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Osteoarthritis (OA) is the most prevalent joint disorder characterized by joint structural pathological changes with the loss of articular cartilage as its hallmark. Tools that can predict cartilage loss would help identify people at high risk, thus preventing OA development. The recent advance of the metabolomics provides a new avenue to systematically investigate metabolic alterations in disease and identify biomarkers for early diagnosis. Using a metabolomics approach, the current study aimed to identify serum metabolomic signatures for predicting knee cartilage volume loss over 10 years in the Tasmania Older Adult Cohort (TASOAC). Cartilage volume was measured in the medial, lateral, and patellar compartments of the knee by MRI at baseline and follow-up. Changes in cartilage volume over 10 years were 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 and pairwise metabolite ratios as the proxies of enzymatic reaction were calculated. Linear regression was used to identify metabolite ratio(s) associated with change in cartilage volume in each of the knee compartments with adjustment for age, sex, and BMI. The significance level was defined at α = 3.0 × 10−6 to control multiple testing. A total of 344 participants (51% females) were included in the study. The mean age was 62.83 ± 6.13 years and the mean BMI was 27.48 ± 4.41 kg/m2 at baseline. The average follow-up time was 10.84 ± 0.66 years. Cartilage volume was 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 the increased ratios of hexadecenoylcarnitine (C16:1) to tetradecanoylcarnitine (C14) and C16:1 to dodecanoylcarnitine (C12) were associated with 0.12 ± 0.02% reduction per year in patellar cartilage volume (both p < 3.03 × 10−6). In conclusion, our data suggested that alteration of long chain fatty acid β-oxidation was involved in patellar cartilage loss. While confirmation is needed, the ratios of C16:1 to C14 and C12 might be used to predict long-term cartilage loss. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: This study aims to describe the relationships between physical activity (PA), body composition, and multimorbidity over 10 years.Method: Participants (N = 373; 49% women; average age 61.3 ± 6.7 years) were followed for 10 years. Multimorbidity was defined by self-report as the presence of 2 or more of 12 listed chronic conditions. PA (steps per day) at baseline was assessed by pedometer, handgrip strength (HGS) by dynamometer, and appendicular lean mass (ALM) and total body fat mass by dual-energy x-ray absorptiometry. Relative HGS and ALM were calculated by dividing each body mass index (BMI). Regression cubic splines were used to assess evidence for a nonlinear relationship.Results: After 10 years, 45% participants had multimorbidity. There was a nonlinear relationship between PA and multimorbidity-PA was associated with lower multimorbidity risk among individuals who engaged in <10 000 steps/d (relative risk [RR] = 0.91, 95% CI: 0.85, 0.97, per 1 000 steps/d), but not among those who participated in ≥10 000 steps/d (RR = 1.04, 95% CI: 0.93, 1.09, per 1 000 steps/d). Higher BMI (RR = 1.05, 95% CI: 1.02, 1.08, per kg/m2) and fat mass (RR = 1.03, 95% CI: 1.01, 1.04, per kg), and lower relative HGS (RR = 0.85, 95% CI: 0.77, 0.94, per 0.1 psi/kg/m2) and ALM (RR = 0.93, 95% CI: 0.88, 0.98, per 0.1 kg/kg/m2) were linearly associated with a higher risk of multimorbidity. Absolute HGS and ALM were not significantly associated with multimorbidity.Discussion: These findings highlight the potential clinical importance of maintaining adequate levels of PA and of reducing adiposity and maintaining muscle function for minimizing the risk of multimorbidity in older adults. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (cm2) 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. A prospective cohort study. Patients (n = 200) with symptomatic knee OA (mean age 63.1 years, range 49-79; female 46.5%) participated. 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. 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. 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. [ABSTRACT FROM AUTHOR]

