Sex differences in osteoarthritis prevalence, pain perception, physical function and therapeutics.

OBJECTIVE: Women have a higher prevalence of osteoarthritis (OA) and worse clinical courses than men. However, the underlying factors and therapeutic outcomes of these sex-specific differences are incompletely researched. This review examines the current state of knowledge regarding sex differences in OA prevalence, risk factors, pain severity, functional outcomes, and use and response to therapeutics. METHODS: PubMed database was used with the title keyword combinations "{gender OR sex} AND osteoarthritis" plus additional manual search of the included papers for pertinent references, yielding 212 references. Additional references were added and 343 were reviewed for appropriateness. RESULTS: Globally, women account for 60% of people with osteoarthritis, with a greater difference after age 40. The higher risk for women may be due to differences in joint anatomy, alignment, muscle strength, hormonal influences, obesity, and/or genetics. At the same radiographic severity, women have greater pain severity than men, which may be explained by biologically distinct pain pathways, differential activation of central pain pathways, differences in pain sensitivity, perception, reporting, and coping strategies. Women have greater limitations of physical function and performance than men independent of BMI, OA severity, injury history, and amount of weekly exercise. Women also have greater use of analgesic medications than men but less use of arthroplasty and poorer prognosis after surgical interventions. CONCLUSIONS: The recognition of sex differences in OA manifestations and management could guide tailoring of sex-specific treatment protocols, and analysis of sex as a biological variable in future research would enhance development of precision medicine.

Association of serum calcium, vitamin D, and C-reactive protein with all-cause and cause-specific mortality in an osteoarthritis population in the UK: a prospective cohort study.

BACKGROUND: Osteoarthritis is a prevalent musculoskeletal condition, but the role of specific serum biomarkers, such as calcium, vitamin D, and C-reactive protein (CRP), in predicting mortality among individuals with osteoarthritis remains unclear. METHODS: This observational study analyzed longitudinal data from over 500,000 participants in the UK Biobank, identifying those with osteoarthritis using ICD-9/10 codes or self-reported history. We performed multivariable cox-regression and flexible parametric survival model (FPSM) for survival analysis, with adjustments made through the inverse probability of treatment weight (IPTW) for baseline covariates identified by directed acyclic graphs (DAGs). RESULTS: Of the 49,082 osteoarthritis population, the average age was 60.69 years, with 58.7% being female. During the follow-up period exceeding 15 years, a total of 5,522 people with osteoarthritis died. High serum calcium levels, compared to normal serum calcium levels, were significantly associated with all-cause mortality (hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.11, 1.59), cardiovascular diseases (CVD)-related deaths (HR 1.55, 95% CI 1.05, 2.29), and other deaths (HR 1.59, 95% CI 1.20, 2.11). Low serum calcium levels, compared to normal serum calcium levels, was linked with CVD-related deaths (HR 2.06, 95% CI 1.02, 4.14). Vitamin D insufficiency, compared to sufficient vitamin D levels, was correlated with all-cause mortality (HR 1.22, 95% CI 1.13, 1.33), CVD-related deaths (HR 1.43, 95% CI 1.20, 1.72), and other deaths (HR 1.26, 95% CI 1.09, 1.45) but not with cancer-related deaths. High serum CRP levels, compared to normal CRP levels, were associated with all outcomes (all-cause mortality: HR 1.22, 95% CI 1.12, 1.33; CVD-related death: HR 1.24, 95%CI 1.03, 1.49; cancer-related death: HR 1.23, 95% CI 1.09, 1.40; other deaths: HR 1.19, 95%CI 1.03, 1.38). CONCLUSIONS: Both high and low serum calcium levels, elevated CRP, and vitamin D insufficiency are potential predictors of increased mortality risk in the osteoarthritis population. These findings emphasize the importance of monitoring and possibly addressing these serum biomarkers in osteoarthritis populations to improve long-term outcomes. Further studies are needed to understand the underlying mechanisms and to propose therapeutic interventions.

Evaluation and Treatment of Knee Pain: A Review.

