Metformin for knee osteoarthritis with obesity: study protocol for a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Over half of the populations with knee osteoarthritis (OA) have obesity. These individuals have many other shared metabolic risk factors. Metformin is a safe, inexpensive, well-tolerated drug that has pleiotropic effects, including structural protection, anti-inflammatory and analgesic effects in OA, specifically the knee. The aim of this randomised, double-blind, placebo-controlled trial is to determine whether metformin reduces knee pain over 6 months in individuals with symptomatic knee OA who are overweight or obese. METHODS AND ANALYSIS: One hundred and two participants with symptomatic knee OA and overweight or obesity will be recruited from the community in Melbourne, Australia, and randomly allocated in a 1:1 ratio to receive either metformin 2 g or identical placebo daily for 6 months. The primary outcome is reduction of knee pain [assessed by 100 mm Visual Analogue Scale (VAS)] at 6 months. The secondary outcomes are OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) responder criteria [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and participant's global assessment (VAS)] at 6 months; change in knee pain, stiffness, function using WOMAC at 6 months and quality of life at 6 months. Adverse events will be recorded. The primary analysis will be by intention to treat, including all participants in their randomised groups. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Alfred Hospital Ethics Committee (708/20) and Monash University Human Research Ethics Committee (28498). Written informed consent will be obtained from all the participants. The findings will be disseminated through peer-review publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12621000710820 .

Negative back beliefs are associated with increased odds of low back pain and disability: a 10-year cohort study in men.

OBJECTIVE: Although negative back beliefs are associated with high-intensity low back pain (LBP)/disability, whether they influence incident high-intensity LBP/high-disability over the long-term is unknown. This study aimed to investigate whether negative back beliefs were associated with developing high-intensity LBP and/or high-disability over 10 years in men. METHODS: Men with no or low-intensity LBP and/or disability attending the Geelong Osteoporosis Study between 2006-2010 were included. Data on age, body mass index, mobility, education, back beliefs (Back Beliefs Questionnaire), LBP and disability (Graded Chronic Pain Scale) were collected between 2006-2010. Beliefs, LBP and disability were re-assessed in 2016-2021. Binary logistic regression was used to examine the association between negative back beliefs and incident high-intensity pain and/or high-disability, adjusting for age, body mass index, mobility, and education. RESULTS: At baseline, 705 participants (mean age 53.8 years) had no or low LBP and no or low-disability; 441 (62.6%) participants completed a 10-year follow-up. Of these, 37 (8.4%) developed high-intensity pain and/or high-disability. In multivariate analyses, participants with more negative back beliefs at baseline were more likely to develop high-intensity pain and/or high-disability (Odds ratio 1.05, 95% CI 1.00-1.11). Developing more negative back beliefs was also associated with incident high-intensity pain and/or high-disability (Odds Ratio 1.20, 95% CI 1.12-1.30). CONCLUSION: In a male community-based population, negative beliefs regarding the consequences of LBP were associated with an increased likelihood of developing high-intensity pain and/or high-disability. Addressing negative back beliefs in the community may reduce the incidence of high-intensity pain and/or high-disability over 10 years in men.

Patterns and natural history of hand pain in individuals with symptomatic hand osteoarthritis in a prospective cohort study: A post-hoc analysis of a randomised controlled trial.

Objective: To investigate the variation in the distribution and the natural history of hand pain over 6 weeks in individuals with symptomatic hand osteoarthritis. Design: Patient-reported outcome data were collected at baseline and weekly for 6 weeks from community-based participants enrolled in a randomised controlled trial. Participants were grouped based on location of significant pain (Visual Analogue Scale, VAS≥40/100 â€‹mm) (both carpometacarpal (CMC) and interphalangeal (IP), CMC only, and IP only). Results: At baseline, of the 106 participants, 55(51.9 %) had pain in both CMC and IP joints, 28(26.4 %) in IP joints only, and 16(15.1 %) in CMC joint only. Those with CMC and IP pain had significantly higher VAS pain [68.1 (2.6) vs 59.3 (3.5) vs 51.2 (4.7)]; Australian Canadian Osteoarthritis Hand Index, (AUSCAN) pain [290.1 (15.7) vs 225.3 (21.2) vs 237.9 (28.4)], stiffness [57.1 (3.7) vs 44.6 (5.0) vs 32.2 (6.7)] and functional limitation [527.5 (30.9) vs 356.0 (41.7) vs 433.3 (55.7)]; and pain sensitization [PainDETECT score 11.1 (1.1) vs 8.1 (1.8) vs 5.8 (1.9)] compared to those with IP or CMC only pain, respectively. All groups showed improvement in outcomes over 6 weeks without significant inter-group differences. Conclusion: In a population with significant hand pain, pain in both CMC and IP joints was most common and identified a more severe phenotype than pain in IP or CMC only with higher pain, more functional limitation and pain sensitization. These data have the potential to inform clinical management of patients with hand pain and patient selection in clinical trials.

Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hand osteoarthritis is a disabling condition with few effective therapies. Hand osteoarthritis with synovitis is a common inflammatory phenotype associated with pain. We aimed to examine the efficacy and safety of methotrexate at 6 months in participants with hand osteoarthritis and synovitis. METHODS: In this multisite, parallel-group, double-blind, randomised, placebo-controlled trial, participants (aged 40-75 years) with hand osteoarthritis (Kellgren and Lawrence grade ≥2 in at least one joint) and MRI-detected synovitis of grade 1 or more were recruited from the community in Melbourne, Hobart, Adelaide, and Perth, Australia. Participants were randomly assigned (1:1) using block randomisation, stratified by study site and self-reported sex, to receive methotrexate 20 mg or identical placebo orally once weekly for 6 months. The primary outcome was pain reduction (measured with a 100 mm visual analogue scale; VAS) in the study hand at 6 months assessed in the intention-to-treat population. Safety outcomes were assessed in all randomly assigned participants. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000877381). FINDINGS: Between Nov 22, 2017, and Nov 8, 2021, of 202 participants who were assessed for eligibility, 97 (48%) were randomly assigned to receive methotrexate (n=50) or placebo (n=47). 68 (70%) of 97 participants were female and 29 (30%) were male. 42 (84%) of 50 participants in the methotrexate group and 40 (85%) of 47 in the placebo group provided primary outcome data. The mean change in VAS pain at 6 months was -15·2 mm (SD 24·0) in the methotrexate group and -7·7 mm (25·3) in the placebo group, with a mean between-group difference of -9·9 (95% CI -19·3 to -0·6; p=0·037) and an effect size (standardised mean difference) of 0·45 (0·03 to 0·87). Adverse events occurred in 31 (62%) of 50 participants in the methotrexate group and 28 (60%) of 47 participants in the placebo group. INTERPRETATION: Treatment of hand osteoarthritis and synovitis with 20 mg methotrexate for 6 months had a moderate but potentially clinically meaningful effect on reducing pain, providing proof of concept that methotrexate might have a role in the management of hand osteoarthritis with an inflammatory phenotype. FUNDING: National Health and Medical Research Council of Australia.

Our biology working against us in obesity: A narrative review on implications for management of osteoarthritis.

Obesity is the major modifiable risk factor for osteoarthritis (OA). A major focus of management in OA is weight loss. Although we live in an obesogenic environment, obesity has a predominantly genetic and epigenetic basis. This explains a person's weight set point which is defended by biological mechanisms making weight loss difficult to achieve and maintain long term, regardless of the methods used. Significant weight regain occurs after weight loss, with weight tending to return to pre-treatment levels after cessation of interventions including the glucagon-like peptide-1 (GLP-1) agonists. An area that has received little attention is the slow, insidious weight creep of 0.5-1 kg/year over adulthood that sees individuals relentlessly increase weight. There is evidence that low intensity, personalised lifestyle interventions can prevent this weight creep, providing patients with achievable goals. In this narrative review, we examine the evidence for weight loss in OA, the biological mechanisms that make weight loss difficult to achieve and maintain and the potential negative impacts on patients. We review the evidence for preventing weight gain, the improvement in patient outcomes and the potential for significant healthcare savings through reduced knee replacements. We propose a combined approach of weight loss when indicated, together with targeting weight creep across adult years and the potential role of metformin. Implementing these combined approaches is likely to be more effective in improving patient related outcomes, reducing joint damage and healthcare costs, than our current focus on achieving weight loss in OA.

Efficacy of tumor necrosis factor inhibitors in hand osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.

Objectives: This study aimed at systematically review the evidence for the efficacy of Tumor Necrosis Factor (TNF) inhibitors on symptoms and structural outcomes in hand osteoarthritis. Methods: Three databases were searched for randomized controlled trials examining the efficacy of TNF inhibitors in hand osteoarthritis. Two authors extracted data and assessed the risk of bias. The mean difference (MD) was calculated, and a random-effects meta-analysis was performed. Results: Four studies were identified involving 276 participants. Meta-analysis showed that TNF inhibitors had no effect on pain at 4-6 weeks (MD -0.93, 95%CI -7.41 to 5.55; 2 studies) and 24-26 weeks (MD -3.82, 95%CI -11.46 to 3.83; 2 studies) and no effect on grip strength at 12 months (MD -0.35, 95%CI -1.08 to 0.37; 2 studies). There was limited evidence for the effect of TNF inhibitors on structural outcomes at 12 months. Subgroup analysis from 2 studies showed beneficial effect of TNF inhibitors on reducing the progression of structural outcomes in hand OA patients with signs of inflammation but not in those without inflammation. The certainty of the evidence was low for the effect of TNF inhibitor on pain and moderate for the effect on grip strength. Conclusion: This study found no effect of TNF inhibitors on clinical outcomes in hand osteoarthritis over the short term (<6 weeks) and within one year, with some evidence for beneficial effect on structural outcomes.

