Results: After adjustment for age, sex, BMI, and ROA status, baseline cartilage defects (grade 2, RR=6.71; grade 3, RR=11.17; grade 4, RR=13.2; all p Compared to the baseline model with age, sex and BMI (area under the ROC curve [AUC = 0.62]), Model 1 with the addition of ROA and WOMAC pain performed better (AUC =0.77). Addition of cartilage defects to Model 1 resulted in a significant increase of AUC to 0.84. However, addition of BMLs and effusion-synovitis to the model 1 resulted in a nonsignificant small increase in AUC (0.78 and 0.76) only. The combination of all MRI pathologies to Model 1 resulted in a significant increase of AUC to 0.82. Conclusion: Baseline knee MRI structural pathology markers can predict TKR over the long-term, suggesting that MRI structural markers are good predictors of rapid knee OA progression in the general population. Semiquantitative MRI measures such as cartilage defects significantly improve the model performance for prediction of TKR over 13 years, and hence could be utilized in prediction/decision making of TKR. Disclosure of Interests: Benny Antony: None declared, Ishanka Munugoda : None declared, Dawn Aitken: None declared, Petr Otahal: None declared, Michelle Lorimer: None declared, Stephen Graves : None declared, Johanne Martel-Pelletier Shareholder of: ArthroLab Inc., Consultant for: TRB Chemedica SA, Jean-Pierre Pelletier Shareholder of: Shareholder in ArthroLab Inc., Grant/research support from: Study funded by TRB Chemedica SA, Consultant for: TRB Chemedica SA, Flavia Cicuttini: None declared, Graeme Jones: None declared

Background:There is increasing use of complementary and alternative medicines (CAMs) alone or as an adjuvant therapy to conventional palliative medicines.1 However, there remains clinical uncertainty about the benefit of CAMs in the management of osteoarthritis in older population.Objectives:To describe the association between CAM use (alone or in combination with conventional analgesics) with knee symptoms and structural changes amongst a representative sample of Tasmanian older adults.Methods:A total of 1,099 participants were selected from the Tasmania Older Adult Cohort Study (TASOAC), an ongoing prospective population-based study. Exposure to CAM and conventional medications was classified into four categories according to the national drug code directory: 2 CAM only, conventional analgesics only, both CAM and conventional analgesics, and neither CAMs nor conventional analgesics. Knee pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and a 1.5-T MRI of the right knee was performed at baseline and follow-up (around 2.6 years). Longitudinal associations were assessed using mixed effect linear models.Results:At baseline, participants‘ mean age was 63, 86.5% (n=951) reported any medication use. The prevalence of CAM use was 35.0% and of conventional analgesics was 58.6%. Over follow-up, the analgesic only group had a significant increase in WOMAC pain, function, and stiffness scores compared to those who took neither CAMs nor conventional analgesics. There was a statistically significant femoral cartilage volume loss across all four groups, and no statistical difference was found between participants who takes both CAMs and analgesics group and the reference group, but participant in the CAM only or the analgesics only groups loss statistically significant more femoral cartilage volume than the reference group (Table 1).Table 1.Association of change in clinical knee symptoms and knee structural changes over 2.6 years with different medications groups.Mean change for reference group*Change for each category, coefficient (95% confident intervals)CAMsBothAnalgesicsReference group*No. of participants327128257387327WOMAC pain (5-50)-0.95 (-1.42, -0.48)0.04 (-0.85, 0.93)0.32 (-0.4, 1.04)0.78 (0.13, 1.43)RefWOMAC function (17-170)-3.09 (-4.52, -1.67)1.02 (-1.7, 3.73)1.39 (-0.81, 3.59)2.32 (0.33, 4.31)RefWOMAC stiffness (2-20)-0.39 (-0.62, -0.17)0.15 (-0.28, 0.58)0.35 (0, 0.7)0.40 (0.09, 0.72)RefFemoral cartilage volume (mL)-187.98 (-228.79, -147.18)-113.81 (-192.60, -35.03)-1.92 (-65.00, 61.17)-127.19 (-186.31, -68.06)Ref*Reference group=participants taken neither CAMs nor conventional analgesicsConclusion:CAM use alone or in combination with conventional analgesics may associate with slower progression of knee pain. Conclusive evidence on the longitudinal benefits of CAM in the management of osteoarthritis among older adults warrants more studies.References:[1]Steel A, McIntyre E, Harnett J, et al. Complementary medicine use in the Australian population: Results of a nationally-representative cross-sectional survey. Sci Rep 2018;8:17325.[2]National Center for Health Statistics. Long-term Care Drug Database System: Drugs by NDC Class Code, Drug Code and Name 2007 Available from: https://www.cdc.gov/nchs/data/nnhsd/DrugsbyNDCClass3.pdf [accessed date: 2020 23 December].The data were fitted using mixed effect linear models, which were constructed by entering baseline medication group, phase, the interaction between medication group and phase, covariates (baseline age, sex, body mass index [BMI], baseline value of outcome), the interaction between the covariates and phase, random intercept, and random slope on phase (time).Disclosure of Interests:None declared

