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.

Krill Oil for Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Knee osteoarthritis is disabling, with few effective treatments. Preliminary evidence suggested that krill oil supplementation improved knee pain, but effects on knee osteoarthritis remain unclear. Objective: To evaluate efficacy of krill oil supplementation, compared with placebo, on knee pain in people with knee osteoarthritis who have significant knee pain and effusion-synovitis. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled clinical trial in 5 Australian cities. Participants with clinical knee osteoarthritis, significant knee pain, and effusion-synovitis on magnetic resonance imaging were enrolled from December 2016 to June 2019; final follow-up occurred on February 7, 2020. Interventions: Participants were randomized to 2 g/d of krill oil (n = 130) or matching placebo (n = 132) for 24 weeks. Main Outcomes and Measures: The primary outcome was change in knee pain as assessed by visual analog scale (range, 0-100; 0 indicating least pain; minimum clinically important improvement = 15) over 24 weeks. Results: Of 262 participants randomized (mean age, 61.6 [SD, 9.6] years; 53% women), 222 (85%) completed the trial. Krill oil did not improve knee pain compared with placebo (mean change in VAS score, -19.9 [krill oil] vs -20.2 [placebo]; between-group mean difference, -0.3; 95% CI, -6.9 to 6.4) over 24 weeks. One or more adverse events was reported by 51% in the krill oil group (67/130) and by 54% in the placebo group (71/132). The most common adverse events were musculoskeletal and connective tissue disorders, which occurred 32 times in the krill oil group and 42 times in the placebo group, including knee pain (n = 10 with krill oil; n = 9 with placebo), lower extremity pain (n = 1 with krill oil; n = 5 with placebo), and hip pain (n = 3 with krill oil; n = 2 with placebo). Conclusions and Relevance: Among people with knee osteoarthritis who have significant knee pain and effusion-synovitis on magnetic resonance imaging, 2 g/d of daily krill oil supplementation did not improve knee pain over 24 weeks compared with placebo. These findings do not support krill oil for treating knee pain in this population. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12616000726459; Universal Trial Number: U1111-1181-7087.

Association between knee magnetic resonance imaging markers and knee symptoms over 6-9 years in young adults.

OBJECTIVES: To describe associations between MRI markers with knee symptoms in young adults. METHODS: Knee symptoms were assessed using the WOMAC scale during the Childhood Determinants of Adult Health Knee Cartilage study (CDAH-knee; 2008-2010) and at the 6- to 9-year follow-up (CDAH-3; 2014-2019). Knee MRI scans obtained at baseline were assessed for morphological markers (cartilage volume, cartilage thickness, subchondral bone area) and structural abnormalities [cartilage defects and bone marrow lesions (BMLs)]. Univariable and multivariable (age, sex, BMI adjusted) zero-inflated Poisson (ZIP) regression models were used for analysis. RESULTS: The participants' mean age in CDAH-knee and CDAH-3 were 34.95 (s.d. 2.72) and 43.27 (s.d. 3.28) years, with 49% and 48% females, respectively. Cross-sectionally, there was a weak but significant negative association between medial femorotibial compartment (MFTC) [ratio of the mean (RoM) 0.99971084 (95% CI 0.9995525, 0.99986921), P < 0.001], lateral femorotibial compartment (LFTC) [RoM 0.99982602 (95% CI 0.99969915, 0.9999529), P = 0.007] and patellar cartilage volume [RoM 0.99981722 (95% CI 0.99965326, 0.9999811), P = 0.029] with knee symptoms. Similarly, there was a negative association between patellar cartilage volume [RoM 0.99975523 (95% CI 0.99961427, 0.99989621), P = 0.014], MFTC cartilage thickness [RoM 0.72090775 (95% CI 0.59481806, 0.87372596), P = 0.001] and knee symptoms assessed after 6-9 years. The total bone area was negatively associated with knee symptoms at baseline [RoM 0.9210485 (95% CI 0.8939677, 0.9489496), P < 0.001] and 6-9 years [RoM 0.9588811 (95% CI 0.9313379, 0.9872388), P = 0.005]. The cartilage defects and BMLs were associated with greater knee symptoms at baseline and 6-9 years. CONCLUSION: BMLs and cartilage defects were positively associated with knee symptoms, whereas cartilage volume and thickness at MFTC and total bone area were weakly and negatively associated with knee symptoms. These results suggest that the quantitative and semiquantitative MRI markers can be explored as a marker of clinical progression of OA in young adults.