Importance: Approximately 5% of all primary care visits in adults are related to knee pain. Osteoarthritis (OA), patellofemoral pain, and meniscal tears are among the most common causes of knee pain. Observations: Knee OA, affecting an estimated 654 million people worldwide, is the most likely diagnosis of knee pain in patients aged 45 years or older who present with activity-related knee joint pain with no or less than 30 minutes of morning stiffness (95% sensitivity; 69% specificity). Patellofemoral pain typically affects people younger than 40 years who are physically active and has a lifetime prevalence of approximately 25%. The presence of anterior knee pain during a squat is approximately 91% sensitive and 50% specific for patellofemoral pain. Meniscal tears affect an estimated 12% of the adult population and can occur following acute trauma (eg, twisting injury) in people younger than 40 years. Alternatively, a meniscal tear may be a degenerative condition present in patients with knee OA who are aged 40 years or older. The McMurray test, consisting of concurrent knee rotation (internal or external to test lateral or medial meniscus, respectively) and extension (61% sensitivity; 84% specificity), and joint line tenderness (83% sensitivity; 83% specificity) assist diagnosis of meniscal tears. Radiographic imaging of all patients with possible knee OA is not recommended. First-line management of OA comprises exercise therapy, weight loss (if overweight), education, and self-management programs to empower patients to better manage their condition. Surgical referral for knee joint replacement can be considered for patients with end-stage OA (ie, no or minimal joint space with inability to cope with pain) after using all appropriate conservative options. For patellofemoral pain, hip and knee strengthening exercises in combination with foot orthoses or patellar taping are recommended, with no indication for surgery. Conservative management (exercise therapy for 4-6 weeks) is also appropriate for most meniscal tears. For severe traumatic (eg, bucket-handle) tears, consisting of displaced meniscal tissue, surgery is likely required. For degenerative meniscal tears, exercise therapy is first-line treatment; surgery is not indicated even in the presence of mechanical symptoms (eg, locking, catching). Conclusions and Relevance: Knee OA, patellofemoral pain, and meniscal tears are common causes of knee pain, can be diagnosed clinically, and can be associated with significant disability. First-line treatment for each condition consists of conservative management, with a focus on exercise, education, and self-management.

Pain, function, and radiographic disease in trapeziometacarpal osteoarthritis.

INTRODUCTION: Trapeziometacarpal joint osteoarthritis (OA) produces significant functional impairment due to pain and loss of strength in both power and precision grips, but few studies have related radiographic scores to functional and pain-based measures. PURPOSE: To investigate the association between markers of radiographic disease and outcomes for symptomatic and functional disease. STUDY DESIGN: This study in an exploratory analysis of baseline data from the first 100 participants in a clinical trial evaluating the efficacy of combined conservative therapies for base of thumb OA (COMBO). METHODS: Functional Index for Hand Osteoarthritis (FIHOA) scores and Visual Analogue Scale (VAS) scores for pain were recorded for the index hand. Bilateral isometric grip and tip-pinch strength measurements were taken, as well as posteroanterior and Eaton stress-view hand radiographs. Generalized estimating equations (GEEs), univariate, and multivariate analyses were used according to whether the data were bilateral or unilateral. RESULTS: A total of 79 females and 21 males were included, with a median Kellgren-Lawrence (KL) grade of 3 in the index hand. Higher KL and Eaton grades were associated with lower grip strength in the GEE analysis (B-coefficients of -1.25 and -1.16, and P-values of .002 and .010, respectively). Higher KL grade was also associated with poorer function and higher pain levels in the multivariable analysis (B-coefficients of 1.029 and 3.681, and P-values of .021 and .047, respectively). Lower radial subluxation ratios were associated with lower grip strength in the GEE analysis, and higher pain scores in the multivariable analysis (B-coefficients of 2.06 and -42.1, and P-values of .006 and .031, respectively). Greater pain scores were also associated with poorer function (B-coefficient 0.082, P-value .001). CONCLUSION: More advanced radiographic trapeziometacarpal OA severity is associated with lower grip strength and poorer self-reported functional outcomes. Lower subluxation ratios were associated with higher pain scores and lower grip strength.

Reliability and Convergent Construct Validity of Quantitative Ultrasound for Synovitis, Meniscal Extrusion, and Osteophyte in Knee Osteoarthritis With MRI.

