Testosterone and the risk of incident atrial fibrillation in older men: further analysis of the ASPREE study.

Background: A cardiovascular safety trial of testosterone in men with cardiovascular risk factors or disease found no difference in rates of major adverse cardiovascular events (MACE) or death but noted more atrial fibrillation (AF) events in testosterone-treated men. We investigated the relationship between endogenous testosterone concentrations with risk of developing AF in healthy older men. Methods: Post-hoc analysis of 4570 male participants in the ASPirin in Reducing Events in the Elderly (ASPREE) study. Men were aged ≥ 70 years, had no history of cardiovascular disease (including AF), thyroid disease, prostate cancer, dementia, or life-threatening illnesses. Risk of AF was modelled using Cox proportional hazards regression. Findings: Median (IQR) age was 73.7 (71.6-77.1) years and median (IQR) follow-up 4.4 (3.3-5.5) years, during which 286 men developed AF (15.3 per 1000 participant-years). Baseline testosterone was higher in men who developed incident AF compared men who did not [17.0 (12.4-21.2) vs 15.7 (12.2-20.0) nmol/L]. There was a non-linear association of baseline testosterone with incident AF. The risk for AF was higher in men with testosterone in quintiles (Q) 4&5 (Q4:Q3, HR = 1.91; 95%CI = 1.29-2.83 and Q5:Q3HR = 1.98; 95%CI = 1.33-2.94). Results were similar after excluding men who experienced MACE or heart failure during follow-up. Interpretation: Circulating testosterone concentrations within the high-normal range are independently associated with an increased risk of incident AF amongst healthy older men. This suggests that AF may be an adverse consequence of high-normal total testosterone concentrations. Funding: National Institute on Aging and National Cancer Institute at the National Institutes of Health; Australian Government (NHMRC, CSIRO); Monash University; and AlfredHealth.

Association of serum phosphate, calcium and alkaline phosphatase with risk of incident fractures in healthy older adults.

BACKGROUND: Aging increases fracture risk through bone loss and microarchitecture deterioration due to an age-related imbalance in bone resorption and formation during bone remodelling. We examined the associations between levels of phosphate, calcium, and alkaline phosphatase, and fracture risk in initially-healthy older individuals. METHODS: A post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial recruited 16,703 Australian participants aged ≥70 years and 2,411 US participants aged ≥65 years. Analyses were conducted on ASPREE-Fracture substudy participants from Australia with serum calcium, phosphate, and alkaline phosphatase measurement. Fracture data were collected post-randomization. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs). Phosphate, calcium, and alkaline phosphatase were analysed in deciles (D1-D10), with deciles 4-7 (31-70%) as the reference category. Restricted cubic spline curves were used to identify nonlinear associations. RESULTS: Of the 9915 participants, 907 (9·2%) persons had incident fractures recorded over 3·9 (SD 1·4) years. In the fully adjusted model, males in the top decile (D10) of phosphate had 78% higher risk of incident fracture (HR 1·78, 95% CI 1·25-2·54). No such association was observed for females (HR 1·09, 95% CI 0·83-1·44). The population attributable fraction in men within the D10 phosphate category is 6·9%. CONCLUSION: This result confirms that, high-normal serum phosphate levels are associated with increased fracture risk in older men.

Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults.