Effect of 6-week treatment with topical betamethasone dipropionate in patients with symptomatic hand osteoarthritis: A randomized double-blind, placebo-controlled trial.

Objective: To examine the efficacy and safety of topical corticosteroid over 6 weeks in patients with symptomatic hand osteoarthritis. Design: In a randomized, double-blind, placebo-controlled trial, community-based participants with hand osteoarthritis were randomly assigned (1:1) to topical Diprosone OV (betamethasone dipropionate 0.5 â€‹mg/g in optimised vehicle, n=54) or placebo (plain paraffin, n=52) ointment to painful joints 3 times daily for 6 weeks. Primary outcome was pain reduction [assessed by 100 â€‹mm visual analogue scale (VAS)] at 6 weeks. Secondary outcomes included changes in pain and function using the Australian Canadian Osteoarthritis Hand Index (AUSCAN), Functional Index for Hand Osteoarthritis (FIHOA), and Michigan Hand Outcomes Questionnaire (MHQ) at 6 weeks. Adverse events were recorded. Results: Of 106 participants (mean age 64.2 years, 85.9% female), 103 (97.2%) completed the study. Change in VAS at 6 weeks was similar in the Diprosone OV and placebo groups (-19.9 vs. -20.9, adjusted difference 0.6, 95% CI -8.9 to 10.2). There were no significant between-group differences in change in AUSCAN pain [adjusted difference 25.8 (-16.0 to 67.5)], AUSCAN function [21.2 (-55.0 to 97.4)], FIHOA [-0.1 (-1.7 to 1.5)], or MHQ [-1.2 (-6.0 to 3.6)]. Incidence of adverse events was 16.7% in Diprosone OV and 19.2% in placebo group. Conclusions: Topical Diprosone OV ointment, although well-tolerated, was no better than placebo in improving pain or function over 6 weeks in patient with symptomatic hand osteoarthritis. Future studies should consider examining joints with synovitis and whether delivery approaches enhancing transdermal penetration of corticosteroids into joints are effective in hand osteoarthritis. Trial registration: ACTRN 12620000599976. Registered May 22, 2020.

High levels of back disability, not back pain, are associated with reduced physical activity across key activity domains.

BACKGROUND: Although remaining physically active is the cornerstone of management for low back pain, our understanding of the physical activity performed by those with back pain is limited. OBJECTIVES: To examine the physical activity reported by individuals with different levels of low back pain and disability across key activity domains. DESIGN: Community-based, cross-sectional study. METHODS: 542 women were recruited from a research database formed from an electoral roll and completed validated, self-report questionnaires. The amount and intensity of physical activity was reported using the International Physical Activity Questionnaire. Low back pain and disability were examined using the Graded Chronic Pain Scale. Participants were categorised into no, low or high pain and disability groups. RESULTS: Individuals who reported high disability performed 55% of the physical activity of those without disability (MET(hours/week):median(95%CI) = 27.1(13.2-41.0); 48.8(37.8-59.9),p = 0.01), including less moderate (18.0(10.4-25.6); 31.0(24.0-38.1),p = 0.007), and domestic and gardening activity (14.7(7.2-22.3); 25.7(19.8-31.7),p = 0.001). Fewer women with high disability performed vigorous (OR(95%CI) = 0.29(0.13-0.65),p = 0.002) and leisure activities (0.17(0.04-0.75),p = 0.02) compared to those with no disability. Those with low disability reported less leisure activity ((0.55(0.35-0.88),p = 0.01), but more work-related activities and active transport than individuals without disability (1.65(1.01-2.7),p = 0.04; 1.6(1.04-2.6),p = 0.03). There were no differences in activity between pain groups, with the exception of those with low intensity pain performing less leisure activity (0.51(0.30-0.88),p = 0.01). CONCLUSIONS: Individuals who reported high back disability, not back pain, were found to perform reduced physical activity, including less total, moderate, vigorous, and discretionary activity. These findings highlight the altered activity levels of people with back disability and the need to examine its impact on their health and wellbeing.

Functional outcomes following knee replacement in community-dwelling older adults.