AIMS: To determine: 1) inter-rater reliability of quantitative measurements of ultrasound-detected synovitis, meniscal extrusion, and osteophytes; and 2) construct (convergent) validity via correlations and absolute agreements between ultrasound- and gold-standard magnetic resonance imaging (MRI)-outcomes in knee osteoarthritis. METHODS: Dynamic ultrasound images for supra-patellar synovitis, meniscal extrusion, and osteophytes were acquired and quantified by a physician operator, musculoskeletal ultrasonographer, and medical student independently. On the same day, 3T MRI images were acquired. Effusion-synovitis, meniscal extrusion, and osteophytes were quantified on sagittal or coronal proton-density-weighted fat-suppressed noncontrast TSE sequences, respectively. Intra-class correlation coefficients (ICCs), Pearson's correlations (r), and Bland-Altman plots were used to analyze inter-rater reliability, and correlations, and agreements between the two imaging modalities. RESULTS: Eighty-nine participants [48 females (53.9%)] with mean (standard deviation) age of 61.5 ± 6.9 years were included. The inter-rater reliability was excellent for osteophytes (ICC range = 0.90-0.96), meniscal extrusion (ICC range = 0.90-0.93), and synovitis (ICC range = 0.86-0.88). The correlations between ultrasound pathologies and their MRI counterparts were very strong (ICC range = 0.85-0.98) except for lateral meniscal extrusion [0.66 (95% CI, 0.52-0.76)]. Bland-Altman plots showed 0.01, 0.05, 0.10, 0.53, and 0.60 mm larger size in ultrasound medial tibial and medial femoral osteophytes, medial meniscal extrusions, synovitis, and lateral meniscal extrusions with 95% limits of agreements [±0.39, ±0.44, ±0.85, ±0.70, and ±0.90 (SDs)] than MRI measures, respectively. The lines of equality were within 95% CI of the mean differences (bias) only for medial osteophytes and medial meniscal extrusion. CONCLUSION: The quantitative assessment of synovitis, meniscal extrusion, and osteophytes generally showed excellent inter-rater reliability and strong correlations with MRI-based measurements. Absolute agreement was strong for medial tibiofemoral pathologies.

Effect of Intra-articular Platelet-Rich Plasma vs Placebo Injection on Pain and Medial Tibial Cartilage Volume in Patients With Knee Osteoarthritis: The RESTORE Randomized Clinical Trial.

Importance: Most clinical guidelines do not recommend platelet-rich plasma (PRP) for knee osteoarthritis (OA) because of lack of high-quality evidence on efficacy for symptoms and joint structure, but the guidelines emphasize the need for rigorous studies. Despite this, use of PRP in knee OA is increasing. Objective: To evaluate the effects of intra-articular PRP injections on symptoms and joint structure in patients with symptomatic mild to moderate radiographic medial knee OA. Design, Setting, and Participants: This randomized, 2-group, placebo-controlled, participant-, injector-, and assessor-blinded clinical trial enrolled community-based participants (n = 288) aged 50 years or older with symptomatic medial knee OA (Kellgren and Lawrence grade 2 or 3) in Sydney and Melbourne, Australia, from August 24, 2017, to July 5, 2019. The 12-month follow-up was completed on July 22, 2020. Interventions: Interventions involved 3 intra-articular injections at weekly intervals of either leukocyte-poor PRP using a commercially available product (n = 144 participants) or saline placebo (n = 144 participants). Main Outcomes and Measures: The 2 primary outcomes were 12-month change in overall average knee pain scores (11-point scale; range, 0-10, with higher scores indicating worse pain; minimum clinically important difference of 1.8) and percentage change in medial tibial cartilage volume as assessed by magnetic resonance imaging (MRI). Thirty-one secondary outcomes (25 symptom related and 6 MRI assessed; minimum clinically important difference not known) evaluated pain, function, quality of life, global change, and joint structures at 2-month and/or 12-month follow-up. Results: Among 288 patients who were randomized (mean age, 61.9 [SD, 6.5] years; 169 [59%] women), 269 (93%) completed the trial. In both groups, 140 participants (97%) received all 3 injections. After 12 months, treatment with PRP vs placebo injection resulted in a mean change in knee pain scores of -2.1 vs -1.8 points, respectively (difference, -0.4 [95% CI, -0.9 to 0.2] points; P = .17). The mean change in medial tibial cartilage volume was -1.4% vs -1.2%, respectively (difference, -0.2% [95% CI, -1.9% to 1.5%]; P = .81). Of 31 prespecified secondary outcomes, 29 showed no significant between-group differences. Conclusions and Relevance: Among patients with symptomatic mild to moderate radiographic knee OA, intra-articular injection of PRP, compared with injection of saline placebo, did not result in a significant difference in symptoms or joint structure at 12 months. These findings do not support use of PRP for the management of knee OA. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617000853347.

Disease modification in osteoarthritis: are we there yet?

A disease-modifying osteoarthritis drug (DMOAD) is a drug that modifies the underlying OA pathophysiology and potentially inhibits the structural damage to prevent or reduce long-term disability with potential symptomatic relief. The focus of this narrative review is on describing the state of the field for disease-modifying pharmacologic agents that are in late-stage development-specifically phase 2/3.

Musculoskeletal ultrasound in symptomatic thumb-base osteoarthritis: clinical, functional, radiological and muscle strength associations.

