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Background: Multiple sclerosis (MS) is a chronic neurological condition and the leading cause of non-traumatic disability in young adults. MS pathogenesis leads to the death of oligodendrocytes, demyelination, and progressive central nervous system neurodegeneration. Endogenous remyelination occurs in people with MS (PwMS) but is insufficient to repair the damage. Our preclinical studies in mice indicate that endogenous remyelination can be supported by the delivery of repetitive transcranial magnetic stimulation (rTMS). Our phase I trial concluded that 20 sessions of rTMS, delivered over 5 weeks, are safe and feasible for PwMS. This phase II trial aims to investigate the safety and preliminary efficacy of rTMS for PwMS. Methods: Participants must be aged 18–65 years, diagnosed with MS by a neurologist, stable and relapse free for 6 months, have an Extended Disability Status Scale (EDSS) between 1.5 and 6 (inclusive), willing to travel to a study site every weekday for 4 consecutive weeks, and able to provide informed consent and access the internet. Participants from multiple centres will be randomised 2:1 (rTMS to sham) stratified by sex. The intervention will be delivered with a Magstim Rapid2 stimulator device and circular 90-mm coil or MagVenture MagPro stimulator device with C100 circular coil, positioned to stimulate a broad area including frontal and parietal cortices. For the rTMS group, pulse intensity will be set at 18% (MagVenture) or 25% (Magstim) of maximum stimulator output (MSO), and rTMS applied as intermittent theta burst stimulation (iTBS) (~ 3 min per side; 600 pulses). For the sham group, the procedure will be the same, but the intensity is set at 0%. Each participant will attend 20 intervention sessions over a maximum of 5 weeks. Outcome measures include MS Functional Composite Score (primary), Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Quality of Life, and Pittsburgh Sleep Quality Index/Numeric Rating Scale and adverse events (secondary) and advanced MRI metrics (tertiary). Outcomes will be measured at baseline and after completing the intervention. Discussion: This study will determine if rTMS can improve functional outcomes or other MS symptoms and determine whether rTMS has the potential to promote remyelination in PwMS. Trial registration: Registered with Australian New Zealand Clinical Trials Registry, 20 January 2022; ACTRN12622000064707. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) prevalence is increasing globally. Objectives: To determine whether increased prevalence is continuing within Australia using our validated prescription-based ascertainment method. Methods: We used methods employed in our 2010 and 2017 prevalence estimates. Disease-modifying therapy (DMT) prescriptions were extracted from Australia's Pharmaceutical Benefits Scheme data for January–December 2021. DMT penetrance was calculated using data from the Australian MS Longitudinal Study. We divided the total number of monthly prescriptions by 12 or 2 (except alemtuzumab), adjusted for DMT penetrance and Australian population estimates. Prevalences in Australian states/territories were age-standardised. 2021 prevalence estimates were compared with 2010 and 2017 prevalence estimates using Poisson regression. Results: Number of people with MS in Australia in 2021 was 33,335; an increase of 7728 from 2017 (30.2%) and 12,092 from 2010 (56.6%) and increasing at a faster rate than population change (+10.1%, +14.1%). Age-standardised prevalence was 136.1/100,000 (increased from 103.7/100,000 in 2017). The previously demonstrated positive latitudinal gradient in 2010 and 2017 persisted in 2021, with Tasmania (southernmost state) having the highest prevalence (age-standardised: 203.5/100,000) while northernmost states had the lowest. Conclusions: In line with global trends, MS prevalence is escalating in Australia, particularly in higher-latitude states. MS prevention is crucial to halt this disturbing trend. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: 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 (β 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 (β ranged from − 0.21 to 0.22/SD). Western dietary pattern scores were detrimentally associated with radial total and cortical bone vBMD and porosity (β ranged from − 0.20 to 0.20/SD). Steps per day were beneficially associated with inner transitional zone area and thickness (β = 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. [ABSTRACT FROM AUTHOR]

We aimed to describe associations between diet quality in adolescence and adulthood and knee symptoms in adulthood. Two hundred seventy-five participants had adolescent diet measurements, 399 had adult diet measurements and 240 had diet measurements in both time points. Diet quality was assessed by Dietary Guidelines Index (DGI), reflecting adherence to Australian Dietary Guidelines. Knee symptoms were collected using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Data were analysed using zero-inflated negative binomial regressions. The overall adolescent DGI was not associated with adult knee symptoms, although lower intake of discretionary foods (e.g. cream, alcohol, bacon and cake) in adolescence was associated with lower pain (mean ratio (MR) 0·96) and dysfunction (MR 0·94). The overall adult DGI was not associated with knee symptoms; however, limiting saturated fat was associated with lower WOMAC (Pain: MR 0·93; stiffness: MR 0·93; dysfunction: MR 0·91), drinking water was associated with lower stiffness (MR 0·90) and fruit intake was associated with lower dysfunction (MR 0·90). Higher DGI for dairy products in adulthood was associated with higher WOMAC (Pain: MR 1·07; stiffness: MR 1·13; dysfunction: MR 1·11). Additionally, the score increases from adolescence to adulthood were not associated with adult knee symptoms, except for associations between score increase in limiting saturated fat and lower stiffness (MR 0·89) and between score increase in fruit intake and lower dysfunction (MR 0·92). In conclusion, the overall diet quality in adolescence and adulthood was not associated with knee symptoms in adulthood. However, some diet components may affect later knee symptoms. [ABSTRACT FROM AUTHOR]

Objective To summarize effects of intravenous bisphosphonates (IVBP) in patients with symptomatic knee OA and bone marrow lesions (BMLs), using a meta-analysis of randomized controlled trials (RCTs). Methods Literature databases were searched for placebo-controlled RCTs of IVBPs for knee OA from inception, and included validated pain and function scales, BML size and incidence of adverse events. Efficacy was compared using standardized mean differences (SMD) and risk ratios (RR) with fixed-effect or random-effects models. Methodological quality was assessed using the Cochrane risk of bias tool, heterogeneity was assessed by I 2 statistics. Results We included 428 patients in four RCTs of 2–24 months duration; most patients (84%) received zoledronic acid (ZA). Risk of bias was low-moderate. IVBP had large effect sizes on pain within 3 months [SMD = − 2.33 (95% CI: − 3.02, − 1.65)] mainly driven by neridronate (resulting in substantial heterogeneity, I 2 = 92%) with no effect for ZA alone. Differences in knee function were statistically significant at 3 months [SMD = − 0.22 (− 0.43, − 0.01), I 2 = 0.2%]. Effect sizes for pain did not reach statistical significance at any other time point. IVBPs improved a semi-quantitative measure of BML size within 6 months [SMD = − 0.52 (− 0.89, − 0.14), I 2 = 0%] but not at 12 months or two years. Adverse events [RR = 1.19 (1.00, 1.41) I 2 = 52%], occurred more frequently with IVBP. Conclusion ZA has no effect on knee pain, possibly a short-term effect on BML size and higher rates of adverse events. Neridronate may improve pain in the short term, but this is based on a single trial. [ABSTRACT FROM AUTHOR]