Background:Osteoarthritis (OA) is the most common form of arthritis, and its impact is increasing year by year due to an aging population and lack of effective treatments. One of the main structural pathological changes of OA is the loss of articular cartilage. Tools that can predict cartilage loss would help identify people at high risk, thus preventing OA development.Objectives:Using a metabolomics approach, the current study aimed to identify serum metabolomic signatures for predicting the loss of knee cartilage volume over 10 years in a well-established community-based cohort - the Tasmania Older Adult Cohort (TASOAC).Methods:TASOAC is an on-going, prospective, population-based study of older adults who were randomly selected from the roll of electors in Southern Tasmania, Australia. Participants had a right knee magnetic resonance imaging (MRI) scan at baseline and a 10-year follow-up. Cartilage volume was measured in the medial, lateral, and patellar compartments and change in cartilage volume over 10 years was calculated as percentage change per year. Fasting serum samples collected at 2.6-year follow-up were metabolomically profiled using the TMIC Prime Metabolomics Profiling Assay which measures a total of 143 metabolites. 129 metabolite concentrations passed the quality control and the pairwise ratios of them as the proxies of enzymatic reaction were calculated. Linear regression models were used to test the association between each of the metabolite ratios and change in cartilage volume in each of the knee compartments with adjustment for age, sex, and body mass index (BMI). The significance was defined at a=3.0×10-6 to control multiple testing of 16,512 ratios with Bonferroni method.Results:A total of 344 participants (51% females) were included. The mean baseline age was 62.83±6.13 years and the mean BMI was 27.48±4.41 kg/m2. The average follow-up time was 10.84±0.66 years. Cartilage volume reduced by 1.34±0.72%, 1.06±0.58%, and 0.98±0.46% per year in the medial, lateral, and patellar compartments, respectively. Our data showed that an increased ratio of hexadecenoylcarnitine (C16:1) to tetradecanoylcarnitine (C14) was associated with a 0.12±0.02% per year reduction in patellar cartilage volume (p = 8.80×10-7). An increased ratio of hexadecenoylcarnitine (C16:1) to dodecanoylcarnitine (C12) was also associated with a 0.12±0.02% per year reduction in patellar cartilage volume (p = 2.66×10-6). While there were several metabolite ratios associated with cartilage volume loss in the medial and lateral compartments, none of them reached the predefined significance level.Conclusion:Our data suggested that alteration of fatty acid β-oxidation is involved in knee cartilage loss, especially in the patellar compartment, and the serum ratio of C16:1 to C14 and to C12 could be used to predict long-term patellar cartilage loss.Acknowledgements:We thank all the study participants who made the study possible. The original TASOAC study was supported by the National Health and Medical Research Council (NHMRC) and the current study was supported by the Canadian Institutes of Health Research (CIHR).Disclosure of Interests:None declared

Background Skeletal muscles are essential components of the neuromuscular skeletal system that have an integral role in the structure and function of the synovial joints which are often affected by osteoarthritis (OA). The aim of this study was to identify the baseline metabolomic signatures for the longitudinal reduction of muscle strength over 10 years in the well-established community-based Tasmanian Older Adult Cohort (TASOAC). Methods Study participants were 50–79 year old individuals from the TASOAC. Hand grip, knee extension, and leg strength were measured at baseline, 2.6-, 5-, and 10-year follow-up points. Fasting serum samples were collected at 2.6-year follow-up point, and metabolomic profiling was performed using the TMIC Prime Metabolomics Profiling Assay. Generalized linear mixed effects model was used to identify metabolites that were associated with the reduction in muscle strength over 10 years after controlling for age, sex, and BMI. Significance level was defined at α=0.0004 after correction of multiple testing of 129 metabolites with Bonferroni method. Further, a genome-wide association study (GWAS) analysis was performed to explore if genetic factors account for the association between the identified metabolomic markers and the longitudinal reduction of muscle strength over 10 years. Results A total of 409 older adults (50% of them females) were included. The mean age was 60.93±6.50 years, and mean BMI was 27.12±4.18 kg/m2 at baseline. Muscle strength declined by 0.09 psi, 0.02 kg, and 2.57 kg per year for hand grip, knee extension, and leg strength, respectively. Among the 143 metabolites measured, 129 passed the quality checks and were included in the analysis. We found that the elevated blood level of asymmetric dimethylarginine (ADMA) was associated with the reduction in hand grip (p=0.0003) and knee extension strength (p=0.008) over 10 years. GWAS analysis found that a SNP rs1125718 adjacent to WISP1gene was associated with ADMA levels (p=4.39*10-8). Further, we found that the increased serum concentration of uric acid was significantly associated with the decline in leg strength over 10 years (p=0.0001). Conclusion Our results demonstrated that elevated serum ADMA and uric acid at baseline were associated with age-dependent muscle strength reduction. They might be novel targets to prevent muscle strength loss over time.