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.

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.

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.

Associations between body composition, physical activity, and diet and radial bone microarchitecture in older adults: a 10-year population-based study.

Bone strength is important to prevent osteoporotic fractures and determined by bone mass and microarchitecture. This study suggests that having higher lean mass and lower fat mass, avoiding western dietary patterns, and improving steps per day may all be important for maintaining bone mass and microarchitecture in aging. PURPOSE: To describe associations between exposures of lean mass and fat mass, dietary patterns, serum 25-hydroxyvitamin D (25(OH)D), physical activity and grip strength, and bone outcome measures including bone mineral density and microarchitecture in older adults. METHODS: Data on 201 older adults (mean age 72 years, female 46% at 10.7-year follow-up (phase 4) from a population-based cohort study collected at baseline and follow-up at 2.6 (phase 2), 5.1 (phase 3), and 10.7 years (phase 4) were analyzed. Exposures were lean and fat mass, dietary patterns, physical activity (steps per day), serum 25(OH)D concentrations, and grip strength during follow-ups. Bone measures at phase 4 including areal bone mineral density (aBMD) at the spine, hip, and whole body by dual-energy X-ray absorptiometry, and radial cortical and trabecular bone microarchitecture by high-resolution peripheral computed tomography (HRpQCT). The cumulative average values of exposures were calculated. Multivariable linear regression was used to analyze associations between exposures and bone measures. RESULTS: Lean mass was beneficially associated with the hip, spine, and total body aBMD, radial cortical and trabecular bone area, and trabecular number and separation (ß ranged from - 0.39/standard deviation (SD) to 0.73/SD). Fat mass was detrimentally associated with radial compact cortical and inner transitional zone bone area, vBMD, and porosity (ß ranged from - 0.21 to 0.22/SD). Western dietary pattern scores were detrimentally associated with radial total and cortical bone vBMD and porosity (ß ranged from - 0.20 to 0.20/SD). Steps per day were beneficially associated with inner transitional zone area and thickness (ß = 0.12/SD and 0.19/SD), but no other measures. Grip strength and serum 25(OH)D were not associated with any radial bone measures. CONCLUSIONS: Lean mass was beneficially associated with aBMD, radial bone area, and trabecular bone microarchitecture. Fat mass had detrimental associations with radial bone area, vBMD, and porosity. A western dietary pattern was detrimental for radial bone microarchitecture while more steps per day (but not grip strength or 25(OH)D) appeared beneficial.

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.

Osteophytes mediate the associations between cartilage morphology and changes in knee symptoms in patients with knee osteoarthritis.

AIMS: To investigate whether the associations between cartilage defects and cartilage volumes with changes in knee symptoms were mediated by osteophytes. METHODS: Data from the Vitamin D Effects on Osteoarthritis (VIDEO) study were analyzed as a cohort. The Western Ontario and McMaster Universities Osteoarthritis Index was used to assess knee symptoms at baseline and follow-up. Osteophytes, cartilage defects, and cartilage volumes were measured using magnetic resonance imaging at baseline. Associations between cartilage morphology and changes in knee symptoms were assessed using linear regression models, and mediation analysis was used to test whether these associations were mediated by osteophytes. RESULTS: A total of 334 participants (aged 50 to 79 years) with symptomatic knee osteoarthritis were included in the analysis. Cartilage defects were significantly associated with change in total knee pain, change in weight-bearing pain, and change in non-weight-bearing pain after adjustment for age, sex, body mass index, and intervention. Cartilage volume was significantly associated with change in weight-bearing pain and change in physical dysfunction after adjustment. Lateral tibiofemoral and patellar osteophyte mediated the associations of cartilage defects with change in total knee pain (49-55%) and change in weight-bearing pain (61-62%) and the association of cartilage volume with change in weight-bearing pain (27-30%) and dysfunction (24-25%). Both cartilage defects and cartilage volume had no direct effects on change in knee symptoms. CONCLUSIONS: The significant associations between cartilage morphology and changes in knee symptoms were indirect and were partly mediated by osteophytes.

