Inflammation as a therapeutic target for osteoarthritis: A literature review of clinical trials.

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.

Association between sarcopenic obesity and knee osteoarthritis: A narrative review.

Sarcopenia and obesity have been studied independently as risk factors for knee osteoarthritis. However, there is now research interest in investigating whether the co-existence of sarcopenia and obesity (sarcopenic obesity) within the same individual significantly increases the risk of knee osteoarthritis, compared to sarcopenia or obesity alone. This review synthesises current literature to explore the association between sarcopenic obesity and knee osteoarthritis, emphasising both the clinical evidence and existing gaps. We highlight the challenges and progress in defining sarcopenic obesity and discuss the impact that the lack of a consensus definition of sarcopenic obesity has on comparing outcomes of studies investigating the relationship between sarcopenic obesity and knee OA. We offer methodological insights to guide future studies investigating whether sarcopenic obesity increases the risk of knee osteoarthritis above and beyond the risk associated with each condition on its own. The implications for clinical practice are discussed, including the need to incorporate effective resistance exercise into weight loss programs for individuals with sarcopenic obesity. This is critical as a general weight loss program alone among individuals with sarcopenic obesity can include substantial loss of muscle mass, potentially predisposing patients to further functional decline.

Prior nonmelanoma skin cancer is associated with fewer fractures, more vitamin D sufficiency, greater bone mineral density and improved bone microarchitecture in older adults.

INTRODUCTION: Prior nonmelanoma skin cancer (NMSC), a biomarker of cumulative lifetime sun exposure, is associated with reduced fracture risk later in life. The mechanism is unknown. METHODS: Prospective cohort analysis of 1,099 community-dwelling adults aged 50-80 years with baseline and 10 year follow up assessments. Histopathologically-confirmed NMSC diagnosis was established by linkage with the Tasmanian Cancer Registry. Bone mineral density (BMD) and vertebral deformity were quantified by DXA, 25(OH)D by radioimmunoassay, bone microarchitecture by high resolution peripheral quantitative CT, melanin density by spectrophotometry and skin photosensitivity and clinical fracture by questionnaire. 25(OH)D <50 nmol/L was considered deficient. RESULTS: Participants with a NMSC reported prior to baseline were less likely to sustain an incident vertebral deformity over 10 years (RR=0.74, p=0.036). There were similar reductions for other fracture types but these did not reach significance. Prior NMSC was associated with baseline (RR=1.23, p=0.005) and 10 year longitudinal (RR=5.9, p=0.014) vitamin D sufficiency and greater total body BMD (ß=0.021g/cm2, p=0.034), but not falls risk or muscle strength. The relationship between prior NMSC and bone microarchitecture was age dependent (pinteraction<0.05). In the oldest age tertile, prior NMSC was associated with greater volumetric BMD (ß=57.8-62.6, p=0.002-0.01) and less porosity (ß= -4.6 - -5.2, p=0.002-0.009) at cortical, compact cortical and outer transitional zones. CONCLUSION: Prior NMSC was associated with fewer incident fractures in community-dwelling older adults. This protective association is most likely mediated by modifiable fracture risk factors associated with an outdoor lifestyle, including 25(OH)D, BMD and bone microarchitecture.

Effect of Intravenous Zoledronic Acid on Total Knee Replacement in Patients With Symptomatic Knee Osteoarthritis and Without Severe Joint Space Narrowing: A Prespecified Secondary Analysis of a Two-Year, Multicenter, Double-Blind, Placebo-Controlled Clinical Trial.

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.

Prevalence and correlates of the use of complementary and alternative medicines among older adults with joint pain.

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.

Effect of Curcuma longa extract on serum inflammatory markers and MRI-based synovitis in knee osteoarthritis: secondary analyses from the CurKOA randomised trial.

BACKGROUND: Curcuma longa (CL) extract is modestly effective for relieving knee symptoms in knee osteoarthritis (OA) patients; however, its mechanism of action is unclear. PURPOSE: We aimed to determine the effects of CL treatment on serum inflammatory markers over 12 weeks and to explore its potential effects on synovitis assessed by contrast-enhanced magnetic resonance imaging (CE-MRI) of the knee. METHODS: Secondary analyses were conducted on the CL for knee OA (CurKOA) trial, which compared CL (n = 36) and placebo (n = 34) over 12 weeks for the treatment of knee OA. Systemic inflammatory markers (TNFα, IL6, and hsCRP) and a cartilage extracellular matrix degradative enzyme (MMP-3) were measured. A subgroup of participants (CL, n = 7; placebo, n = 5) underwent CE-MRI at baseline and a 12-week follow-up. RESULTS: Over 12 weeks, there were no between-group differences in change in hsCRP, IL-6, and TNFα levels. MMP-3 levels decreased in both CL (-1.31 ng/ml [95%CI: -1.89 to -0.73]) and placebo (-2.34 ng/ml [95%CI: -2.95 to -1.73]) groups, with the placebo group having a slightly greater decrease (1.03 ng/ml [95%CI: 0.19 to 1.88]). Most (10 of 12) sub-study participants had normal synovial thickness scores at baseline. One participant had mild synovitis in each of the placebo and CL groups. Synovitis status was stable for all except two participants, one each in the CL and placebo group, whose synovitis score increased. CONCLUSION: This is the first study that explored the effect of CL treatment on local and systemic inflammation using biochemical markers and CE-MRI outcomes on knee OA patients. Secondary analyses from this pilot study suggest that CL is unlikely to have clinically significant effects on systemic (inflammatory and cartilage) or local synovitis (CE-MRI) biomarkers compared to placebo. The mechanism of action for CL effect on pain remains unclear.