BACKGROUND: Knee replacements are increasingly performed in older adults but uncertainty remains regarding their benefits in the context of age-related decline in physical function and other comorbidities. This study aimed to examine (1) the effect of knee replacement on functional outcomes in the context of age-related decline in physical function and (2) the factors associated with minimal important improvement in physical function after knee replacement in community-dwelling older adults aged ≥ 70 years. METHODS: This cohort study was performed within the ASPREE trial, with 889 participants undergoing knee replacement during the trial and 858 age- and sex-matched controls without knee or hip replacement identified from 16,703 Australian participants aged ≥ 70 years. Health-related quality of life was assessed annually using the SF-12, including its physical and mental component summary (PCS and MCS). Gait speed was measured biennially. Multiple linear regression and analysis of covariance were used to adjust for potential confounders. RESULTS: Participants with knee replacement had significantly lower pre- and post-replacement PCS scores and gait speed compared with age- and sex-matched controls. Participants with knee replacement had significant improvement in PCS score following knee replacement (mean change 3.6, 95% CI 2.9-4.3) while PCS score remaining unchanged in age- and sex-matched controls (-0.02, 95% CI -0.6 to 0.6) during follow-up period. The greatest improvements were observed for bodily pain and physical function. Following knee replacement, 53% of participants experienced minimal important improvement in PCS score (increased by ≥ 2.7), while 24% experienced worsened PCS score (reduced by > 2.7). Participants experiencing improved PCS score postoperatively had significantly lower PCS and higher MCS scores pre-surgery. CONCLUSIONS: Although community-based older adults experienced a significant improvement in PCS scores after knee replacement, their postoperative physical functional status remained significantly lower than age- and sex-matched controls. The degree of preoperative physical function impairment was a strong predictor of functional improvement, suggesting that this could be an important consideration when identifying older people most likely to benefit from knee replacement surgery.

Associations of Change in Body Size With All-Cause and Cause-Specific Mortality Among Healthy Older Adults.

Importance: The association between weight change and subsequent cause-specific mortality among older adults is not well described. The significance of changes in waist circumference (WC) has also not been compared with weight change for this purpose. Objective: To examine the associations of changes in body weight and WC with all-cause and cause-specific mortality. Design, Setting, and Participants: This cohort study is a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial, which recruited participants between March 1, 2010, and December 31, 2014. The study included community-based older adults (16 703 Australian participants aged ≥70 years and 2411 US participants aged ≥65 years) without evident cardiovascular disease (CVD), dementia, physical disability, or life-limiting chronic illness. Data analysis was performed from April to September 2022. Exposures: Body weight and WC were measured at baseline and at annual visit 2. Analysis models were adjusted for baseline body mass index because height and weight were measured at baseline, allowing for calculation of body mass index and other variables. Both body weight and WC changes were categorized as change within 5% (stable), decrease by 5% to 10%, decrease by more than 10%, increase by 5% to 10%, and increase by more than 10%. Main Outcomes and Measures: All-cause, cancer-specific, CVD-specific, and noncancer non-CVD-specific mortality. Mortality events were adjudicated by an expert review panel. Cox proportional hazards regression and competing risk analyses were used to calculate hazard ratios (HRs) and 95% CIs. Results: Among 16 523 participants (mean [SD] age, 75.0 [4.3] years; 9193 women [55.6%]), 1256 deaths were observed over a mean (SD) of 4.4 (1.7) years. Compared with men with stable weight, those with a 5% to 10% weight loss had a 33% higher (HR, 1.33; 95% CI, 1.07-1.66) risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 289% higher (HR, 3.89; 95% CI, 2.93-5.18) risk. Compared with women with stable weight, those with a 5% to 10% weight loss had a 26% higher (HR, 1.26; 95% CI, 1.00-1.60) risk of all-cause mortality, and those with more than a 10% decrease in body weight had a 114% higher (HR, 2.14; 95% CI, 1.58-2.91) risk. Weight loss was associated with a higher cancer-specific mortality (>10% decrease among men: HR, 3.49; 95% CI, 2.26-5.40; 5%-10% decrease among women: HR, 1.44; 95% CI, 1.46-2.04; >10% decrease among women: HR, 2.78; 95% CI, 1.82-4.26), CVD-specific mortality (>10% decrease among men: HR, 3.14; 95% CI, 1.63-6.04; >10% decrease among women: HR, 1.92; 95% CI, 1.05-3.51), and noncancer non-CVD-specific mortality (>10% decrease among men: HR, 4.98; 95% CI, 3.14-7.91). A decrease in WC was also associated with mortality. Conclusions and Relevance: This cohort study of healthy older adults suggests that weight loss was associated with an increase in all-cause and cause-specific mortality, including an increased risk of cancer, CVD, and other life-limiting conditions. Physicians should be aware of the significance of weight loss, especially among older men.