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.

Does aerobic exercise effect pain sensitisation in individuals with musculoskeletal pain? A systematic review.

BACKGROUND: Pain sensitisation plays a major role in musculoskeletal pain. However, effective treatments are limited, and although there is growing evidence that exercise may improve pain sensitisation, the amount and type of exercise remains unclear. This systematic review examines the evidence for an effect of aerobic exercise on pain sensitisation in musculoskeletal conditions. METHODS: Systematic searches of six electronic databases were conducted. Studies were included if they examined the relationship between aerobic physical activity and pain sensitisation in individuals with chronic musculoskeletal pain, but excluding specific patient subgroups such as fibromyalgia. Risk of bias was assessed using Cochrane methods and a qualitative analysis was conducted. RESULTS: Eleven studies (seven repeated measures studies and four clinical trials) of 590 participants were included. Eight studies had low to moderate risk of bias. All 11 studies found that aerobic exercise increased pressure pain thresholds or decreased pain ratings in those with musculoskeletal pain [median (minimum, maximum) improvement in pain sensitisation: 10.6% (2.2%, 24.1%)]. In these studies, the aerobic exercise involved walking or cycling, performed at a submaximal intensity but with incremental increases, for a 4-60 min duration. Improvement in pain sensitisation occurred after one session in the observational studies and after 2-12 weeks in the clinical trials. CONCLUSIONS: These findings provide evidence that aerobic exercise reduces pain sensitisation in individuals with musculoskeletal pain. Further work is needed to determine whether this translates to improved patient outcomes, including reduced disability and greater quality of life.

Prospective Association Between Inflammatory Markers and Knee Cartilage Volume Loss and Pain Trajectory.

INTRODUCTION: Inflammation has been suggested to be involved in the pathogenesis of osteoarthritis and pain. We sought to explore the associations between inflammatory serum markers and magnetic resonance imaging-defined long-term structural change and pain trajectory. METHODS: A total of 169 randomly selected participants (mean age 63 years; 47% female) from a prospective cohort study were included in this study. Circulating levels of interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α) and high-sensitivity C-reactive protein (CRP) were measured at baseline. A knee MRI scan was performed to measure cartilage volume (CV) and bone marrow lesions (BMLs) at baseline and at 10.7 years. Knee pain at four visits was measured by the WOMAC pain questionnaire, and pain trajectories were identified using group-based trajectory modelling. Linear, log-binomial and multi-nominal logistic regression were used for the analyses. RESULTS: IL-6 was associated with lateral but not medial tibial CV loss (ß = - 0.25% per annum, per standard deviation [SD] log pg/ml; P < 0.05) in the multivariate analysis. IL-6 was also associated with a 'Moderate pain' trajectory (relative risk ratio 1.93 per SD log pg/ml; 95% confidence interval 1.02-3.65) relative to the 'Minimal pain' trajectory group. There was no significant association of TNF-α and CRP with CV loss and pain trajectory groups with the exception of a beneficial relationship between CRP and medial tibial CV loss (ß = 0.20% per annum, per SD log mg/l). No association between inflammatory markers and change in BML size was observed. CONCLUSIONS: IL-6 was independently associated with compartment-specific CV loss and worse pain trajectory, but the other markers studied were not, suggesting that components of inflammation are implicated in the pathogenesis of cartilage loss and developing a worse pain course.

Association between clusters of back and joint pain with opioid use in middle-aged community-based women: a prospective cohort study.