The aim of this study is to describe the association of bone marrow lesions (BMLs) present on two different MRI sequences with clinical outcomes, cartilage defect progression, cartilage volume loss over 2.7 years, and total knee replacement (TKR) over 13.3 years. 394 participants (50-80 years) were assessed at baseline and 2.7 years. BML presence at baseline was scored on T1-weighted fat-suppressed 3D gradient-recalled acquisition (T1) and T2-weighted fat-suppressed 2D fast spin-echo (T2) sequences. Knee pain, function, and stiffness were assessed using WOMAC. Cartilage volume and defects were assessed using validated methods. Incident TKR was determined by data linkage. BMLs were mostly present on both MRI sequences (86%). BMLs present on T2, T1, and both sequences were associated with greater knee pain and functional limitation (odds ratio = 1.49 to 1.70; all p < 0.05). Longitudinally, BMLs present on T2, T1, and both sequences were associated with worsening knee pain (β = 1.12 to 1.37, respectively; p < 0.05) and worsening stiffness (β = 0.45 to 0.52, respectively; all p < 0.05) but not worsening functional limitation or total WOMAC. BMLs present on T2, T1, and both sequences predicted site-specific cartilage defect progression (relative risk = 1.22 to 4.63; all p < 0.05) except at the medial tibial and inferior patellar sites. Lateral tibial and superior patellar BMLs present on T2, T1, and both sequences predicted site-specific cartilage volume loss (β = - 174.77 to - 140.67; p < 0.05). BMLs present on T2, T1, and both sequences were strongly associated with incident TKR. BMLs can be assessed on either T2- or T1-weighted sequences with no clinical predictive advantage of either sequence. [ABSTRACT FROM AUTHOR]

Aim: To describe the associations of between-person and within-person variability in serum 25-hydroxyvitamin D (25(OH)D), physical activity (PA), and knee pain and dysfunction with muscle mass, strength, and muscle quality over 10 years in community-dwelling older adults.Method: Participants (N = 1033; 51% women; mean age 63 ± 7.4 years) were measured at baseline, 2.5, 5, and 10 years. Lower limb lean mass (LLM) was assessed using dual energy X-ray absorptiometry, lower limb muscle strength (LMS) using a dynamometer, and lower limb muscle quality (LMQ) calculated as LMS/LLM. Knee pain and dysfunction were assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index. PA was measured using pedometers. Linear-mixed effect regression models, with adjustment for confounders, were used to estimate the association of within-person and between-person variability in PA, 25(OH)D, and WOMAC scores with muscle mass, strength, and muscle quality.Results: Both between-person and within-person increases in PA were associated with LLM, LMS, and LMQ (all P < 0.05). Within-person and between-person increases in knee pain and dysfunction were associated with LLS and LMQ, but not with LLM (all P < 0.05). Between-person effects showed that higher average 25(OH)D was associated with a higher 10-year average LLM, LMS, and LMQ (all P < 0.05), whereas within-person increases in average 25(OH)D were associated with a higher LMS and LMQ, but not with LLM.Conclusions: Variability in 25(OH)D, pain, and dysfunction within an individual over time is related to muscle changes in that individual. Increasing one's own PA level further increases muscle mass, strength, and quality supporting the clinical recommendation of promoting PA to reduce age-related muscle loss. [ABSTRACT FROM AUTHOR]

Background: There is limited longitudinal data available on the natural history of meniscal tears especially in middle-aged adults with a low prevalence of osteoarthritis (OA). The aim of this study was to describe the natural history of meniscal tears over 8 years and the relationship with change in knee pain and structures.Methods: One hundred ninety eight participants [mean age 47 (28-63); 57% female] were studied at baseline and 8 years later. Approximately half were the adult offspring of subjects who had a knee replacement performed for knee OA and the remainder were randomly selected controls. Meniscal tears/extrusion, cartilage volume/defects, bone marrow lesions (BMLs) and effusion were assessed on MRI. Knee pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index.Results: 22% of the participants had at least one meniscal tear at any site at baseline. Over 8 years, 16% of the participants had an increase in severity of meniscal tears while none improved. Increase in meniscal tear score was associated with worsening knee pain (β = +2.81 (+1.40, +4.22)), with offspring having a significantly greater increase in pain severity compared to controls. BMI and presence of osteophytes at baseline, but not knee injury, predicted change in tears, whereas change in meniscal tears was independently associated with cartilage volume loss, change in BMLs and change in meniscal extrusion.Conclusion: Change in meniscal tears shares risk factors with knee OA and is independently associated with worsening knee pain and structural damage suggesting that meniscal tears are on the knee OA causal pathway. [ABSTRACT FROM AUTHOR]