Neuropathic Pain Associated With First Metatarsophalangeal Joint Osteoarthritis: Frequency and Associated Factors.

OBJECTIVE: To determine whether neuropathic pain is a feature of first metatarsophalangeal (MTP) joint osteoarthritis (OA). METHODS: A total of 98 participants (mean ± SD age 57.4 ± 10.3 years) with symptomatic radiographic first MTP joint OA completed the PainDETECT questionnaire (PD-Q), which has 9 questions regarding the intensity and quality of pain. The likelihood of neuropathic pain was determined using established PD-Q cutoff points. Participants with unlikely neuropathic pain were then compared to those with possible/likely neuropathic pain in relation to age, sex, general health (Short Form 12 [SF-12] health survey), psychological well-being (Depression, Anxiety and Stress Scale), pain characteristics (self-efficacy, duration, and severity), foot health (Foot Health Status Questionnaire [FHSQ]), first MTP dorsiflexion range of motion, and radiographic severity. Effect sizes (Cohen's d coefficient) were also calculated. RESULTS: A total of 30 (31%) participants had possible/likely neuropathic pain (19 possible [19.4%], 11 likely [11.2%]). The most common neuropathic symptoms were sensitivity to pressure (56%), sudden pain attacks/electric shocks (36%) and burning (24%). Compared to those with unlikely neuropathic pain, those with possible/likely neuropathic pain were significantly older (d = 0.59, P = 0.010), had worse SF-12 physical scores (d = 1.10, P < 0.001), pain self-efficacy scores (d = 0.98, P < 0.001), FHSQ pain scores (d = 0.98, P < 0.001), and FHSQ function scores (d = 0.82, P < 0.001), and had higher pain severity at rest (d = 1.01, P < 0.001). CONCLUSION: A significant proportion of individuals with first MTP joint OA report symptoms suggestive of neuropathic pain, which may partly explain the suboptimal responses to commonly used treatments for this condition. Screening for neuropathic pain may be useful in the selection of targeted interventions and may improve clinical outcomes.

Patient-Reported Outcomes following Total Knee Replacement in Patients Aged 65 Years and Over-A Systematic Review.

A previous systematic review showed positive patient-reported outcomes following total knee replacement (TKR) in patients aged < 65 years. However, the question remains as to whether these results are replicated for older individuals. This systematic review evaluated the patient-reported outcomes following TKR in individuals aged ≥ 65 years. A systematic search of Ovid MEDLINE, EMBASE, and Cochrane library were performed to identify studies examining disease-specific or health-related quality of life outcomes following TKR. Qualitative evidence synthesis was performed. Eighteen studies with low (n = 1), moderate (n = 6), or serious (n = 11) overall risk of bias were included, with evidence syntheses derived from 20,826 patients. Four studies reported on pain scales, showing improvement of pain from 6 months to 10 years postoperatively. Nine studies examined functional outcomes, showing significant improvements from 6 months to 10 years after TKR. Improvement in health-related quality of life was evident in six studies over 6 months to 2 years. All four studies examining satisfaction reported overall satisfaction with TKR results. TKR results in reduced pain, improved function, and increased quality of life for individuals aged ≥ 65 years. The improvement in patient-reported outcomes needs to be utilised in conjunction with physician expertise to determine what would comprise clinically significant differences.

Association between popliteal artery wall thickness and structural progression in patients with symptomatic knee osteoarthritis.

OBJECTIVE: There is increasing evidence for the involvement of vascular disease in the pathogenesis of knee OA. Popliteal artery wall thickness can be used as a surrogate marker of atherosclerosis. We examined the association between popliteal artery wall thickness and knee cartilage volume in individuals with symptomatic knee OA. METHODS: This prospective cohort study analysed 176 participants from a randomized placebo-controlled trial examining the effect of atorvastatin on structural progression in knee OA. The participants underwent MRI of the study knee at baseline and 2-year follow-up. Popliteal artery wall thickness and tibial cartilage volume were measured from MRI using validated methods. The top quartile of the rate of tibial cartilage volume loss was defined as rapid progression. RESULTS: At baseline, every 10% increase in popliteal artery wall thickness was associated with 120.8 mm3 (95% CI 5.4, 236.2, P = 0.04) lower of medial tibial cartilage volume and 151.9 mm3 (95% CI 12.1, 291.7, P = 0.03) lower of lateral tibial cartilage volume. Longitudinally, for every 10% increase in popliteal artery wall thickness, the annual rate of medial tibial cartilage volume loss was increased by 1.14% (95% CI 0.09%, 2.20%, P = 0.03), and there was a 2.28-fold (95% CI 1.07, 4.83, P = 0.03) risk of rapid progression of medial tibial cartilage loss, adjusted for age, sex, BMI, tibial bone area, smoking, vigorous physical activity, and intervention group allocation. CONCLUSION: The findings support a role for vascular pathology in the progression of knee OA. Targeting atherosclerosis has the potential to improve outcomes in knee OA.