Purpose: To compare the performance of low muscle mass and function with falls risk, incident fracture and mortality over 10 years.1041 participants (50% women; mean age 63±7.5 years) were prospectively followed for 10 years. Falls risk was measured using the Physiological Profile Assessment, fractures were self-reported and mortality was ascertained from the death registry. Appendicular lean mass (ALM) was assessed using dual energy X-ray absorptiometry. Four anthropometric: (ALM/height2, ALM/body mass index, ALM/weight×100, a residuals method of ALM on height and total body fat) and four performance-based measures: (handgrip strength, lower-limb muscle strength, upper and lower-limb muscle quality) were examined. Participants in the lowest 20% of the sex-specific distribution for each anthropometric and performance-based measure were classified has having low muscle mass or function. Regression analyses were used to estimate associations between each anthropometric and performance-based measure at baseline and 10-year falls risk, incident fractures and mortality.Mean falls risk z-score at 10 years was 0.64 (SD 1.12), incident fractures and mortality over 10 years were 16% and 14% respectively. All baseline performance-based measures were significantly associated with higher falls risk score at 10 years. Low handgrip (RR 1.55, 95% CI: 1.09, 2.20) and ALM/body mass index (RR 1.54, 95% CI: 1.14, 2.08) were the only significant predictors of fracture and mortality respectively.Low handgrip strength, a simple and inexpensive test could be considered in clinical settings for identifying future falls and fractures. ALM/ body mass index could be most suitable in estimating 10-year mortality risk, but requires specialised equipment.

Background and purpose The Beagley–Gibson (BG) grading system utilizes microtopographical skin changes to generate an individualized, objective estimate of cumulative, lifetime ultraviolet radiation (UVR) exposure. However, predictors of BG grade are ill-defined, particularly in older populations. The aim of this cross-sectional study was to describe the factors associated with skin damage as measured by the BG method in 835 community-dwelling older adults. Methods Study participants aged 53–83 years had silicone casts taken from the dorsum of both hands and graded by the BG method. Lifetime sun exposure, skin phenotypic traits and smoking status were assessed by questionnaire. 25-hydroxyvitamin D and melanin density were measured using radioimmunoassay and spectrophotometry, respectively. Ordered logistic regression was used to compute a single odds ratio (OR) by taking BG grade as the outcome variable. Results Higher 25-hydroxyvitamin D was associated with increasing BG grade (OR = 1.39, P = 0.02) in adjusted analysis. Age (OR = 1.14, P < 0.001), occupational sun exposure (OR = 1.62, P < 0.001), ability to tan (OR = 1.40, P < 0.001), melanin density (OR=0.79, P = 0.001), lifetime leisure time sun exposure (OR = 1.21, P = 0.004), current smoking (OR = 1.82, P = 0.007), propensity to sunburn (OR = 1.18, P = 0.016), and waist–hip ratio (OR = 1.10, P = 0.02) were independent predictors of BG grade. Hair colour, number of sunburns, body mass index and gender were not independent predictors of BG grade. Conclusions Beagley–Gibson skin cast grade is a biologically relevant marker of UVR exposure in older adults influenced by both intrinsic and extrinsic factors.

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

Purpose The aim of this study was to determine and compare risk factors associated with incident fractures in older adults with and without obesity, defined by both body mass index (BMI) and body fat percentage. Methods 1,099 older adults (mean ± standard deviation age = 63.0 ± 7.5) years, participated in this prospective cohort study. Obesity status at baseline was defined by BMI (≥30 kg/m2) obtained by anthropometry and body fat percentage (≥30% for men and ≥40% for women) assessed by dual-energy X-ray absorptiometry (DXA). Total hip and lumbar spine areal bone mineral density (aBMD) were assessed by DXA up to five years. Incident fractures were self-reported up to 10 years. Results Prevalence of obesity was 28% according to BMI and 43% according to body fat percentage. Obese older adults by BMI, but not body fat percentage, had significantly higher aBMD at the total hip and spine compared with non-obese (both p-value 0.05). Mediation analysis confirmed that aBMD meditated the effects of BMI, but not body fat percentage, on all incident fractures. Higher baseline falls risk score was the only consistent predictor of increased likelihood of incident fracture in obese individuals only, according to both BMI and body fat percentage (both p-value

Background:Pharmacological therapies are limited, associated with off-target effects, are frequently contraindicated, and only modestly effective for pain in osteoarthritis (OA). Effusion and synovitis are common in OA and are associated with symptomatic and structural progression of OA.Curcuma longa(Turmeric) extract has anti-inflammatory effects and is gaining popularity in the treatment of OA despite the lack of high-quality evidence.Objectives:The CurKOA trial aimed to determine the efficacy ofCurcuma longaextract for reducing knee symptoms and effusion-synovitis in patients with symptomatic knee OA and knee effusion-synovitis.Methods:In this randomised, double-blind, placebo-controlled trial, participants with significant knee pain (≥ 40 mm on a 100-mm visual analog scale [VAS]), symptomatic knee OA (by ACR criteria) and ultrasound defined effusion-synovitis were randomised to receiveCurcuma longaextract (80% aqueous based extract standardized to turmerosaccharides + 20% curcuminoids, 2 × 500 mg capsules/day) or identical placebo for 12 weeks. Knee MRI scans were obtained at baseline and 12 weeks. Coprimary outcomes were changes in knee pain assessed by VAS and change in knee effusion-synovitis volume assessed by MRI over 12 weeks.Results:Among 70 participants (36 receivedCurcuma longa, 34 received placebo, age 61.8±8.6 years, 56% female),Curcuma longasignificantly improved VAS knee pain compared to placebo (-9.11mm, 95% confidence interval [CI] [- 17.79 to -0.44]) over 12 weeks, equivalent to a standardised effect size of 0.50. There was no significant between group difference in change in effusion-synovitis volume (3.24 mL [-0.33, 6.82]). There were significantly greater reductions in WOMAC knee pain (-47.22mm [-81.22, -13.22]), WOMAC function (-112.26mm [-222.79 to -1.74]) and significantly more OARSI-OMERACT treatment responders (63% treatment vs. 38% placebo [Risk Ratio=1.64 (1.00 to 2.70)]) in theCurcuma longagroup compared to the placebo group. There was no significant between-group difference in lateral femoral cartilage T2 relaxation time (-0.38 ms [- 1.10 to 0.34]) assessed from compositional MRI. The incidence of adverse events was similar in theCurcuma longa(n=14 (39%)) and placebo (n=18 (53%)) groups over 12 weeks (P=0.24).Conclusion:An extract ofCurcuma longasignificantly improved knee pain in an inflammatory phenotype of knee OA patients over 12 weeks compared to placebo but had no effect on knee effusion-synovitis and cartilage composition assessed using MRI. The moderate effect size of the treatment supports the use ofCurcuma longaextract for the symptomatic management of knee OA.Figure 1.Change in VAS and WOMAC subscale scores in treatment and control groups over the course of the study. (VAS = Visual analog scale, WOMAC = Western Ontario and McMaster University Index, CL = Curcuma longa extract)Disclosure of Interests:None declared