Background: Recent studies have reported associations between high plasma high-density lipoprotein cholesterol (HDL-C) levels and risk of all-cause mortality, age-related macular degeneration, sepsis and fractures, but associations with dementia risk remain unclear. To determine whether high plasma HDL-C levels are associated with increased incident dementia risk in initially-healthy older people. Methods: We conducted a post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial; a double-blind, randomized, placebo-controlled trial of daily low-dose aspirin in healthy older people. ASPREE recruited 16,703 participants aged ≥70 years (from Australia) and 2411 participants aged ≥65 years (from the US) between 2010 and 2014. Participants had no diagnosed cardiovascular disease, dementia, physical disability, or life-threatening illness at enrolment and were cognitively healthy (3MS score ≥78). All-cause dementia was a primary trial endpoint, and determined by DSM-IV criteria. Cox regression was used to examine hazard ratios between HDL-C categories <40 mg/dL, 40-60 mg/dL (reference category), 60-80 mg/dL, and >80 mg/dL and dementia. Restricted cubic spline curves were used to determine nonlinear associations. Data analysis was performed from October 2022 to January 2023. Findings: Of the 18,668 participants, 850 (4.6%) cases of incident dementia were recorded over 6.3 (SD 1.8) years. Participants with high HDL-C (>80 mg/dL) had a 27% higher risk of dementia (HR 1.27, 95% CI 1.03, 1.58). Age stratified analyses demonstrated that the risk of incident dementia was higher in participants ≥75 years compared to participants <75 years (HR 1.42, 95% CI 1.10, 1.83 vs HR 1.02, 95% CI 0.68, 1.51). Associations remained significant after adjusting for covariates including age, sex, country of enrolment, daily exercise, education, alcohol consumption, weight change over time, non-HDL-C, HDL-C-PRS, and APOE genotype. Interpretation: In a population of initially-healthy older adults aged ≥75 years, high HDL-C levels were associated with increased risk of all-cause dementia. Funding: National Institutes of Health, USA; National Health and Medical Research Council Australia; Monash University (Melbourne, VIC, Australia); and the Victorian Cancer Agency (Australia).

Sex-dependent associations of plasma high-density lipoprotein cholesterol and mortality risk in healthy older men and women: two prospective cohort studies.

The relationship between high plasma high-density lipoprotein cholesterol (HDL-C) and cause and mortality are not well established in healthy older people. This study examined the associations between HDL-C levels and mortality in initially healthy older men and women. This analysis included participants from the Aspirin in Reducing Events in the Elderly (ASPREE; n=18,668) trial and a matched cohort from the UK Biobank (UKB; n=62,849 ≥65 years). Cox regression was used to examine hazard ratios between HDL-C categories <1.03 mmol/L, 1.03-1.55 mmol/L (referent category), 1.55-2.07 mmol/L, and >2.07 mmol/L and all-cause, cancer, cardiovascular disease (CVD), and "non-cancer non-CVD" mortality. Genetic contributions were assessed using a polygenic score for HDL-C. Among ASPREE participants (aged 75±5 years), 1836 deaths occurred over a mean follow-up of 6.3±1.8 years. In men, the highest category of HDL-C levels was associated with increased risk of all-cause (HR 1.60, 95% CI 1.26-2.03), cancer (HR 1.37, 95% CI 0.96-2.00), and "non-cancer non-CVD" mortality (HR 2.35, 95% CI 1.41-3.42) but not CVD mortality (HR 1.08, 95% CI 0.60-1.94). The associations were replicated among UKB participants (aged 66.9±1.5 years), including 8739 deaths over a mean follow-up of 12.7±0.8 years. There was a non-linear association between HDL-C levels and all-cause and cause-specific mortality. The association between HDL-C levels and mortality was unrelated to variations in the HDL-C polygenic score. No significant association was found between HDL-C levels and mortality in women. Higher HDL-C levels are associated with increased risk from cancer and "non-cancer non-CVD" mortality in healthy older men but no such relationship was observed in women.

Associations Between Blood Concentrations of Sex Hormones and Physical Function in Community-Dwelling Older Women: A Prospective Cohort Study.

BACKGROUND: Blood concentrations of testosterone and estrone tend to increase in women aged ≥70 years, whereas concentrations of their precursor hormone dehydroepiandrosterone decline. It is unknown whether these changes influence physical function. We investigated whether concentrations of these hormones were associated with grip strength and self-reported physical function in community-dwelling older women. METHODS: A total of 9 179 Australian women, aged ≥70 years, were recruited to the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Sex hormones were measured in Sex Hormones in Older Women, an ASPREE substudy, by liquid chromatography-tandem mass spectrometry in 6 358 women. The associations between hormone concentrations and physical function (handgrip strength and self-reported physical function assessed by SF-12v2 physical component summary [PCS]) were examined using multiple linear regression. RESULTS: The median age of the 5,447 participants was 74.0 (interquartile range 71.7-77.6) years. Testosterone concentrations above the lowest quartile were associated with less decline in grip strength (mean -1.39 [95% CI -1.54 to -1.24] vs -1.75 [-2.00 to -1.50] kg, p = .02), and dehydroepiandrosterone concentrations above the lowest quartile were associated with less decline in grip strength (-1.39 [-1.54 to -1.25] vs -1.82 [-2.11 to -1.55] kg, p = .007) and PCS scores (-1.49 [-1.80 to -1.17] vs -2.33 [-2.93 to -1.72], p = .02) over 4 years, compared with those in the respective lowest quartile. CONCLUSIONS: Low endogenous concentrations of testosterone and dehydroepiandrosterone were associated the greatest likelihood of physical function decline in community-based women aged ≥70 years. Further studies are warranted to determine whether testosterone and dehydroepiandrosterone therapy prevent functional decline in this at-risk group using sensitive measures of muscle strength and performance.