Recommendations for weight management in osteoarthritis: A systematic review of clinical practice guidelines.

Objective: While targeting obesity is central to osteoarthritis management, recent meta-analyses demonstrate only modest effects of weight loss on symptoms, and little on structure. The World Health Organisation recommends that effective management of obesity include prevention of weight gain, weight maintenance and weight loss. Therefore, we systematically reviewed the recommendations and approaches for management of obesity in clinical practice guidelines (CPGs) for osteoarthritis. Design: Nine databases were searched (01.01.2010-15.03.2022) to identify guidelines informing the non-pharmacological management of osteoarthritis. Three reviewers appraised guidelines according to the AGREE II instrument, and independently extracted data on their characteristics. One author extracted and summarised guideline recommendations on weight management. This systematic review is registered on PROSPERO (CRD42021274195). Results: Of the included fifteen CPGs (median AGREE II domain score 78.7%), weight loss was recommended for knee (12 of 13) and hip (10 of 11) but not hand (0 of 4) osteoarthritis. Combination approaches of diet and/or exercise were recommended for overweight or obese individuals in knee (8 of 12) and hip (4 of 10) osteoarthritis. Two guidelines specified ≥5% weight loss. One guideline specified strategies for maintenance of lost weight; none specifically recommended preventing weight gain. There was discordance between strength of recommendation for weight loss and level of evidence (3 of 15). Conclusion: Most CPGs for knee and hip osteoarthritis recommend weight loss to manage obesity in osteoarthritis. As steady weight accumulation is common in adults, preventing weight gain should also be considered as it is a missed opportunity to improve outcomes in osteoarthritis.

No increased risk of cancer associated with metal-on-metal or ceramic-on-ceramic procedures compared to other bearing surfaces in patients with total hip arthroplasty: A nationwide linked registry cohort analysis of 167,837 patients.

OBJECTIVES: Studies have identified increased cancer risk among patients undergoing total hip arthroplasty (THA) compared to the general population. However, evidence of all-cause and site-specific cancer risk associated with different bearing surfaces has varied, with previous studies having short latency periods with respect to use of modern Metal-on-Metal (MoM) bearings. Using the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) linked to Australasian Association of Cancer Registries data, our aim was to evaluate risk of all-cause and site-specific cancer according to bearing surfaces in patients undergoing THA for osteoarthritis and whether risk increased with MoM bearings. METHODS: Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing number of observed cancer cases to expected number based on incidence rate in the Australian population. All-cause and site-specific cancer rates were calculated for all conventional stemmed THA (csTHA) and resurfacing THA (rsTHA) procedures performed for osteoarthritis. Cox proportional hazards models were used to compare cancer rates for MoM, ceramic-on-ceramic (CoC) and resurfacing procedures with a comparison group comprising metal-on-polyethylene (MoP) or ceramic-on-polyethylene (CoP) procedures. RESULTS: There were 156,516 patients with csTHA procedures and 11,321 with rsTHA procedures for osteoarthritis performed between 1999 and 2012. Incidence of all-cause cancer was significantly higher for csTHA (SIR 1.24, 95% CI 1.22-1.26) and rsTHA (SIR 1.74, 95% CI 1.39-2.04) compared to the Australian population. For csTHA, there was no significant difference in all-site cancer rates for MoM (Hazard Ratio (HR) 1.01, 95%CI 0.96-1.07) or CoC (HR 0.98, 95%CI 0.94-1.02) compared to MoP and CoP bearings. Significantly increased risk of melanoma, non-Hodgkins lymphoma, myeloma, leukaemia, prostate, colon, bladder and kidney cancer was found for csTHA and, prostate cancer, melanoma for rsTHA procedures when compared to the Australian population, although risk was not significantly different across bearing surfaces. CONCLUSIONS: csTHA and rsTHA procedures were associated with increased cancer incidence compared to the Australian population. However, no excess risk was observed for MoM or CoC procedures compared to other bearing surfaces.

Antidepressants for hip and knee osteoarthritis.