BACKGROUND: To determine the relationship between clusters of back pain and joint pain and prescription opioid dispensing. METHODS: Of 11,221 middle-aged participants from the Australian Longitudinal Study of Women's Health, clusters of back pain and joint pain from 2001 to 2013 were identified using group-based trajectory modelling. Prescription opioid dispensing from 2003 to 2015 was identified by linking the cohort to Pharmaceutical Benefit Scheme dispensing data. Multinomial logistic regression was used to examine the association between back pain and joint pain clusters and dispensing of prescription opioids. The proportion of opioids dispensed in the population attributable to back and join pain was calculated. RESULTS: Over 12 years, 68.5 and 72.0% women reported frequent or persistent back pain and joint pain, respectively. There were three clusters ('none or infrequent', 'frequent' and 'persistent') for both back pain and joint pain. Those in the persistent back pain cluster had a 6.33 (95%CI 4.38-9.16) times increased risk of having > 50 opioid prescriptions and those in persistent joint pain cluster had a 6.19 (95%CI 4.18-9.16) times increased risk of having > 50 opioid prescriptions. Frequent and persistent back and joint pain clusters together explained 41.7% (95%CI 34.9-47.8%) of prescription opioid dispensing. Women in the frequent and persistent back pain and joint pain clusters were less educated and reported more depression and physical inactivity. CONCLUSION: Back pain and joint pain are major contributors to opioid prescription dispensing in community-based middle-aged women. Additional approaches to reduce opioid use, targeted at those with frequent and persistent back pain and joint pain, will be important in order to reduce the use of opioids and their consequent harm in this population.

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.

Effect of Stem Cell Injections on Osteoarthritis-related Structural Outcomes: A Systematic Review.

OBJECTIVE: To systematically review the evidence for the efficacy of mesenchymal stem cell (MSC) injections in improving osteoarthritis (OA)-related structural outcomes. METHODS: Ovid Medline and EMBASE were searched from their inceptions to April 2020 using MeSH terms and key words. Independent reviewers extracted data and assessed methodological quality. Qualitative evidence synthesis was performed due to the heterogeneity of interventions and outcome measures. RESULTS: Thirteen randomized controlled trials (phase I or II) were identified: 10 in OA populations and 3 in populations at risk of OA, with low (n = 9), moderate (n = 3), or high (n = 1) risk of bias. Seven studies used allogeneic MSCs (4 bone marrow, 1 umbilical cord, 1 placenta, 1 adipose tissue), 6 studies used autologous MSCs (3 adipose tissue, 2 bone marrow, 1 peripheral blood). Among the 11 studies examining cartilage outcomes, 10 found a benefit of MSCs on cartilage volume, morphology, quality, regeneration, and repair, assessed by magnetic resonance imaging, arthroscopy, or histology. The evidence for subchondral bone was consistent in all 3 studies in populations at risk of OA, showing beneficial effects. Sixteen unpublished, eligible trials were identified by searching trial registries, including 8 with actual or estimated completion dates before 2016. CONCLUSION: Our systematic review of early-phase clinical trials demonstrated consistent evidence of a beneficial effect of intraarticular MSC injections on articular cartilage and subchondral bone. Due to the heterogeneity of MSCs, modest sample sizes, methodological limitations, and potential for publication bias, further work is needed before this therapy is recommended in the management of OA.

Rates, costs and determinants of lumbar spine imaging in population-based women born in 1973-1978: Data from the Australian Longitudinal Study on Women's Health.

OBJECTIVE: There are concerns that lumbar spine imaging represents low value care. Our aim was to examine the use of lumbar spine imaging [radiography, computed tomography (CT), magnetic resonance imaging (MRI)] over 20 years, and costs and person-level characteristics of imaging in a large cohort of Australian women. METHODS: The Australian Longitudinal Study on Women's Health (ALSWH) is a longitudinal population-based survey of women randomly selected from national health insurance scheme (Medicare) database. This study examined 13458 women born in 1973-1978 who consented to link their ALSWH and Medical Benefits Scheme records. Self-reported data on demographics, body mass index, depression, physical and mental health, and back pain were collected in each survey performed in 1996, 2000, 2003, 2006, 2009, 2012, and 2015. Data on lumbar spine imaging from 1996 to 2015 were obtained from the Medical Benefits Scheme database. RESULTS: 38.9% of women underwent some form of lumbar spine imaging over 20 years. While radiography increased from 1996 to 2011 and decreased thereafter, CT and MRI continued to increase from 1996 to 2015. In women with self-reported back pain, depression and poorer physical health were associated with imaging, with no significant differences in types of imaging. Based on imaging rates in ALSWH, the estimated costs for Australian women aged 30-39 years were AU$51,735,649 over 2011-2015. CONCLUSIONS: Lumbar spine imaging was common in population-based Australian women, with rates increasing over 20 years. Depression and poor physical health were associated with lumbar spine imaging. Raising awareness of this in clinicians is likely to result in significant cost savings if clinical guidelines are followed, with the potential of freeing resources for high value care and health outcomes.