Navigating the maze of osteoarthritis treatment: A qualitative study exploring the experience of individuals with osteoarthritis in Tasmania, Australia.

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.

A Randomised Controlled Trial of YOGa and Strengthening Exercise for Knee OsteoArthritis: Protocol for a Comparative Effectiveness Trial (YOGA Trial).

Osteoarthritis (OA) is a common joint disorder for which there is no cure. Current treatments are suboptimal. Exercise is a core treatment for knee OA, with muscle strengthening exercise commonly recommended. Yoga is a mind-body exercise intervention that can improve flexibility, muscle strength, balance, and fitness and potentially reduce symptoms of OA. However, there is a scarcity of robust, high-quality conclusive evidence on the efficacy of yoga in knee OA. We are currently conducting the first randomised comparative effectiveness and cost-effectiveness trial of a yoga program compared with a strengthening exercise program in patients with symptomatic knee OA. This study protocol describes the design and conduct of this trial. The YOGA study is a phase III, single-centre, parallel, superiority, randomised, active-controlled trial which will be conducted in Hobart, Australia. One hundred and twenty-six participants (63 in each arm) aged over 40 years with symptomatic knee OA will be recruited from the community and randomly allocated to receive either a 24-week yoga program (3×/week) or a strengthening exercise program (3×/week). The primary outcome will be change in knee pain over 12 weeks, assessed using a 100 mm visual analogue scale (VAS). The secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life, gait speed, biomarkers, and others over 12 and 24 weeks. We will also assess whether the presence of neuropathic pain moderates the effects of yoga compared to strengthening exercise. Additional data, such as cost and resource utilization, will be collected for the cost-effectiveness analysis. The primary analysis will be conducted using an intention-to-treat approach. Adverse events will be monitored throughout the study. Once completed, this trial will contribute to the knowledge of whether yoga can be used as a simple, effective, low-cost option for the management of knee OA, thus saving economic costs in the healthcare system.

Association between radiographic hand osteoarthritis and bone microarchitecture in a population-based sample.

BACKGROUND: Subchondral bone plays an important role in the pathogenesis of radiographic osteoarthritis (OA). However, the bony changes that occur in hand OA (HOA) are much less understood. This study aimed to describe the association between radiographic HOA and high-resolution peripheral quantitative computed tomography (HRpQCT) measures of the hand and radius in a population-based sample. METHODS: A total of 201 participants (mean age 72, 46% female) from the Tasmanian Older Adult Cohort (TASOAC) study underwent HRpQCT assessment of the 2nd distal and proximal interphalangeal (DIP, PIP), 1st carpometacarpal (CMC) joint, and distal radius. Radiographic HOA was assessed at the 2nd DIP, PIP joints, and the 1st CMC joint using the OARSI atlas. RESULTS: Proximal osteophyte and joint space narrowing (JSN) scores were consistently more strongly associated with HRpQCT measures compared to the distal site with positive associations for indices of bone size (total and trabecular bone area and cortical perimeter but inconsistent for cortical area) and negative associations for volumetric bone mineral density (vBMD). There was a decrease in trabecular number and bone volume fraction with increasing osteophyte and JSN score as well as an increase in trabecular separation and inhomogeneity. Osteophyte and JSN scores in the hand were not associated with HRpQCT measures at the distal radius. CONCLUSIONS: This hypothesis generating data suggests that bone size and trabecular disorganization increase with both osteophyte formation and JSN (proximal more than distal), while local vBMD decreases. This process appears to be primarily at the site of pathology rather than nearby unaffected bone.

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.

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 zoledronic acid with or without methylprednisolone on 3D bone area and bone shape in patients with symptomatic knee osteoarthritis: A post-hoc analysis of the ZAP2 trial.