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 mm(3) vs −919 mm(3); between-group difference, 41 mm(3) [95% CI, −79 to 161 mm(3)]; 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 mm(2) vs −6 mm(2); between-group difference, −27 mm(2) [95% CI, −127 to 73 mm(2)]; 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

Summary 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.

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.

To determine whether older adults with low muscle mass (sarcopenia) and strength (dynapenia), in the presence of osteoporosis/osteopenia, have an increased risk of fracture and mortality over 10 years, compared to those with low muscle or low bone mass alone or with neither condition.1032 participants (52% women; mean age 62.9 ± 7.4 years) were prospectively followed for 10 years. Mortality was ascertained from the death registry and fractures were self-reported. Baseline appendicular lean mass (ALM) was assessed using dual-energy X-ray absorptiometry and normalised to body mass index (BMI). Hand grip strength (HGS) was assessed by dynamometer. Osteosarcopenia and osteodynapenia were defined as having T-scores of the total hip and/or lumbar spine bone mineral density (BMD)-1 combined with being in the lowest 20% of the sex-specific distribution for ALM/BMI or HGS respectively.Incident fracture risk was significantly higher in participants who were osteodynapenic (RR = 2.07, 95% CI: 1.26-3.39), dynapenic alone (RR = 1.74, 95% CI: 1.05-2.87), and osteopenic alone (RR = 1.63, 95% CI: 1.15-2.31), compared to those without dynapenia or osteopenia. Mortality risk was significantly higher only in participants with osteosarcopenia (RR = 1.49, 95% CI: 1.01-2.21) compared to those without sarcopenia or osteopenia. However, osteosarcopenia and osteodynapenia did not lead to a significantly greater fracture or mortality risk compared to having these conditions on their own.These findings suggest that the combined effect of osteopenia and sarcopenia or dynapenia on fracture and mortality risk, respectively, may not be greater than that of each individual condition.

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 D3 (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.

Background The patellar tendon works together with the quadriceps tendon to enable knee flexion and straightening. Its attachment site (enthesis) is at risk of micro damage and degeneration. Recent studies suggest that enthesis abnormalities are associated with development of osteoarthritis. 1, 2 However, no studies have assessed the presence of patellar enthesis abnormalities in older adults and its association with osteoarthritis outcomes. Objectives To describe the associations of patellar tendon enthesis (PTE) abnormalities visible on magnetic resonance (MR) images; and knee pain, physical function limitations, osteoarthritic structural abnormalities cross-sectionally and longitudinally over 10.7 years. Methods PTE abnormalities were defined as presence of abnormal bone signal and/or bone erosion. They were measured on T2-weighted fat suppressed fast spin echo MR images at baseline in 961 community-dwelling older adults and followed for 10.7 years. Knee pain and physical function limitation score were assessed using WOMAC. Bone marrow lesions (BMLs), cartilage volume and defects, tibial bone area, and infrapatellar fat pad (IPFP) area were assessed using validated methods. Associations were assessed using hurdle, log binomial, linear, and mixed models, after adjusting for confounders. Results 20% of participants had bone signal and/or erosion at PTE. Cross-sectionally, presence of PTE abnormalities were associated with greater intensity of pain while going up and down stairs (β=0.22 (95% CI; 0.03, 0.41)), greater risk of having a femoral BML (RR=1.46 (1.22, 1.90)), greater lateral tibial bone area (β=25.95 (1.00, 50.91)), smaller IPFP area (β=−0.26 (-0.46,–0.05)), and a worse tibial cartilage defects cross sectionally (RR=1.70 (1.16, 2.47), after adjustment of demographic and structural confounders. Longitudinally, PTE abnormalities at baseline predicted an increased risk of deleterious changes in tibial BML size (RR=1.52 (1.12, 2.05)) but not clinical symptoms, and other structural changes over 10.7 years. Conclusions Patellar tendon enthesis abnormalities are common in the elderly. The presence of cross-sectional but not longitudinal associations suggests they commonly co-exist with other knee structural abnormalities, but that they are not be a major player in symptom development or structural changes, excepting tibial BMLs. References [1] Binks DA, Bergin D, Freemont AJ, Hodgson RJ, Yonenaga T, McGonagle D, et al. Potential role of the posterior cruciate ligament synovio-entheseal complex in joint effusion in early osteoarthritis: a magnetic resonance imaging and histological evaluation of cadaveric tissue and data from the Osteoarthritis Initiative. Osteoarthritis Cartilage. 2014;22(9):1310–7. [2] Benjamin M, McGonagle D. Histopathologic changes at “synovio-entheseal complexes” suggesting a novel mechanism for synovitis in osteoarthritis and spondylarthritis. Arthritis Rheum2007;56(11):3601–9. Acknowledgements National Health and Medical Research Council of Australia; Tasmanian Community Fund; Masonic Centenary Medical Research Foundation. Disclosure of Interest None declared