BACKGROUND: Thumb-base osteoarthritis (OA) is a common cause of pain and disability This study aimed to investigate the associations of musculoskeletal ultrasound OA pathologies with the extent of pain, function, radiographic scores, and muscle strength in symptomatic thumb-base osteoarthritis. METHODS: This is a cross-sectional study of an ongoing clinical trial with eligibility criteria including thumb-base pain on Visual Analogue Scale (VAS) ≥40 (0 to 100 mm), Functional Index for Hand OA (FIHOA) ≥ 6 (0 to 30) and Kellgren Lawrence (KL) grade ≥ 2. The most symptomatic side was scanned to measure synovitis and osteophyte severity using a 0-3 semi-quantitative score, power Doppler and erosion in binary score. A linear regression model was used for associations of ultrasound findings with VAS pain, FIHOA and hand grip and pinch strength tests after adjusting for age, gender, body mass index, disease duration and KL grade as appropriate. For correlation of ultrasound features with KL grade, OARSI ((Osteoarthritis Research Society International) osteophyte and JSN scores, Eaton grades, Spearman coefficients were calculated, and a significant test defined as a p-value less than 0.05. RESULTS: The study included 93 participants (mean age of 67.04 years, 78.5% females). Presence of power Doppler has a significant association with VAS pain [adjusted ß coefficient = 11.29, P = 0.02] while other ultrasound pathologies revealed no significant associations with all clinical outcomes. In comparison to radiograph, ultrasonographic osteophyte score was significantly associated with KL grade [rs = 0.44 (P < 0.001)], OARSI osteophyte grade [rs = 0.35 (P = 0.001)], OARSI JSN grade [rs = 0.43 (P < 0.001)] and Eaton grade [rs = 0.30 (P < 0.01)]. Ultrasonographic erosion was significantly related with radiographic erosion [rs = - 0.49 (P = 0.001)]. CONCLUSION: From a clinical perspective the significant relationship of power Doppler with pain severity in thumb base OA suggests this might be a useful tool in understanding pain aetiology. It is important to recognise that power Doppler activity was only detected in 14% of the study so this might be an important subgroup of persons to monitor more closely. TRIAL REGISTRATION: Registered at Australian New Zealand Clinical Trials Registry (ANZCTR), http://www.anzctr.org.au/ , ACTRN12616000353493.

What is the role of imaging in the clinical diagnosis of osteoarthritis and disease management?

While OA is predominantly diagnosed on the basis of clinical criteria, imaging may aid with differential diagnosis in clinically suspected cases. While plain radiographs are traditionally the first choice of imaging modality, MRI and US also have a valuable role in assessing multiple pathologic features of OA, although each has particular advantages and disadvantages. Although modern imaging modalities provide the capability to detect a wide range of osseous and soft tissue (cartilage, menisci, ligaments, synovitis, effusion) OA-related structural damage, this extra information has not yet favourably influenced the clinical decision-making and management process. Imaging is recommended if there are unexpected rapid changes in clinical outcomes to determine whether it relates to disease severity or an additional diagnosis. On developing specific treatments, imaging serves as a sensitive tool to measure treatment response. This narrative review aims to describe the role of imaging modalities to aid in OA diagnosis, disease progression and management. It also provides insight into the use of these modalities in finding targeted treatment strategies in clinical research.

Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics.

INTRODUCTION: Osteoarthritis (OA) is a leading cause of pain and disability among adults with a current prevalence of around 15% and a predicted prevalence of 35% in 2030 for symptomatic OA. It is increasingly recognized as a heterogeneous multi-faceted joint disease with multi-tissue involvement of varying severity. Current therapeutic regimens for OA are only partially effective and often have significant associated toxicities. There are no disease-modifying drugs approved by the regulatory bodies. Areas covered: We reviewed the opportunities within key OA pathogenetic mechanism: cartilage catabolism/anabolism, pathological remodeling of subchondral bone and synovial inflammation to identify targeted disease-modifying osteoarthritis drugs, based on compounds currently in Phase II and III stages of clinical development in which x-ray and/or MRI was used as the structural outcome with/without symptomatic outcomes according to regulatory requirements. Expert opinion: Given the heterogeneity of the OA disease process and complex overlapping among these phenotypes, a 'one size fits all' approach used in most clinical trials would unlikely be practical and equally effective in all patients, as well as in all anatomical OA sites. On the other hand, it is a challenge to develop a targeted drug with high activity, specificity, potency, and bioavailability in the absence of toxicity for long-term use in this chronic disease of predominantly older adults. Further research and insight into evaluation methods for drug-targeted identification of early OA and specific characterization of phenotypes, improvement of methodological designs, and development/refinement of sensitive imaging and biomarkers will help pave the way to the successful discovery of disease-modifying drugs and the optimal administration strategies in clinical practice.