OBJECTIVE: To evaluate the effect of annual infusions of zoledronic acid (ZA) with or without a single injection of methylprednisolone, compared to placebo, on quantitative magnetic resonance imaging 3-D bone area and bone shape in participants with symptomatic knee osteoarthritis (OA). METHODS: This was a post-hoc analysis of the ZAP2 trial. Active appearance modelling was used to assess bone area (mm2) and femur bone shape (B-score) in 262 participants (mean 61.8 ± 8.0 years, 51% female) at baseline, 6, and 24 months. Radiographic joint space narrowing (JSN) was measured at baseline. An 'OA shape' was defined as a B-score of >1.96. RESULTS: At baseline 65% of participants demonstrated an OA shape. Treatment with ZA plus methylprednisolone but not ZA alone, compared to placebo, was associated with significantly slower expansion in bone area at the medial femoral (-33.9 mm2, 95% confidence interval [CI] -61.8 to -6.0) and lateral femoral (-22.0 mm2, 95%CI -40.7 to -3.4) compartments over 24 months. B-score increased in all groups, with no significant between-group differences. There were significant interactions of JSN (grade 0 vs grade 1-2) and B-score (≤1.96 vs >1.96) with treatment effect on bone area (p < 0.05), such that ZA plus methylprednisolone slowed the expansion of medial and lateral femoral bone area over 24 months in participants with JSN grade 1-2 or a B-score of >1.96. CONCLUSIONS: ZA plus methylprednisolone may retard expansion of bone area over 24 months, but ZA alone may not. Neither ZA with or without methylprednisolone slowed progression of bone shape over 6 or 24 months.

Serum Metabolomic Signatures for Knee Cartilage Volume Loss over 10 Years in Community-Dwelling Older Adults.

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 ß-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.

Restricting Branched-Chain Amino Acids within a High-Fat Diet Prevents Obesity.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Metabolomic signatures for the longitudinal reduction of muscle strength over 10 years.

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.

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.

Systematic Review and Meta-Analysis of Health State Utility Values for Osteoarthritis-Related Conditions.

OBJECTIVE: Health state utility values (HSUVs) are a key input in health economic modeling, but HSUVs of people with osteoarthritis (OA)-related conditions have not been systematically reviewed and meta-analyzed. Our objective was to systematically review and meta-analyze the HSUVs for people with OA. METHODS: Searches within health economic/biomedical databases were performed to identify eligible studies reporting OA-related HSUVs. Data on study design, participant characteristics, affected OA joint sites, treatment type, HSUV elicitation method, considered health states, and the reported HSUVs were extracted. HSUVs for people with knee, hip, and mixed OA in pre- and posttreatment populations were meta-analyzed using random effects models. RESULTS: A total of 151 studies were included in the systematic review, and 88 in meta-analyses. Of 151 studies, 56% were conducted in Europe, 75% were in people with knee and/or hip OA, and 79% were based on the EuroQoL 5-dimension instrument. The pooled mean baseline HSUVs for knee OA core interventions, medication, injection, and primary surgery treatments were 0.64 (95% confidence interval [95% CI] 0.61-0.66), 0.56 (95% CI 0.45-0.68), 0.58 (95% CI 0.50-0.66), and 0.52 (95% CI 0.49-0.55), respectively. These were 0.71 (95% CI 0.59-0.84) for hip OA core interventions and 0.52 (95% CI 0.49-0.56) for hip OA primary surgery. For all knee OA treatments and hip OA primary surgery, pooled HSUVs were significantly higher in the post- than the pretreatment populations. CONCLUSION: This study provides a comprehensive summary of OA-related HSUVs and generates an HSUV database for people with different affected OA joint sites undergoing different treatments to guide HSUV choices in future health economic modeling of OA interventions.

Associations between socioeconomic status and obesity, sarcopenia, and sarcopenic obesity in community-dwelling older adults: The Tasmanian Older Adult Cohort Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%. CONCLUSION: 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.

Clinical relevance of MRI knee abnormalities in Australian rules football players: a longitudinal study.

BACKGROUND/AIM: The clinical relevance of MRI knee abnormalities in athletes is unclear. This study aimed to determine the prevalence of MRI knee abnormalities in Australian Rules Football (ARF) players and describe their associations with pain, function, past and incident injury and surgery history. METHODS: 75 male players (mean age 21, range 16-30) from the Tasmanian State Football League were examined early in the playing season (baseline). History of knee injury/surgery and knee pain and function were assessed. Players underwent MRI scans of both knees at baseline. Clinical measurements and MRI scans were repeated at the end of the season, and incident knee injuries during the season were recorded. RESULTS: MRI knee abnormalities were common at baseline (67% bone marrow lesions, 16% meniscal tear/extrusion, 43% cartilage defects, 67% effusion synovitis). Meniscal tears/extrusion and synovial fluid volume were positively associated with knee symptoms, but these associations were small in magnitude and did not persist after further accounting for injury history. Players with a history of injury were at a greater risk of having meniscal tears/extrusion, effusion synovitis and greater synovial fluid volume. In contrast, players with a history of surgery were at a greater risk of having cartilage defects and meniscal tears/extrusion. Incident injuries were significantly associated with worsening symptoms, BML development and incident meniscal damage. CONCLUSIONS: MRI abnormalities are common in ARF players, are linked to a previous knee injury and surgery history, as well as incident injury but do not dictate clinical symptomatology.

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.