Association Between Triglycerides and Risk of Dementia in Community-Dwelling Older Adults: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: It has been suggested that higher triglyceride levels were associated with a lower risk of Alzheimer disease. This study aimed to examine the association of triglycerides with dementia and cognition change in community-dwelling older adults. METHODS: This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial of adults aged 65 years or older without dementia or previous cardiovascular events at enrollment. The main outcome was incident dementia. Other outcomes included changes in composite cognition and domain-specific cognition (global cognition, memory, language and executive function, and psychomotor speed). The association between baseline triglycerides and dementia risk was estimated using Cox proportional hazard models adjusting for relevant risk factors. Linear mixed models were used to investigate cognitive change. The analysis was repeated in a subcohort of participants with available APOE-ε4 genetic data with additional adjustment for APOE-ε4 carrier status and an external cohort (UK Biobank) with similar selection criteria applied. RESULTS: This study included 18,294 ASPREE participants and 68,200 UK Biobank participants (mean age: 75.1 and 66.9 years; female: 56.3% and 52.7%; median [interquartile range] triglyceride: 106 [80-142] mg/dL and 139 [101-193] mg/dL), with dementia recorded in 823 and 2,778 individuals over a median follow-up of 6.4 and 12.5 years, respectively. Higher triglyceride levels were associated with lower dementia risk in the entire ASPREE cohort (hazard ratio [HR] with doubling of triglyceride: 0.82, 95% CI 0.72-0.94). Findings were similar in the subcohort of participants with APOE-ε4 genetic data (n = 13,976) and in the UK Biobank cohort (HR was 0.82 and 0.83, respectively, all p ≤ 0.01). Higher triglycerides were also associated with slower decline in composite cognition and memory over time (p ≤ 0.05). DISCUSSION: Older adults with higher triglyceride levels within the normal to high-normal range had a lower dementia risk and slower cognitive decline over time compared with individuals with lower triglyceride levels. Higher triglyceride levels may be reflective of better overall health and/or lifestyle behaviors that would protect against dementia development. Future studies are warranted to investigate whether specific components within the total circulating pool of plasma triglycerides may promote better cognitive function, with the hope of informing the development of new preventive strategies.

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.

Longitudinal association between handgrip strength, gait speed and risk of serious falls in a community-dwelling older population.

OBJECTIVE: Both grip strength and gait speed can be used as markers of muscle function, however, no previous study has examined them in the same population with respect to risk of falls. METHODS: In this prospective cohort study, utilising data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and ASPREE-Fracture substudy, we analysed the association of grip strength and gait speed and serious falls in healthy older adults. Grip strength was measured using a handheld dynamometer and gait speed from 3-metre timed walks. Serious falls were confined to those involving hospital presentation. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associations with falls. RESULTS: Over an average of 4.0±1.3 years, amongst 16,445 participants, 1,533 had at least one serious fall. After adjustment for age, sex, physical activity, body mass index, Short Form 12 (state of health), chronic kidney disease, polypharmacy and aspirin, each standard deviation (SD) lower grip strength was associated with 27% (HR 1.27, 95% CI 1.17-1.38) higher risk of falls. The results remained the same for males and females. There was a dose-response relationship in the association between grip strength and falls risk. The higher risk of falls was observed in males in all body mass index (BMI) categories, but only in obese females. The association between gait speed and falls risk was weaker than the association between grip strength and falls risk. CONCLUSIONS: All males and only obese females with low grip strength appear to be at the greatest risk of serious falls. These findings may assist in early identification of falls.