The aim of this cross-sectional study was to describe the associations between history of knee injury and knee structure using magnetic resonance imaging (MRI). This study included two population-based samples: the Tasmanian Older Adult Cohort (TASOAC) study ( n = 430; mean age, 63.0 years; range, 51-79 years; 51 % female) and the Offspring study ( n = 372; mean age, 45.0 years; range, 26-61 years; 57.5 % female). In both studies, 1.5 T MRI scans of the right knee were performed to measure bone marrow lesions (BMLs), cartilage volume, tibial bone area, cartilage defects and meniscal pathology. History of knee injury was assessed using a self-administered questionnaire. The association between knee injury and knee structure was determined using multiple linear and log binomial regression models. Nineteen percent of the middle-aged and 12 % of the older adults reported a history of knee injury. In middle-aged adults, BML presence (prevalence ratio (PR) = 1.6 (95 % CI, 1.2; 2.1)), tibial bone area (difference of means (DM) = +86 (+23, +149)) and meniscal extrusion presence (PR = 2.7 (1.1, 6.8)) were significantly higher in those with knee injury. In older adults, cartilage defect presence (PR = 1.3 (1.0, 1.7)), lateral (DM = −265 (−439, −92)) and total tibial (DM = −325 (−600, −51)) cartilage volume, BML presence (PR = 1.4 (1.0, 1.9)) and tibial bone area (DM = +140 (+19, +260)) were significantly associated with knee injury. Meniscal tears showed no significant associations in either cohorts. The association between knee injury and MRI-assessed structural pathology in the knee joint is moderate and appears to be stronger in older adults compared to middle-aged adults. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The aim of this study was to describe the relationship between accelerometer-determined physical activity (PA) and adiposity in community-dwelling older adults. In addition, we were interested in comparing the extent of correlation between questionnaire and accelerometer determined PA. Methods: 636 community-dwelling older adults (66±7years) were studied. Adiposity was measured using dual-energy X-ray absorptiometry and BMI was calculated. We measured minutes/day spent in sedentary, light, moderate and vigorous intensity activity using both questionnaires and Actigraph GT1M accelerometers. Results: Participants spent a median of 583(IQR 522–646), 225(176–271), 27(12–45) and 0(0–0) minutes in sedentary, light, moderate and vigorous activities respectively. There was a non linear dose–response inverse relationship between activity intensity and adiposity. After adjusting for age, sex and other levels of PA, for every 10minute increase in activity, total body fat decreased by 169g(95% CI 61–277), 905g(632–1178), and 2208g(759–3657) for light, moderate and vigorous activities respectively. There was an interaction between age and activity; as age increased, the magnitude of the effects of light and moderate activities on adiposity decreased. Sedentary minutes were not associated with adiposity after adjusting for time spent at other PA intensities. Questionnaire measures of PA were weakly correlated with body fat measures when compared to accelerometer determined PA. Conclusion: Both the amount and intensity of PA, but not sedentary time, have an independent dose–response association with adiposity. The association is much stronger using objective assessment compared to questionnaire. The magnitude of these associations decrease with age suggesting that physical activity programmes may need to be modified with increasing age. [Copyright &y& Elsevier]