Background Disease-modifying therapeutic options are needed for patients with osteoarthritis (OA). Zoledronic acid (ZA) is a potential option as it reduced both knee pain and knee bone marrow lesion (BML) size over 6 months in patients with knee OA. However, ZA infusions are often accompanied by a suite of side effects within 3 days of infusion (acute phase reactions (APRs)), which include flu-like symptoms. These may be caused by upregulation of pro-inflammatory cytokines. A preliminary study (n=20) suggested that a combination of ZA and prednisolone (VOLT01) was superior to ZA alone in reducing APR and knee pain in knee OA patients. A larger study was needed to confirm these findings and examine the new combination’s effect on OA outcomes. Objectives To compare the effect of once-off infusion of ZA, VOLT01 and placebo on APRs, knee BML size and knee pain symptoms over 6 months in knee OA patients with significant knee pain and BMLs. Methods Knee OA patients≥50 years with significant knee pain (defined as a 100 mm Visual Analogue Scale (VAS) ≥40 mm) and knee BMLs visualised on proton density weighted MRI were randomised to receive one infusion of ZA (5 mg in 100 ml saline), VOLT01 (5 mg ZA in 100 ml saline plus a 10 mg prednisolone bolus) or placebo (100 ml saline). Co-primary hypotheses were that VOLT01 would significantly reduce APRs compared to ZA, and that VOLT01 would be non-inferior to ZA in reducing BML size over 6 months. Secondary hypothesis was that VOLT01 would be non-inferior to ZA in improving knee pain and dysfunction (assessed using the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) and VAS) over 6 months. Mixed effect models were performed for data analyses. Analyses for change in knee pain and function scores were adjusted for baseline imbalanced values (baseline pain and utility scores, and pain medications). Non-inferiority margins were defined as 140 mm 2 for change in knee BML size and 8 mm for change in knee pain and function scores (WOMAC pain and function scores were averaged to a 100 mm VAS). Results 117 knee OA patients (63 females, mean ±standard deviation (SD) age 62.2±8.1 years) were enrolled. At baseline, mean ±SD knee pain VAS score was 50.1±18.9 mm and median BML size 370 mm 2 . APRs were more frequent in the two active treatment groups (ZA: 87%; VOLT01: 90%) than the placebo group (55%) (both p Conclusions Combining prednisolone with ZA does not appear useful for reducing APRs, though there may be a small benefit over ZA alone for knee symptoms. Neither showed evidence of disease modification by changing BML size. Disclosure of Interest None declared

Background The relationship between physical activity (PA) and osteoarthritis (OA) has been controversial, with some studies showing a detrimental effect and others showing either no effect or a beneficial effect. Traditionally, analysis has focused on examining the effect PA and/or strength have on OA between individuals (between-person comparison). Yet, how the variability in PA and strength over time within the same individual (within-person comparison) is associated with OA is not well recognised. Statistical methods, such as multilevel models that properly capture the within-person processes can be used to tell us whether changes within an individual over time relate to changes in OA outcomes in that same individual. Objectives This study aimed to investigate the associations of between-person and within-person variability in PA and leg strength with knee cartilage volume loss over 10.7 years in older adults. Methods 479 community-dwelling older-adults (50% female, mean age 61±6 years, range 50–80 years) were studied at baseline, 2.7, 5.1, and 10.7 years. PA (measured objectively as steps/day) and leg strength (measured objectively in kg) were assessed at all four time-points. Knee cartilage volume was measured using MRI at baseline and 10.7 years. Linear mixed-effect regression models were used to estimate the association of between-person and within-person variability in PA and leg strength with cartilage volume loss over 10.7 years. Models were adjusted for age, sex, body mass index and history of knee injury or surgery. Results Mean cartilage volume loss over 10.7 years was 465±231 mm3. No between-person associations existed between PA and cartilage volume loss (Beta: 18.8 per 1000 steps/day, 95% CI −6.1, 43.7). However, within-person variability in PA was protectively associated with changes in cartilage volume, such that having higher PA compared to an individual’s average level of PA minimised their cartilage volume loss over time (Beta: 32.8 per 1000 steps/day, 95% CI 20.8, 44.6). Between-person effects showed that participants with greater leg strength lost less cartilage volume over time (Beta: 5.4 per 1 kg, 95% CI 3.1, 7.8). Within-person variability in leg strength was also protectively associated with changes in cartilage volume, such that having higher leg strength compared to an individual’s average strength minimised their cartilage volume loss over time (Beta: 3.3 per 1 kg, 95% CI 2.1, 4.5). Conclusions Our unique analysis method adds a new perspective to the PA and OA debate. The implication of these findings demonstrate that individuals can minimise cartilage volume loss by increasing their own PA and strength, which supports the clinical recommendations of promoting PA and strength to prevent and treat OA. Disclosure of Interest None declared