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 of Plasma High-Density Lipoprotein Cholesterol Level With Risk of Fractures in Healthy Older Adults.

Importance: Increased levels of high-density lipoprotein cholesterol (HDL-C) have been associated with osteoporosis. Preclinical studies have reported that HDL-C reduces bone mineral density by reducing osteoblast number and function. However, the clinical significance of these findings is unclear. Objective: To determine whether higher HDL-C levels are predictive of an increased fracture risk in healthy older adults. Design, Setting, and Participants: This cohort study is a post hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial and the ASPREE-Fracture substudy. ASPREE was a double-blind, randomized, placebo-controlled primary prevention trial of aspirin that recruited participants between 2010 and 2014. These comprised community-based older adults (16 703 Australians aged ≥70 years, 2411 US participants ≥65 years) without evident cardiovascular disease, dementia, physical disability, and life-limiting chronic illness. The ASPREE-Fracture substudy collected data on fractures reported postrandomization from Australian participants. Cox regression was used to calculate hazard ratio (HR) and 95% CI. Data analysis for this study was performed from April to August 2022. Exposure: Plasma HDL-C. Main Outcomes and Measures: Fractures included were confirmed by medical imaging and included both traumatic and minimal trauma fractures. Fractures were adjudicated by an expert review panel. Results: Of the 16 262 participants who had a plasma HDL-C measurement at baseline (8945 female participants [55%] and 7319 male [45%]), 1659 experienced at least 1 fracture over a median (IQR) of 4.0 years (0.02-7.0 years). In a fully adjusted model, each 1-SD increment in HDL-C level was associated with a 14% higher risk of fractures (HR, 1.14; 95% CI, 1.08-1.20). The results remained similar when these analyses were stratified by sex. Sensitivity and stratified analyses demonstrated that these associations persisted when the analyses were repeated to include only (1) minimal trauma fractures, (2) participants not taking osteoporosis medications, (3) participants who were never smokers and reported that they did not drink alcohol, and (4) participants who walked outside for less than 30 minutes per day and reported no participation in moderate/vigorous physical activity and to examine only (5) statin use. No association was observed between non-HDL-C levels and fractures. Conclusions and Relevance: This study suggests that higher levels of HDL-C are associated with an increased fracture risk. This association was independent of common risk factors for fractures.

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.

Daily Low-Dose Aspirin and Risk of Serious Falls and Fractures in Healthy Older People: A Substudy of the ASPREE Randomized Clinical Trial.

Importance: Falls and fractures are frequent and deleterious to the health of older people. Aspirin has been reported to reduce bone fragility and slow bone loss. Objective: To determine if daily low-dose aspirin (100 mg) reduces the risk of fractures or serious falls (fall-related hospital presentations) in healthy older men and women. Design, Setting, and Participants: This substudy of a double-blind, randomized, placebo-controlled trial studied older adult men and women in 16 major sites across southeastern Australia. The ASPREE-FRACTURE substudy was conducted as part of the Australian component of the ASPREE trial. Between 2010 and 2014 healthy (free of cardiovascular disease, dementia or physical disability), community-dwelling volunteers aged 70 years or older were recruited to participate in the ASPREE trial. Potentially eligible participants were identified by medical practitioners and trial personnel and were then sent a letter of invitation to participate. Interested participants were screened for suitability. Eligible participants with medical practitioner authorization and adherent to a 4-week run-in medication trial were randomized. Data were analyzed from October 17, 2019, to August 31, 2022. Interventions: Participants in the intervention group received a daily dose of oral 100 mg enteric-coated (low-dose) aspirin. The control group received a daily identical enteric-coated placebo tablet. Main Outcomes and Measures: The primary outcome of ASPREE-FRACTURE was the occurrence of any fracture. The secondary outcome was serious fall resulting in hospital presentation. Results: In total, 16 703 people with a median (IQR) age of 74 (72-78) years were recruited, and 9179 (55.0%) were women. There were 8322 intervention participants and 8381 control participants included in the primary and secondary outcome analysis of 2865 fractures and 1688 serious falls over the median follow-up of 4.6 years. While there was no difference in the risk of first fracture between the intervention and control participants (hazard ratio, 0.97; 95% CI, 0.87-1.06; P = .50), aspirin was associated with a higher risk of serious falls (total falls 884 vs 804; incidence rate ratio, 1.17; 95% CI, 1.03-1.33; P = .01). Results remained unchanged in analyses that adjusted for covariates known to influence fracture and fall risk. Conclusions and Relevance: In this substudy of a randomized clinical trial, the failure of low-dose aspirin to reduce the risk of fractures while increasing the risk of serious falls adds to evidence that this agent provides little favorable benefit in a healthy, White older adult population. Trial Registration: This substudy is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000347561).