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.

Association Between Inflammatory Biomarkers and Nonspecific Low Back Pain: A Systematic Review.

OBJECTIVES: Chronic inflammation increases the production of cytokines and activates proinflammatory pathways which may lead to nonspecific low back pain (LBP). We systematically reviewed the literature to investigate whether inflammatory biomarkers are associated with nonspecific LBP. MATERIALS AND METHODS: CINAHL, Medline, and Embase were searched between January 1946 and May 2018. MeSH terms and key words were used to identify studies examining the association between inflammatory biomarkers and LBP. Two reviewers performed the risk of bias assessment and 3 reviewers extracted data independently. Qualitative evidence synthesis was performed. RESULTS: Thirteen studies, ranging from fair to low quality, were included. Five studies examined the association between C-reactive protein (CRP)/high-sensitivity CRP and LBP; 6 studies assessed tumor necrosis factors (TNFs); 8 studies assessed interleukins (ILs); and 2 studies assessed fibrinogen. There was evidence for an association of elevated levels of CRP, TNFs, and IL-6 with LBP. There was conflicting evidence for an association between IL-1ß, fibrinogen, and LBP. DISCUSSION: Our findings support the notion of a positive association between inflammatory biomarkers and nonspecific LBP, specifically for CRP, TNFs, and IL-6. Although further high quality longitudinal studies are needed to confirm these findings and evaluate the magnitude of these associations, our findings suggest a role of inflammation in the pathogenesis of nonspecific LBP.

Identifying subgroups of community-dwelling older adults and their prospective associations with long-term knee osteoarthritis outcomes.

OBJECTIVES: To identify subgroups of community-dwelling older adults and to assess their longitudinal associations with long-term osteoarthritis (OA) outcomes. METHODS: 1046 older adults aged 50-80 years were studied. At baseline, body mass index (BMI), pedometer-measured ambulatory activity (AA), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) determined knee pain and information on comorbidities were obtained. Tibial cartilage volume and bone-marrow lesions (BMLs) were assessed using MRI at baseline and 10 years and total knee replacements (TKR) by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Latent class analysis was used to determine participant subgroups, considering baseline BMI, AA, pain and comorbidities, and linear mixed-effects or log-binomial models were used to assess the associations. RESULTS: Three subgroups/classes were identified: subgroup 1 (43%): Normal/overweight participants with higher AA, lower pain and lower comorbidities; subgroup 2 (32%): Overweight participants with lower AA, mild pain and higher comorbidities; subgroup 3 (25%): Obese participants with lower AA, mild pain and higher comorbidities. Subgroup 3 had greater cartilage volume loss (ß - 60.56 mm3, 95% CI - 105.91, - 15.21) and a higher risk of TKR (RR 3.19, 95% CI 1.75, 5.81), compared to subgroup 1. Subgroup 2 was not associated with cartilage volume change (ß 13.06 mm3, 95% CI - 30.87, 57.00) or risk of TKR (RR 1.16, 95% CI 0.56, 2.36), compared to subgroup 1. Subgroup membership was not associated with worsening BMLs. CONCLUSIONS: Our findings suggest the existence of homogeneous subgroups of participants and support the utility of identifying patterns of characteristics/risk factors that may cluster together and using them to identify subgroups of people who may be at a higher risk of developing and/or progressing OA. Key Points • Complex interplay among characteristics/factors leads to conflicting evidence between ambulatory activity and knee osteoarthritis. • Distinct subgroups are identifiable based on ambulatory activity, body mass index, knee pain, and comorbidities. • Identifying subgroups can be used to determine those who are at risk of developing/progressing osteoarthritis.