Studies examining the association between muscle size, muscle strength, and bone mineral density (BMD) are limited. Thus, this study aimed to describe the association between hip muscles cross-sectional area (CSA), muscle strength, and BMD of the hip and spine. A total of 321 subjects from the Tasmanian Older Adult Cohort study with a right hip MRI scan conducted between 2004 and 2006 were included. Hip muscles were measured on MR images by OsiriX (Geneva) software measuring maximum muscle CSA (cm) of gluteus maximus, obturator externus, gemelli, quadratus femoris, piriformis, pectineus, sartorius, and iliopsoas. Dual-energy X-ray absorptiometry measured total hip, femoral neck, and spine BMD, and lower limb muscle strength was assessed by dynamometer. Muscle CSA of the hip flexors (pectineus, sartorius, and iliopsoas) and the hip rotators, obturator externus, and quadratus femoris were associated with both total hip and femoral neck BMD (all p < 0.05). The associations between CSA of pectineus and sartorius and BMD were stronger in women ( p = 0.01-0.001) compared to men ( p = 0.12-0.54). Additionally, only gemelli CSA was associated with BMD of the spine ( p = 0.002). Gluteus maximus and piriformis showed no relationship with BMD. CSA of most hip muscles (except gluteus maximus and gemelli) were positively associated with leg strength ( p = 0.02 to <0.001). Lastly, leg strength was weakly associated with BMD ( p = 0.11-0.007). Hip muscle CSA, and to a lesser extent muscle strength, were positively associated with hip BMD. These data suggest that both higher muscle mass and strength may contribute to the maintenance of bone mass and prevention of disease progression in older adults. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Objective To investigate the impact of total number and patterns of comorbidities on health-related quality of life (HRQoL) and identify the most prevalent and influential comorbidity patterns in people with OA over 10 years. Methods Participants from the Tasmanian Older Adult Cohort aged 50–80 years, with self-reported OA and data on comorbidities and HRQoL were included. Participants were interviewed at baseline (n  = 398), 2.5 (n  = 304), 5 (n  = 269) and 10 years (n  = 191). Data on the self-reported presence of 10 chronic comorbidities were collected at baseline. HRQoL was assessed using the Assessment of Quality of Life-4-Dimensions. The long-term impacts of the number and of the nine most prevalent combinations of cardiovascular (CVD), non-OA musculoskeletal (Ms), metabolic and respiratory comorbidities on HRQoL over 10 years were analysed using linear mixed regressions. Results Compared with comorbidity-free OA participants, the health state utility (HSU) of those with 2 or ≥3 comorbidities was respectively −0.07 and −0.13 units lower over 10 years, largely driven by reduced scores for independent living, social relationships and psychological wellness. Comorbidity patterns including 'CVD+Ms' were most influential, and associated with up to 0.13 units lower HSU, mostly through negative impacts on independent living (up to −0.12), psychological wellness (up to −0.08) and social relationship (up to −0.06). Conclusion Having more comorbidities negatively impacted OA patients' long-term HRQoL. OA patients with CVD and non-OA musculoskeletal conditions had the largest HSU impairment, and therefore optimal management and prevention of these conditions may yield improvements in OA patients' HRQoL. [ABSTRACT FROM AUTHOR]

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 (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.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. [ABSTRACT FROM AUTHOR]