Background Although depression is prevalent in osteoarthritis (OA) patients and the positive association between vitamin D deficiency and depression has been demonstrated, no study has examined the effect of vitamin D supplementation on depression in OA patients. Objectives To determine the effect of vitamin D supplementation and maintaining sufficient serum vitamin D on depression in patients with knee OA and vitamin D deficiency. Methods Participants with symptomatic knee OA and vitamin D deficiency were enrolled in a randomised, placebo-controlled trial and received 50,000IU vitamin D3 (n=209) or placebo (n=204) monthly for 24 months. Serum 25-hydroxyvitamin D [25(OH)D] was measured at baseline, month 3 and 24. Depression was measured using the patient health questionnaire (PHQ-9), and knee symptoms were assessed using Western Ontario and McMaster Universities Arthritis Index (WOMAC) at baseline, month 3, 6, 12 and 24. Multilevel mixed-effect models were used to estimate the association between exposures and outcomes adjusting for potential confounders. Results Over 24 months, 340 participants (82.3% retention rate) completed the study. The prevalence and incidence of depression were 25.4% and 11.2%, respectively. Depression improved more in the vitamin D supplementation group (β: −0.45, 95% CI: −0.84 to −0.07) compared to the placebo group (β: 0.21, 95% CI: −0.19 to 0.61) (p=0.02) and in those participants who maintained vitamin D sufficiency (β: −0.44, 95% CI: −0.88 to −0.00) compared to those who did not maintain sufficiency (β: 0.40, 95% CI: −0.18 to 0.97) (p=0.02) over 24 months. Conclusions These findings suggest that vitamin D supplementation and maintaining sufficient vitamin D levels over 24 months may have beneficial effects on depression in patients with knee OA. References [1] Stubbs B, Aluko Y, Myint PK, et al. Prevalence of depressive symptoms and anxiety in osteoarthritis: a systematic review and meta-analysis. Age Ageing2016;45(2):228–35. doi:10.1093/ageing/afw001 [2] Anglin RE, Samaan Z, Walter SD, et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry2013;202:100–7. doi:10.1192/bjp.bp.111.106666 Acknowledgements We specially thank the participants who made this study possible, and we gratefully acknowledge the role of Vitamin D Effect on Osteoarthritis Study staff and volunteers in collecting the data. Disclosure of Interest None declared

Background No disease-modifying drugs are currently available for the treatment of osteoarthritis (OA). Bone marrow lesions (BMLs) visualised on magnetic resonance imaging (MRI) have been identified as a promising therapeutic target. Our pilot study showed that a single infusion of zoledronic acid (ZA) reduced knee pain and BML size in knee OA patients over 6 months.1 A longer, larger study was required to assess whether these improvements can be reproduced in a larger multicentre design. Objectives To compare the effect of once-yearly intravenous infusion of ZA to placebo on knee pain and BML size over 24 months in knee OA patients with significant knee pain and BMLs. Methods The Zoledronic Acid for Osteoarthritis Knee Pain (ZAP2) study is a multicentre, randomised, double-blinded, placebo-controlled trial over 24 months. Patients≥50 years who had significant knee pain (defined as a visual analogue scale (VAS)≥40 mm) and MRI-detected knee BML were randomised to receive either ZA (5 mg in 100 ml saline) or placebo (100 ml saline) once-yearly. Those with severe knee OA (joint space narrowing (JSN) on X-ray of Grade 3 using the Osteoarthritis Research Society International (OARSI) atlas) were excluded. Outcomes included knee pain and function by the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC), knee pain by VAS and change in knee total BML size (sum of medial femoral, lateral femoral, medial tibial, lateral tibial and patellar sites) by proton density weighted MRI from baseline to 24 months. Effect modification of the absence or presence of radiographic OA (JSN grade 0 or grade 1–2) was pre-specified. Mixed effect modelling using an intent-to-treat design was performed for data analyses. Adjustment for baseline values were performed for knee pain and function outcomes due to baseline imbalances. Results 223 patients (mean ±SD age 62.0±8.0 years, 117 females) were enrolled. At baseline, mean ±SD knee WOMAC pain (0–500), WOMAC function (0–1700) and VAS pain scores (0–100) were 200.0±105.0, 656.9±352.9 and 51.0±20.5, and median BML size was 489.6 mm2. After 24 months, there was no significant difference in changes in knee pain (WOMAC pain: −37.5 vs −58.0, p=0.205; VAS pain: −11.5 vs −16.8, p=0.17) or function scores (−134.9 vs −159.2, p=0.65), or knee BML size (−33.5 mm2 vs −11.7 mm2, p=0.68) between the ZA group and the placebo group. Pre-specified analyses consistently showed that ZA was more effective than placebo in patients without radiographic OA (JSN Grade 0) on changes in WOMAC pain (−88.3 vs −42.6, p=0.21), VAS pain (−21.8 to −8.3, p=0.11), WOMAC function (−296.9 vs −78.5, p=0.06) and BML size (−67.4 vs 98.2, p=0.14). Adverse events were more frequent in the ZA group, primarily flu-like symptoms and musculoskeletal pain and stiffness. Conclusions Once-yearly infusion of ZA did not significantly reduce knee pain or BML size overall in knee OA patients over 24 months but may have symptomatic benefit in milder disease. Reference [1] Laslett LL, et al. Ann Rheum Dis2012;71:1322–8. Disclosure of Interest None declared