Efficacy of corticosteroids for hand osteoarthritis - a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There is some evidence that corticosteroids may have a beneficial effect in hand osteoarthritis. We examined the efficacy of corticosteroids on symptoms and structural outcomes in hand osteoarthritis. METHODS: Ovid MEDLINE, Embase and Cochrane Central Register of Controlled Trials were searched from inception to October 2021 for randomized controlled trials investigating the efficacy of corticosteroids in hand osteoarthritis. Two authors independently screened records, extracted data, and assessed risk of bias using the RoB 2 tool. Standardized mean difference (SMD) or mean difference (MD) was calculated, and random-effects meta-analyses were performed. RESULTS: Of 13 included trials, 3 examined oral corticosteroids and clinical outcomes in any hand joints, 9 examined intra-articular injection of corticosteroids and clinical outcomes at the first carpometacarpal joint and one in the interphalangeal joints. In meta-analysis, oral corticosteroids reduced pain (SMD -0.53, 95% CI -0.79 to -0.28) and improved stiffness (MD -5.03, 95% CI -9.91 to -0.15; Australian Canadian Osteoarthritis Hand Index stiffness subscale) and function (SMD -0.37, 95% CI -0.63 to -0.12) at 4-6 weeks. However, there was no significant persistent effect on pain and function at 3 months which was 6-8 weeks after study medication was stopped. There was no significant effect of intra-articular corticosteroids on pain or function at 4-6 weeks or over 3-12 months in first carpometacarpal osteoarthritis. Two trials evaluated joint structure at 4-6 weeks: one study showed oral corticosteroids reduced synovial thickening, neither showed an effect on synovitis. CONCLUSIONS: There was low-certainty evidence for a medium effect of oral corticosteroids on pain relief and stiffness improvement and small-to-medium effect on functional improvement at 4-6 weeks, with no significant effect for intra-articular corticosteroids. Corticosteroids had no significant effect on any outcomes over longer term (3-12 months) off treatment. No trials examined the effect of corticosteroids on disease progression. The role of corticosteroids in hand osteoarthritis is limited.

Severe low back or lower limb pain is associated with recurrent falls among older Australians.

BACKGROUND: Few studies have explored the impact of low back or lower limb pain severity on recurrent (≥2) falls in older adults. OBJECTIVES: Investigate the association between the severity of low back or lower limb pain, and ≥2 falls or falls-related injuries. METHODS: Community-dwelling Australian males and females in the ASPREE Longitudinal Study of Older Persons (ALSOP), aged ≥70 years. Self-reported, cross-sectional questionnaire data regarding number of falls and falls-related injuries in the last 12 months; and sites and severity of pain experienced on most days. Adjusted relative risks (RR) were estimated from multivariable Poisson regression models, for males and females separately. RESULTS: Of 14,892 ALSOP participants, 13% (n = 1983) reported ≥2 falls ('recurrent fallers') in the last 12 months. Males and females who reported severe low back, or severe lower limb pain on most days were more likely to report ≥2 falls in the last 12 months compared to those with mild pain (lower back: males RR = 1.70 and females RR = 1.5, p = 0.001; lower limb: males RR = 2.0, p < 0.001 and females RR = 1.4, p = 0.003). Female recurrent fallers who reported severe low back (RR = 1.3, p = 0.029) or lower limb (RR = 1.2, p = 0.024) pain on most days were more likely to report a falls-related injury in the last 12 months compared to females with mild pain. CONCLUSION: Severe low back or lower limb pain was associated with an increased likelihood of recurrent falls (males/females) or falls-related injuries (females only). Assessment of severe low back and lower limb pain should be considered as a priority when undertaking falls-risk evaluation. SIGNIFICANCE: Severe low back pain, or severe lower limb pain is associated with an increased likelihood of recurrent falls in older males and females, and an increased likelihood of falls-related injuries in older female recurrent fallers. Assessment and management of severe low back and lower limb pain should be prioritized when undertaking falls-risk assessment. Future longitudinal research is required to further interrogate this relationship and its underlying mechanisms.