Background: There is increasing use of complementary and alternative medicines (CAMs) alone or as an adjuvant therapy to conventional medicines in osteoarthritis (OA) patients. Objectives: This study aimed to describe the prevalence and correlates of the use of CAMs among community‐dwelling older adults. Methods: Data from the Tasmania Older Adult Cohort Study (TASOAC, n = 1099) were used to describe the prevalence of CAM use. Correlates of CAM use were assessed by comparing CAM users and non‐users. To further assess correlates of CAM use, participants with at least one joint with pain were classified into four categories: CAM‐only, analgesics‐only, co‐therapy, and "neither CAMs nor analgesics" (NCNA). Results: In all, 385 (35.0%) of our participants reported use of CAMs, among which vitamins/minerals were used most (22.6%, n = 232). Compared with CAM non‐users, CAM users were more likely to be female, were less likely to be overweight, were better educated, had more joints with OA, had fewer WOMAC scores, and did more steps per day. Among participants with any joint pain, the CAM‐only group were less likely to be overweight, consumed more alcohol, had higher quality of life, had more steps per day, and had fewer pain‐related symptoms compared with the analgesic‐only group. Conclusion: Complementary and alternative medicines were commonly used among Tasmanian older adults, with 35% of the population using CAMs either alone or in combination with conventional analgesics. CAM users were more likely to be female, be better educated, have more joints with OA, and had healthier lifestyles, including lower body mass index and higher number of steps per day. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 x 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 x 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The burden of osteoarthritis (OA) is rapidly increasing with population aging, but there are still no approved disease-modifying drugs available. Accumulating evidence has shown that OA is a heterogeneous disease with multiple phenotypes, and it is unlikely to respond to one-size-fits-all treatments. Inflammation is recognized as an important phenotype of OA and is associated with worse pain and joint deterioration. Therefore, it is believed that anti-inflammatory treatments may be more effective for OA with an inflammatory phenotype. In this review, we summarized clinical trials that evaluated anti-inflammatory treatments for OA and discussed whether these treatments are more effective in inflammatory OA phenotypes compared to general OA patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To describe the impact of OA on health-related quality of life (HRQoL) in the forms of health state utilities (HSUs) and health-dimension scores, and to compare the longitudinal changes in HRQoL for people with and without OA, using an Australian population-based longitudinal cohort. Methods Participants of the Tasmanian Older Adult Cohort with data on OA diagnosis and HRQoL were included [interviewed at baseline (n  = 1093), 2.5 years (n  = 871), 5 years (n  = 760) and 10 years (n  = 562)]. HRQoL was assessed using the Assessment of Quality of Life four-dimensions and analysed using multivariable linear mixed regressions. Results Compared with participants without OA, HSUs for those with OA were 0.07 (95% confidence interval: 0.09, 0.05) units lower on average over 10 years. HSUs for participants with knee and/or hip OA were similar to those with other types of OA at the 2.5 year follow-up and then diverged, with HSUs of the former being up to 0.09 units lower than the latter. Those with OA had lower scores for psychological wellness, independent living and social relationships compared with those without OA. Independent living and social relationships were mainly impacted by knee and/or hip OA, with the effect on the former increasing over time. Conclusion Interventions to improve HRQoL should be tailored to specific OA types, health dimensions, and times. Support for maintaining psychological wellness should be provided, irrespective of OA type and duration. However, support for maintaining independent living could be more relevant to knee and/or hip OA patients living with the disease for longer. [ABSTRACT FROM AUTHOR]

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 . [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study aims to assess whether older adults with low muscle mass or strength, in the presence of obesity, have an increased risk of knee (TKR) and hip replacement (THR) over 13 years. 1082 community-dwelling older adults (51% women; mean age 62.9 ± 7.5 years) were studied at baseline and multiple time points over 13 years. The incidence of TKR and THR was determined by data linkage to National Joint Replacement Registry. Appendicular lean and fat mass were measured using DXA. Lower-limb muscle strength (LMS) was assessed by dynamometer. Low muscle mass and strength were defined as the lowest sex-specific tertiles for appendicular lean mass (adjusted for height and total body fat mass) and lower-limb strength, respectively. Obesity was defined as the highest sex-specific tertile for total body fat mass. Competing risk regression models were used to estimate the sub-distribution hazard ratio (SHR) for TKR and THR. Over 13 years of follow-up, 6.8% (n = 74/1082) of the participants had a TKR and 4.7% (n = 50/1066) had THR. Participants with the combination of obesity and low muscle strength (SHR   3.36, 95% CI 1.50, 7.53) but low muscle mass (SHR 1.11, 95% CI 0.52, 2.40) had a significantly increased risk of TKR, compared to individuals with neither obesity nor low muscle mass/strength. However, obesity with low muscle strength did not lead to a significantly greater risk of TKR compared to having low muscle strength or obesity alone. There was no evidence for an association between obesity with low muscle mass or strength and THR (all p > 0.05). This finding suggests that combining muscle and fat assessments to predict the future risk of TKR is no better than each condition on its own. [ABSTRACT FROM AUTHOR]

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 mm3, 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 mm3, 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. [ABSTRACT FROM AUTHOR]