BACKGROUND: Although pain is common in osteoarthritis, most people fail to achieve adequate analgesia. Increasing acknowledgement of the contribution of pain sensitisation has resulted in the investigation of medications affecting pain processing with central effects. Antidepressants contribute to pain management in other conditions where pain sensitisation is present. OBJECTIVES: To assess the benefits and harms of antidepressants for the treatment of symptomatic knee and hip osteoarthritis in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was January 2021. SELECTION CRITERIA: We included randomised controlled trials of adults with osteoarthritis that compared use of antidepressants to placebo or alternative comparator. We included trials that focused on efficacy (pain and function), treatment-related adverse effects and had documentation regarding discontinuation of participants. We excluded trials of less than six weeks of duration or had participants with concurrent mental health disorders. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Major outcomes were pain; responder rate; physical function; quality of life; and proportion of participants who withdrew due to adverse events, experienced any adverse events or had serious adverse events. Minor outcomes were proportion meeting the OARSI (Osteoarthritis Research Society International) Response Criteria, radiographic joint structure changes and proportion of participants who dropped out of the study for any reason. We used GRADE to assess certainty of evidence. MAIN RESULTS: Nine trials (2122 participants) met the inclusion criteria. Seven trials examined only knee osteoarthritis. Two also included participants with hip osteoarthritis. All trials compared antidepressants to placebo, with or without non-steroidal anti-inflammatory drugs. Trial sizes were 36 to 388 participants. Most participants were female, with mean ages of 54.5 to 65.9 years. Trial durations were 8 to 16 weeks. Six trials examined duloxetine. We combined data from nine trials in meta-analyses for knee and hip osteoarthritis. One trial was at low risk of bias in all domains. Five trials were at risk of attrition and reporting bias. High-certainty evidence found that antidepressants resulted in a clinically unimportant improvement in pain compared to placebo. Mean reduction in pain (0 to 10 scale, 0 = no pain) was 1.7 points with placebo and 2.3 points with antidepressants (mean difference (MD) -0.59, 95% confidence interval (CI) -0.88 to -0.31; 9 trials, 2122 participants). Clinical response was defined as achieving a 50% or greater reduction in 24-hour mean pain. High-certainty evidence demonstrated that 45% of participants receiving antidepressants had a clinical response compared to 28.6% receiving placebo (RR 1.55, 95% CI 1.32 to 1.82; 6 RCTs, 1904 participants). This corresponded to an absolute improvement in pain of 16% more responders with antidepressants (8.9% more to 26% more) and a number needed to treat for an additional beneficial effect (NNTB) of 6 (95% CI 4 to 11). High-certainty evidence showed that the mean improvement in function (on 0 to 100 Western Ontario and McMaster Universities Arthritis Index, 0 = best function) was 10.51 points with placebo and 16.16 points with antidepressants (MD -5.65 points, 95% CI -7.08 to -4.23; 6 RCTs, 1909 participants). This demonstrates a small, clinically unimportant response. Moderate-certainty evidence (downgraded for imprecision) showed that quality of life measured using the EuroQol 5-Dimension scale (-0.11 to 1.0, 1.0 = perfect health) improved by 0.07 points with placebo and 0.11 points with antidepressants (MD 0.04, 95% CI 0.01 to 0.07; 3 RCTs, 815 participants). This is clinically unimportant. High-certainty evidence showed that total adverse events increased in the antidepressant group (64%) compared to the placebo group (49%) (RR 1.27, 95% CI 1.15 to 1.41; 9 RCTs, 2102 participants). The number needed to treat for an additional harmful outcome (NNTH) was 7 (95% CI 5 to 11). Low-certainty evidence (downgraded twice for imprecision for very low numbers of events) found no evidence of a difference in serious adverse events between groups (RR 0.94, 95% CI 0.46 to 1.94; 9 RCTs, 2101 participants). The NNTH was 1000.  Moderate-certainty evidence (downgraded for imprecision) showed that 11% of participants receiving antidepressants withdrew from trials due to an adverse event compared to 5% receiving placebo (RR 2.15, 95% CI 1.56 to 2.97; 6 RCTs, 1977 participants). The NNTH was 17 (95% CI 10 to 35). AUTHORS' CONCLUSIONS: There is high-certainty evidence that use of antidepressants for knee osteoarthritis leads to a non-clinically important improvement in mean pain and function. However, a small number of people will have a 50% or greater important improvement in pain and function. This finding was consistent across all trials. Pain in osteoarthritis may be due to a variety of causes that differ between individuals. It may be that the cause of pain that responds to this therapy is only present in a small number of people. There is moderate-certainty evidence that antidepressants have a small positive effect on quality of life with heterogeneity between trials. High-certainty evidence indicates antidepressants result in more adverse events and moderate-certainty evidence indicates more withdrawal due to adverse events. There was little to no difference in serious adverse events (low-certainty evidence due to low numbers of events). This suggests that if antidepressants were being considered, there needs to be careful patient selection to optimise clinical benefit given the known propensity for adverse events with antidepressant use. Future trials should include alternative antidepressant agents or phenotyping of pain in people with osteoarthritis, or both.