Background The identification of phenotypes to reduce heterogeneity of characteristics is important in understanding the development and progression of knee osteoarthritis. Objectives This study aimed to identify physical activity (PA) phenotypes and to investigate the association of these phenotypes with tibial cartilage volume, bone marrow lesions (BMLs) and knee replacements (KR) over 10.7 years. Methods 1046 community-dwelling older adults aged 50–80 years were studied. At baseline, PA was measured by pedometers (steps/day), knee pain was assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and body mass index (BMI) was determined utilising objective weight and height measures. MRI scans were conducted at baseline and 10.7 years to assess tibial cartilage volume and BMLs. The incidence of KR was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Latent class analysis was used to determine ‘PA phenotypes’ based on PA, BMI and WOMAC pain at baseline. Linear mixed-effects models and log-binomial models were used to estimate the associations between the identified PA phenotypes with change in cartilage volume, incident BMLs, and KR surgery over 10.7 years. All models were adjusted for age, sex, and history of knee injury or surgery, while the KR model was additionally adjusted for the prevalence of knee radiographic osteoarthritis. Results Three PA phenotypes were identified: Class 1: Normal/overweight participants with low levels of PA and low pain (42%); Class 2: Obese participants with low levels of PA and high pain (26%); Class 3: Normal/overweight participants with high levels of PA and low pain (32%). Mean cartilage volume loss over 10.7 years was 465±231 mm 3 . 221 participants had an incident BML while 74 had an incident KR. Class 2 participants had greater cartilage volume loss over 10.7 years (Beta: −79.9, 95% CI −135.8,–23.9) and, had a higher risk of KR (RR 2.36, 95% CI 1.20, 4.67) compared to Class 1 participants. Class 3 was not associated with cartilage volume loss (Beta: −36.2, 95% CI −86.6, 14.1) or risk of KR (RR 0.86, 95% CI 0.40, 1.84) compared to Class 1. Similarly, PA phenotypes were not associated with incident BMLs (Class 2: RR 1.15, 95% CI 0.88, 1.50; Class 3: RR 1.19, 95% CI 0.93, 1.54; compared to Class 1). Conclusions Our findings support the existence of homogeneous PA profiles, and suggest that PA interacts with body weight and knee pain and has long-term impacts on osteoarthritis outcomes. Disclosure of Interest None declared

Summary Objectives To identify distinct pain trajectories over 10.7 years and to examine predictors of identified pain trajectories in an older population and those with radiographic knee osteoarthritis (ROA). Methods 963 participants (aged 50–80 years) from a population-based cohort had baseline demographic, psychological, lifestyle and comorbidities data collected. T1-and T2-weighted magnetic resonance imaging (MRI) of the right knee was performed to measure knee structural pathology-cartilage defects, bone marrow lesions (BMLs) and effusion-synovitis. Group-based trajectory modelling (GBTM) was applied to identify trajectories of knee pain over 10.7 years measured by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results Three distinct pain trajectories were defined: ‘Minimal pain' (n = 501, 52%), ‘Mild pain' (n = 329, 34%) and ‘Moderate pain' (n = 165, 14%). In multivariable analysis, having cartilage defects, BMLs and effusion-synovitis were associated with an increased risk of being in the ‘Mild pain' (relative risk [RR]: 1.40 to 1.92) and ‘Moderate pain' trajectory (RR: 1.72 to 2.26), compared with the ‘Minimal pain' trajectory. Being obese and having more painful sites were associated with ‘Mild pain' and ‘Moderate pain' trajectories, while unemployment, lower education level and presence of emotional problems were associated with ‘Moderate pain' trajectory group. Similar results were found for those with ROA. Conclusion Distinct pain trajectories identified suggest that homogeneous subgroups exist, which might be useful for phenotypic assessment for pain management, particularly in knee osteoarthritis. Structural pathology was associated with worse pain trajectories, suggesting that peripheral stimuli are critical for the development and maintenance of pain severity. Environmental and psychological factors may exacerbate pain perception.

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. 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 (mm3) 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. 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. Australian New Zealand Clinical Trials Registry: ACTRN12613000039785 , registered on 14 January 2013.

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.

Introduction The aim of this study was to describe the relationship between accelerometer-determined physical activity (PA), muscle mass, and lower-limb strength in community-dwelling older adults. Methods Six hundred thirty-six community-dwelling older adults (66±7years) were studied. Muscle mass was measured using dual-energy x-ray absorptiometry, whilst lower limb strength was measured via dynamometry. We measured minutes/day spent in sedentary, light, moderate, and vigorous intensity activity using Actigraph GT1M accelerometers. Results Participants spent a median of 583(Interquartile ratio (IQR) 522–646), 225(176–271), 27(12–45) and 0(0–0) min in sedentary, light, moderate, and vigorous activity, respectively. PA intensity was positively associated with both lean mass percentage and lower limb strength in a dose–response fashion. Sedentary activity was negatively associated with lean mass percentage, but not lower-limb strength. There was a positive association between PA and appendicular lean mass in men only. There was an interaction between age and activity; as age increased, the magnitude of the association of PA with lean mass percentage decreased. Those who adhered to the Australian Department of Health PA guidelines (moderate/vigorous PA >/=150min/week) had greater lean mass percentage, appendicular lean mass, and lower limb strength. Conclusions Using accelerometer technology, both the amount and intensity of accelerometer-determined PA had an independent, dose–response relationship with lean mass percentage and lower limb strength, with the largest effect for vigorous activity. Time spent in sedentary activity was negatively associated with lean mass percentage, but was not associated with lower limb strength. The magnitude of the association between PA and lean mass percentage decreased with age, suggesting that PA programmes may need to be modified with increasing age.