Highlights • Osteodynapenia but not osteosarcopenia increased the risk of fracture. • Osteodynapenia did not lead to a significantly greater fracture risk compared to having osteopenia or dynapenia alone. • Osteosarcopenia but not osteodynapenia increased the risk of mortality. • Osteosarcopenia did not lead to a significantly greater mortality risk compared to having osteopenia or sacropenia alone. Abstract Aim: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Abstract Aims This study aims to describe the associations of low muscle mass, handgrip (HGS) and lower-limb muscle strength (LMS) with health-related quality of life (HRQoL) over 10 years in community-dwelling older adults. Methods Participants (N = 1002; 51% women; mean age 63 ± 7.4 years) were prospectively followed for 10 years. HRQoL was measured using the validated assessment of quality of life (AQoL) instrument. Appendicular lean mass (ALM) was assessed using dual energy X-ray absorptiometry and normalized to body mass index (BMI). HGS and LMS were assessed using dynamometers. Low ALM/BMI (ALM/BMI LOW), LMS (LMS LOW) and HGS (HGS LOW) at baseline were defined as the lowest 20% of the sex-specific distribution for each measure. Linear mixed effect regression models, adjusting for confounders, were used to estimate the association between ALM/BMI LOW , LMS LOW , and HGS LOW at baseline and HRQoL over 10 years. Results Participants with LMS LOW (β = −0.061, 95% CI: −0.089, −0.033) and women (β = −0.089, 95% CI: −0.129, −0.049) but not men (β = −0.023, 95% CI: −0.064, 0.019) with HGS LOW had clinically meaningful reductions in HRQoL over 10 years compared to those with normal strength. There was a weaker but statistically significant association between ALM/BMI LOW and 10-year HRQoL (β = −0.038, 95% CI: −0.068, −0.008). Conclusions Lower-limb muscle strength and handgrip strength (in women only), which can be easily measured in clinical practice, appear more important than muscle mass for HRQoL. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To identify factors associated with non-medical health professionals' engagement in physical activity (PA) promotion.Methods: Five electronic databases were searched for studies including practising health professionals (excluding medical doctors), a PA promotion practice measure, a test of association between potential influencing factors and PA promotion practice, and written in English. Two researchers independently screened studies and extracted data. Extracted data were synthesized in a tabular format with a narrative summary (thematic analysis).Results: Thirty studies involving 7734 non-medical health professionals were included. Self-efficacy in PA promotion, positive beliefs in the benefits of PA, assessing patients' PA, and PA promotion training were the main factors associated with engaging in PA promotion. Lack of remuneration was not associated. Common study limitations included a lack of information on non-responders, data collection by survey only and limited reliability or validity testing of measurements.Conclusions: There are common factors influencing PA promotion, but the absence of studies from some health professions, limitations related to study measures, and the lack of randomised controlled intervention trials highlights the need for further research.Practice Implications: The factors identified may prove useful for guiding the development of strategies to encourage greater engagement in PA promotion by health professionals. [ABSTRACT FROM AUTHOR]