Variation in Mean Arterial Pressure Increases Falls Risk in Elderly Physically Frail and Prefrail Individuals Treated With Antihypertensive Medication.

BACKGROUND: Impaired cerebral blood flow has been associated with an increased risk of falls. Mean arterial pressure (MAP) and variability in MAP have been reported to affect cerebral blood flow but their relationships to the risk of falls have not previously been reported. METHODS: Utilising data from the Aspirin in Reducing Events in the Elderly trial participants, we estimated MAP and variability in MAP, defined as within-individual SD of MAP from baseline and first 2 annual visits. The relationship with MAP was studied in 16 703 participants amongst whom 1539 falls were recorded over 7.3 years. Variability in MAP was studied in 14 818 of these participants who experienced 974 falls over 4.1 years. Falls were confined to those involving hospital presentation. Cox regression was used to calculate hazard ratio and 95% CI for associations with falls. RESULTS: Long-term variability in MAP was not associated with falls except amongst frail or prefrail participants using antihypertensive medications. Within this group each 5 mm Hg increase in long-term variability in MAP increased the risk of falls by 16% (hazard ratio, 1.16 [95% CI, 1.02-1.33]). Amongst the antihypertensive drugs studied, beta-blocker monotherapy (hazard ratio, 1.93 [95% CI, 1.17-3.18]) was associated with an increased risk of falls compared with calcium channel blockers. CONCLUSIONS: Higher levels of long-term variability in MAP increase the risk of serious falls in older frail and prefrail individuals taking antihypertensive medications. The observation that the relationship was limited to frail and prefrail individuals might explain some of the variability of previous studies linking blood pressure indices and falls.

Association between arthritis and cardiovascular risk factors in community-based adults: an opportunity to target cardiovascular risk.

BACKGROUND: Undertreated risk factors are major contributors to the burden of cardiovascular disease (CVD). Those with arthritis have an increased prevalence of CVD risk factors. CVD risk factors are often asymptomatic, which may be a barrier their treatment. Arthritis causes pain and immobility, and is a common reason for individuals to seek healthcare. Our aims were to (1) examine the relationship between arthritis and CVD risk factors in Australian adults, and (2) calculate the proportion of CVD risk factors that could be reduced if individuals with arthritis were targeted. METHODS: This cross-sectional study uses data from the 2017-18 Australian National Health Survey which included 13,776 participants, categorised into young (18-39 years), middle aged (40-64 years) and older (≥ 65 years) adults. Hypertension, height and weight were measured. Arthritis, dyslipidemia and diabetes were self-reported. The associations between arthritis and CVD risk factors were examined using logistic regression, and the population attributable fraction (PAF) of arthritis for each CVD risk factor was calculated. RESULTS: Arthritis was reported by 4.0% of young adults, 28.8% of middle-aged adults and 54.5% of older adults. Those with arthritis were at increased odds of obesity (2.07 fold in young, 1.75 fold in middle-aged and 1.89 fold in older adults), increased odds of diabetes (5.70 fold in young, 1.64 fold in middle-aged and 1.37 fold in older adults), increased odds of hypertension (2.72 fold in young, 1.78 fold in middle-aged and 1.48 fold in older adults) and an increased odds of dyslipidaemia (4.64 fold in young, 2.14 fold in middle-aged and 1.22 fold in older adults) compared to those without arthritis. This elevated chance remained significant even after adjusting for obesity, with the exception of diabetes in the older population. This elevated chance remained significant even after adjusting for obesity, with the exception of diabetes in the older population. The PAF of the presence of arthritis for having at least one CVD risk factor was 30.7% in middle-aged adults and 70.4% in older adults. CONCLUSION: Australian adults of all ages with arthritis are at increased odds of having CVD risk factors. For young and middle-aged adults, this increased odds remains significant even when adjusted for obesity. Presentation to healthcare practitioners with arthritis is an opportunity to screen for asymptomatic CVD risk factors with the potential of improving outcomes for both diseases. By adopting an approach of managing arthritis and CVD risk factors in parallel, rather than in silos, we could reduce the burden of CVD risk factors by 20-30%.