Functional Outcomes Following Hip Replacement in Community-Dwelling Older Adults.

Uncertainty remains regarding the benefit of hip replacement in older adults in the context of age-related decline in physical function. This study aimed to examine the effect of hip replacement on functional outcomes and identify factors associated with clinically important improvement in physical function postoperatively in community-dwelling older adults. This cohort study was performed within the ASPREE trial, with 698 participants receiving hip replacement and 677 age- and sex-matched controls without knee or hip replacement during the trial drawn from 16,703 Australian participants aged ≥70 years. Health status (physical and mental component summary [PCS and MCS]) was assessed annually using the SF-12. Participants receiving hip replacement had significantly lower pre- and post-replacement PCS scores compared with controls (p < 0.0001). There was significant improvement in PCS score following hip replacement (mean change 4.9, 95%CI 4.0−5.7) but no change in controls (0.01, 95%CI −0.7−0.7). Following hip replacement, 46.7% of participants experienced clinically important improvement in PCS score, while 15.5% experienced worsened PCS score. Participants experiencing improved postoperative PCS score had significantly lower PCS and higher MCS scores preoperatively. The degree of preoperative physical function impairment was a significant indicator of older people most likely to benefit from hip replacement surgery.

Study protocol for a randomised controlled trial of diacerein versus placebo to treat knee osteoarthritis with effusion-synovitis (DICKENS).

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.

Effect of atorvastatin on skeletal muscles of patients with knee osteoarthritis: Post-hoc analysis of a randomised controlled trial.

Objective: Populations with knee osteoarthritis (KOA) are at increased risk of cardiovascular disease, due to higher prevalence of risk factors including dyslipidaemia, where statins are commonly prescribed. However, the effect of statins on muscles and symptoms in this population is unknown. Thus, this study examined the effect of atorvastatin on muscle properties in patients with symptomatic KOA. Design: Post-hoc analysis of a 2-year multicentre randomised, double-blind, placebo-controlled trial. Setting: Australian community. Participants: Participants aged 40-70 years (mean age 55.7 years, 55.6% female) with KOA who met the American College of Rheumatology clinical criteria received atorvastatin 40 mg daily (n = 151) or placebo (n = 153). Main outcome measures: Levels of creatinine kinase (CK), aspartate transaminase (AST), and alanine transaminase (ALT) at 1, 6, 12, and 24 months; muscle strength (by dynamometry) at 12 and 24 months; vastus medialis cross-sectional area (CSA) on magnetic resonance imaging at 24 months; and self-reported myalgia. Results: There were no significant between-group differences in CK and AST at all timespoints. The atorvastatin group had higher ALT than placebo group at 1 (median 26 vs. 21, p = 0.004) and 6 (25 vs. 22, p = 0.007) months without significant between-group differences at 12 and 24 months. Muscle strength increased in both groups at 24 months without between-group differences [mean 8.2 (95% CI 3.5, 12.9) vs. 5.9 (1.3, 10.4), p = 0.49]. Change in vastus medialis CSA at 24 months favoured the atorvastatin group [0.11 (-0.10, 0.31) vs. -0.23 (-0.43, -0.03), p = 0.02] but of uncertain clinical significance. There was a trend for more myalgia in the atorvastatin group (8/151 vs. 2/153, p = 0.06) over 2 years, mostly occurring within 6 months (7/151 vs. 1/153, p = 0.04). Conclusions: In those with symptomatic KOA, despite a trend for more myalgia, there was no clear evidence of an adverse effect of atorvastatin on muscles, including those most relevant to knee joint health.

Smartphone-Based Ecological Momentary Assessment for Collecting Pain and Function Data for Those with Low Back Pain.

Smartphone-based ecological momentary assessment (EMA) methods are widely used for data collection and monitoring in healthcare but their uptake clinically has been limited. Low back pain, a condition with limited effective treatments, has the potential to benefit from EMA. This study aimed to (i) determine the feasibility of collecting pain and function data using smartphone-based EMA, (ii) examine pain data collected using EMA compared to traditional methods, (iii) characterize individuals' progress in relation to pain and function, and (iv) investigate the appropriation of the method. Our results showed that an individual's 'pain intensity index' provided a measure of the burden of their low back pain, which differed from but complemented traditional 'change in pain intensity' measures. We found significant variations in the pain and function over the course of an individual's back pain that was not captured by the cohort's mean scores, the approach currently used as the gold standard in clinical trials. The EMA method was highly acceptable to the participants, and the Model of Technology Appropriation provided information on technology adoption. This study highlights the potential of the smartphone-based EMA method for enhancing the collection of outcome data and providing a personalized approach to the management of low back pain.