Aims To describe the longitudinal associations between physiological falls risk, and between-person and within-person effects of 25-hydroxyvitamin D (25OHD), physical activity (PA), knee pain and dysfunction in community-dwelling older people. Methods Data for 1053 participants (51% women; mean age 63 ± 7.4 years) studied at baseline, 2.5, 5, and 10 years were analysed. Falls risk (Z-score) was measured using the Physiological Profile Assessment. Knee pain and dysfunction were assessed using the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC). Moderate-to-vigorous PA (MVPA) was measured using accelerometer. Linear mixed-effect regression models, with adjustment for confounders, were used to estimate the association between physiological falls risk and between-person and within-person effects of PA, 25OHD and WOMAC score. Results Between-person effects showed that 10-year average physiological falls risk was lower in participants who had a higher 10-year average 25OHD (β = −0.005 per nmol/l, 95% CI: −0.008, −0.002), log-MVPA (β = −0.16 per minute, 95% CI: −0.22, −0.10) and lower mean WOMAC score (β = 0.005 per-unit score, 95% CI: 0.003, 0.01). Within-person effects showed that a higher physiological falls risk at any time-point was associated with higher than average WOMAC score (β = 0.002 per-unit score, 95% CI: 0.0003, 0.004) and lower than average log-MVPA (β = −0.15 per minute, 95% CI: −0.24, −0.06), but not 25OHD, at the same time-point. Conclusion Having higher WOMAC global score above an individual's average increases the risk of falling, whereas, increasing one's own MVPA level further reduces their risk of falling. The presence of between-person but not within-person associations for 25OHD suggests the former may be confounded by other factors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Social disadvantage may contribute to increased prevalence of sarcopenia and obesity. This study investigated if socioeconomic factors are associated with obesity, sarcopenia, or sarcopenic obesity (SO), in community-dwelling older adults. This was a cross-sectional analysis of data from the Tasmanian Older Adult Cohort study. Obesity was defined by body fat percentage (Men: ≥25%; Women: ≥35%) and sarcopenia was defined as the lowest 20% of sex-specific appendicular lean mass (ALM)/height (m2) and handgrip strength. Socioeconomic factors investigated were education (tertiary degree, secondary or no secondary school), occupation (high skilled white-collar, low skilled white-collar, or blue-collar) and residential area (advantaged or disadvantaged area). Multinomial logistic regression analyses yielding odds ratios (95% confidence intervals) were performed and adjusted for potential confounders. Mediation analysis was performed. 1099 older adults (63.0 ± 7.5 years; 51.1% women) participated. Older adults with a tertiary degree were significantly less likely to have obesity (0.68; 0.47, 0.98) and SO (0.48; 0.24, 0.94) compared with those who had no secondary schooling. No associations were found for occupation. Similarly, older adults living in advantaged areas were significantly less likely to have obesity (0.61; 0.39, 0.95). Steps per day mediated the association between residential area and body fat percentage by 51%. Lower educational attainment, but not occupation, was associated with increased likelihood for both obesity and SO in community-dwelling older adults. Low physical activity levels in disadvantaged areas substantially contributed to higher obesity prevalence in this population. Further research is necessary to confirm whether similar associations exist in populations with greater levels of social disadvantage and to design effective community-based interventions. • Lower education is associated with increased risk of obesity and sarcopenic obesity. • Occupation types were not associated with obesity, sarcopenia or sarcopenic obesity. • Disadvantaged area of residence is associated with increased risk of obesity. • Physical activity mediated the association of area of residence with obesity. [ABSTRACT FROM AUTHOR]

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. 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. 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). Obese older adults by body fat percentage had significantly higher likelihood of all incident fractures (OR: 1.71; CI:1.08, 2.71) and non-vertebral fractures (OR: 1.88; CI:1.16, 3.04) compared with non-obese after adjusting for confounders. Conversely, obese older adults by BMI had a significantly lower likelihood (OR: 0.54; CI:0.31, 0.94) of non-vertebral fractures although this was no longer significant after adjustment for total hip aBMD (all 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<0.05). Obesity defined by body fat percentage is associated with increased likelihood of incident fractures in community-dwelling older adults, whereas those who are obese according to BMI have reduced likelihood of incident fracture which appears to be explained by higher aBMD. Falls risk assessment may improve identification of obese older adults at increased risk of incident fractures. • Prevalence of obesity was 28% (body mass index) and 43% (body fat %). • Obese older adults defined by body fat % have increased risk of incident fractures. • High body mass index was associated with reduced risk of incident fractures. • High falls risk score was predictive of incident fracture among obese older adults. [ABSTRACT FROM AUTHOR]

• In addition to inter-individual differences, intra-individual variability in physical activity is associated with knee pain and functional limitation. • When participants engaged in more physical activity than their average level, they had lower knee pain and functional limitation. • Conversely, having higher functional limitations compared with an individual's average was associated with lower levels of physical activity. 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. 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). 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. 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. [ABSTRACT FROM AUTHOR]

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. 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. 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. The primary outcome was the depressive symptoms change over 24 months, which was measured using the Patient Health Questionnaire (PHQ-9, 0-27). 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. 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. [ABSTRACT FROM AUTHOR]

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 A2 (PLA2), we assessed and found that a specific PLA2, PLA2G5, 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. [ABSTRACT FROM AUTHOR]