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.

Determinants of worse care for non-COVID-19 health or disability needs in Australia in the first month of COVID-19 restrictions: A national survey.

We examined the effect of person-related factors on capacity to obtain needed healthcare for non-COVID-19 health conditions/disabilities under COVID-19 restrictions. This was an anonymous online survey of Australian residents ≥18 years (3rd April to 2nd May 2020). We determined the ability to obtain care needed for non-COVID-19 health conditions/disabilities, experience of COVID-19, COVID-19 restrictions and sociodemographic characteristics using study-specific questions; and clinically significant depressive and anxiety symptoms using Patient Health Questionnaire 9 and Generalised Anxiety Disorder Scale 7 respectively. We calculated the population attributable fraction (PAF) to determine the proportion of worse access to non-COVID-19 health/disability care attributable to independent risk factors. 13,829 (91.5%) participants had complete data. 6,712 (46.4%) identified a need for healthcare/disability services (<45 years 42.1%, ≥45 years 50.3%). 31.6% aged <45 years and 24.3% aged ≥45 years reported worse access to health/disability care than experienced prior to the pandemic. In those aged <45 years the PAF was highest for depressive symptoms (21.4%; 95% CI 12.6%-29.3%) and anxiety (PAF 19.9%, 12.3%-26.9%). with a PAF of 49.6% (40.1%-57.6%) if any one of the following was being experienced: doing unpaid work; being a student; depressive symptoms; symptoms of anxiety; experiencing high adverse impact of COVID-19 restrictions. In those ≥45 years, PAF was highest for having depressive symptoms (PAF 20.9%, 16.6-24.8) with a PAF of 44.1% (36.0%-51.2%) if any one of the following was being experienced: depressive symptoms; symptoms of anxiety; doing unpaid work; living alone; being in lowest socioeconomic quintile; main source of income from government benefits; any personal experience of COVID-19. The identified risk factors, which include many that characterise those with worse health outcomes generally, explained 44%-50% of worse access to necessary health/disability care. These data have the potential to inform targeted strategies aimed at reducing a post-pandemic escalation of poor health outcomes, especially in vulnerable populations.

Topical corticosteroid for treatment of hand osteoarthritis: study protocol for a randomised controlled trial.

BACKGROUND: Hand osteoarthritis is a common and disabling chronic joint disease with a lack of effective therapies. Emerging evidence suggests the role of local inflammation in causing pain in hand osteoarthritis. Corticosteroids are potent anti-inflammatory drugs used in many rheumatic diseases. The aim of this randomised, double-blind, placebo-controlled trial is to determine whether topical corticosteroid reduces pain over 6 weeks in patients with hand osteoarthritis. METHODS: One hundred participants with hand osteoarthritis will be recruited from the community in Melbourne, Australia, and randomly allocated in a 1:1 ratio to receive either topical Diprosone OV or placebo ointment administered 3 times daily on the painful hand joints for 6 weeks. The primary outcome is pain reduction (assessed by 100 mm visual analogue scale) at 6 weeks. The secondary outcomes include changes in pain and function assessed using Functional Index for Hand Osteoarthritis, Australian Canadian Osteoarthritis Hand Index, Michigan Hand Outcomes Questionnaire, and tender and swollen joint count at 6 weeks. Adverse events will be recorded. The primary analysis will be by intention to treat, including all participants in their randomised groups. DISCUSSION: This study will provide high-quality evidence to determine whether topical corticosteroid reduces pain over 6 weeks in patients with hand osteoarthritis, with major clinical and public health importance by informing clinical practice guidelines for the management of hand osteoarthritis and reducing the burden of the disabling disease. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12620000599976 . Registered 22 May 2020.