The aim of this study was to evaluate the effect of zoledronic acid (ZA) and denosumab on low back pain (LBP) and Modic change (MC) over 6 months. Adults aged ≥40 years with significant LBP for at least 6 months duration and MC (type 1, 2, or mixed) were randomized to receive ZA (5 mg/100 mL), denosumab (60 mg), or placebo. LBP was measured monthly by visual analogue scale (VAS) and the LBP Rating Scale (RS). MC was measured from MRIs of T

BACKGROUND/OBJECTIVES Vitamin D deficiency is common in adolescents but the optimal dosage regimen for correcting deficiency is unknown. To test the safety and efficacy of two different vitamin D dosage regimens to correct vitamin D deficiency in adolescents. SUBJECTS/METHODS In this 12-month, double-blind, randomized placebo-controlled trial, 28 adolescents (serum 25 hydroxyvitamin D (25(OH)D) of 21 to 50 nmol/L) were randomly assigned to one of three groups: monthly (n = 9; vitamin D3 50,000 IU orally monthly plus three placebo tablets 3-monthly), 3-monthly (n = 9; 150,000 IU (3 × 50,000 IU tablets) 3-monthly and placebo orally monthly), or placebo (n = 10; placebo monthly and three placebo tablets 3-monthly). Serum 25(OH)D was measured at baseline, 3, 6 and 12 months. RESULTS Two participants withdrew after their baseline measurement from the 3-monthly group. At 12 months, one participant was deficient (≤50 nmol/L) in both the monthly and 3-monthly groups, whereas six out of ten in the placebo remained deficient (P = 0.055). At 12 months, the average serum 25(OH)D levels for the monthly, 3-monthly and placebo groups were 76.4, 64.7 and 49.7 nmol/L, respectively (P

Aims: To describe the associations between falls risk, and between-person and within-person variability in 25-hydroxyvitamin D (25OHD), physical activity (PA), knee pain and dysfunction in community-dwelling older people.

Background Knee pain is the most common manifestation of knee osteoarthritis (OA) and is generally thought to get worse with time. Risk factors for knee pain have been extensively investigated; however, whether the risk factors are associated with a specific pain trajectory has not yet been comprehensively explored. Furthermore, knee structural pathology on MRI, such as bone marrow lesions (BMLs), effusion-synovitis and cartilage defects, are thought to be the origin of knee pain. However, its underlying mechanisms remain to be elucidated and hampered by a large individual variation of pain course. Objectives To identify distinct trajectories of knee pain over 10.7 years in an older population, to describe risk factors with identified trajectories, and to explore MRI-detected structural pathology with the trajectories. Methods 1,099 participants (mean age 63 years) from a population-based cohort study were recruited at baseline. 875, 768 and 563 participants attended years 2.6, 5.1 and 10.7 follow-up, respectively. Demographic, psychological, lifestyle and comorbidities data were obtained at baseline. Knee pain was assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at each time-point. T1-weighted or T2-weighted MRI of the right knee was performed to measure knee structural pathology. Knee radiographic OA was assessed by X-ray at baseline. Group-based trajectory modelling was applied to identify pain trajectories. Multi-nominal logistic regression was used for the analyses with adjustment for potential confounders. Results 1,099 participants were included for the identification of pain trajectories and three distinct pain trajectories were defined. Participants in Group 1 (“Mild pain” n=568, 51.7%) had relatively stable mild pain over time. Participants in Group 2 (“Moderate pain”, n=366, 33.2%) had moderate pain over time. Participants in Group 3 (“Severe pain”, n=165, 15.1%) developed or displayed fluctuating severe pain over time. Compared with the “Mild pain”, higher BMI, emotional problems, and musculoskeletal diseases were significantly associated with both “Moderate pain” and “Severe pain” trajectories. Also, younger age, lower education level and unemployment status were associated with “Severe pain” trajectory. The presence of cartilage defects and BMLs were associated with increased risk of “Moderate pain” and “Severe pain” trajectories before or after adjustment for potential confounders. Effusion-synovitis was not statistically associated with “Moderate pain” (P=0.082), but associated with “Severe pain” trajectory. Furthermore, a dose-response relationship was observed between number of knee structural abnormalities, and “Moderate pain” and “Severe pain” trajectories (both P for trend Conclusions This is the first long-term study to identify pain trajectories and their risk factors, and explore the associations between structural pathology and pain trajectories. Three distinct pain trajectory groups were identified, suggesting that homogeneous subgroups exist and follow a specific trajectory over time despite large individual variation of pain course. Significant associations between structural pathology and pain trajectories suggest that peripheral stimuli may play a role in the development and maintenance of pain severity. Disclosure of Interest None declared