Single nucleotide polymorphism genes and mitochondrial DNA haplogroups as biomarkers for early prediction of knee osteoarthritis structural progressors: use of supervised machine learning classifiers.

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.

Association between socioeconomic status and joint replacement of the hip and knee: a population-based cohort study of older adults in Tasmania.

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.

Cross-sectional and temporal differences in health-related quality of life of people with and without osteoarthritis: a 10-year prospective study.

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.

The impact of comorbidities on health-related quality of life of people with osteoarthritis over 10 years.

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.

The association between change in bone marrow lesion size and change in tibiofemoral cartilage volume and knee symptoms.

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.

Depression in patients with knee osteoarthritis: risk factors and associations with joint symptoms.

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 .

Effectiveness of Curcuma longa Extract for the Treatment of Symptoms and Effusion-Synovitis of Knee Osteoarthritis : A Randomized Trial.

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.

Do Older Adults with Low Muscle Mass or Strength, in the Presence of Obesity, Have an Increased Risk of Joint Replacement Over 13 Years?

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.

Quantification of hip effusion-synovitis and its cross-sectional and longitudinal associations with hip pain, MRI findings and early radiographic hip OA.

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 (ßeta: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.

Effect of Intravenous Zoledronic Acid on Tibiofemoral Cartilage Volume Among Patients With Knee Osteoarthritis With Bone Marrow Lesions: A Randomized Clinical Trial.

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.

Differentiating knee pain phenotypes in older adults: a prospective cohort study.

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.

How Do MRI-Detected Subchondral Bone Marrow Lesions (BMLs) on Two Different MRI Sequences Correlate with Clinically Important Outcomes?

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 (ß = 1.12 to 1.37, respectively; p < 0.05) and worsening stiffness (ß = 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 (ß = - 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.

Vitamin D supplementation and inflammatory and metabolic biomarkers in patients with knee osteoarthritis: post hoc analysis of a randomised controlled trial.

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

A protocol for a multicentre, randomised, double-blind, placebo-controlled trial to compare the effect of annual infusions of zoledronic acid to placebo on knee structural change and knee pain over 24 months in knee osteoarthritis patients - ZAP2.

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.

Signal intensity alteration in the infrapatellar fat pad at baseline for the prediction of knee symptoms and structure in older adults: a cohort study.

OBJECTIVE: To describe the associations between infrapatellar fat pad (IPFP) signal intensity alteration at baseline and knee symptoms and structural changes in older adults. METHODS: A total of 874 subjects (mean 62.1 years, 50.1% female) selected randomly from local community were studied at baseline and 770 were followed up (only 357 had MRI at follow-up) over 2.6 years. T1-weighted or T2-weighted fat suppressed MRI was used to assess IPFP signal intensity alteration (0-3), cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and 2.6 years later. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index questionnaire. Radiographic osteoarthritis (OA) was assessed. RESULTS: In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with total knee pain as well as knee cartilage defects, BMLs and knee radiographic OA and negatively associated with patellar cartilage volume after adjustment for age, sex, body mass index and/or radiographic OA. Longitudinally, baseline signal intensity alteration within IPFP was significantly and positively associated with increases in knee pain when going upstairs/downstairs as well as increases in tibiofemoral cartilage defects and BMLs, and negatively associated with change in lateral tibial cartilage volume in multivariable analyses. CONCLUSIONS: IPFP signal intensity alteration at baseline was associated with knee structural abnormalities and clinical symptoms cross-sectionally and longitudinally in older adults, suggesting that it may serve as an important imaging biomarker in knee OA.

Fish oil in knee osteoarthritis: a randomised clinical trial of low dose versus high dose.

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

Lysophosphatidylcholines to phosphatidylcholines ratio predicts advanced knee osteoarthritis.

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

Does cartilage volume measurement or radiographic osteoarthritis at baseline independently predict ten-year cartilage volume loss?

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 (ß(95 % CI) = -300 (-399,-200)) and lateral (ß = -338 (-443,-233)) compartments and percentage per annum loss in the lateral compartment(ß = -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.

Natural history and clinical significance of meniscal tears over 8 years in a midlife cohort.

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 (ß = +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.

Interventions to improve adherence to exercise for chronic musculoskeletal pain in adults.

BACKGROUND: This article is facilitated by the Australian Cochrane Musculoskeletal Group (CMSG) editorial base. The CMSG is one of the largest Cochrane review groups and produces reliable, up-to-date systematic reviews of interventions for the prevention, treatment or rehabilitation of musculoskeletal disorders. OBJECTIVE: Our aim is to place the findings of recent Cochrane musculoskeletal reviews in a context immediately relevant to general practitioners (GPs) by summarising the findings of a review of interventions to improve adherence to exercise for adults with chronic musculoskeletal pain (CMP). DISCUSSION: The findings indicate that there are various strategies that may be effective in increasing adherence to exercise and physical activity in patients suffering from CMP. These strategies are discussed in detail and general practice scenarios are presented to show how the results can be applied in practice.