Role of Ultrasonography in Knee Osteoarthritis.

Ultrasound has become popular among rheumatologists as the first-choice imaging investigation for the evaluation and monitoring of osteoarthritis (OA). Because of recent improvement in technology, ultrasound has the ability to demonstrate and assess the minimal structural abnormalities, which involve the pathophysiology and progression of OA, such as articular cartilage, synovial tissue, bony cortex, and other soft tissue. Nowadays, ultrasonography is a promising technique for assessing soft tissue abnormalities such as joint effusion, synovial hypertrophy, Baker cyst, and other structural changes including the decrease in cartilage thickness, meniscus bulging, and formation of osteophyte. Ultrasonography not only possesses diagnostic potential in knee OA but also reveals long-term predictability for disease progress as imaging biomarker. Ultrasonography has also been proven as a useful tool in guiding therapeutic interventions and monitoring treatment effectiveness. This review addresses the utility, reliability, and potential utilization of ultrasonography as an imaging technique in knee OA.

Efficacy of addition of transcutaneous electrical nerve stimulation to standardized physical therapy in subacute spinal spasticity: a randomized controlled trial.

OBJECTIVE: To study the immediate and short-term efficacy of adding transcutaneous electrical nerve stimulation (TENS) to standardized physical therapy on subacute spasticity within 6 months of spinal cord injury. DESIGN: Randomized controlled trial for 3 weeks. SETTING: A university hospital. PARTICIPANTS: Subjects (N=16) with clinically determined spasticity were randomly assigned to either the experimental group (n=8) or the control group (n=8). INTERVENTION: Sixty-minute sessions of TENS over the bilateral common peroneal nerves before 30 minutes of physical therapy for the experimental group and 30 minutes of physical therapy alone for the control group. All patients in both groups had access to standardized rehabilitation care. MAIN OUTCOME MEASURES: The composite spasticity score, which included 3 subscores (ankle jerk, muscle tone, and ankle clonus scores), was used as the primary end point to assess plantar flexor spasticity. These subscores were designated as secondary end points. Serial evaluations were made at baseline before study entry and immediately after the first and last sessions in both groups. RESULTS: On analysis for immediate effects, there was a significant reduction only in the composite spasticity score (mean difference, 1.75; 99% confidence interval [CI], 0.47-3.03; P=.002) in the experimental group, but no significant reduction was observed in all outcome variables in the control group. A significant difference in the composite spasticity score (1.63; 99% CI, 0.14-3.11; P=.006) was observed between the 2 groups. After 15 sessions of treatment, a significant reduction was determined in the composite spasticity score (2.75; 99% CI, 1.31-4.19; P<.001), the muscle tone score (1.75; 99% CI, 0.16-3.34; P=.006), and the ankle clonus score (0.75; 99% CI, 0.18-1.32; P=.003) in the experimental group, whereas none of the outcome variables revealed a significant reduction in the control group. The between-group difference was significant only for the composite spasticity score (2.13; 99% CI, 0.59-3.66; P=.001) and the muscle tone score (1.50; 99% CI, 0.15-2.85; P=.005) after 15 intervention sessions. CONCLUSION: Addition of TENS to standardized physical therapy had synergistically antispastic action, providing more effective reduction of clinical spasticity.

Prospects of Disease-Modifying Osteoarthritis Drugs.

Osteoarthritis (OA) causes a massive disease burden with a global prevalence of nearly 23% in 2020 and an unmet need for adequate treatment, given a lack of disease-modifying drugs (DMOADs). The author reviews the prospects of active DMOAD candidates in the phase 2/3 clinical trials of drug development pipeline based on key OA pathogenetic mechanisms directed to inflammation-driven, bone-driven, and cartilage-driven endotypes. The challenges and possible research opportunities are stated in terms of the formulation of a research question known as the PICO approach: (1) population, (2) interventions, (3) comparison or placebo, and (4) outcomes.

New therapeutic strategies in osteoarthritis.

Osteoarthritis (OA) is the most prevalent arthritis-type and is a major contributor to chronic joint pain, impaired physical function, and limited mobility. By the end of 2020, a total of 595 million, equal to 7·6% of the global population, had OA; this figure is expected to rise exponentially by 2050. Even while the disorder's intricate pathophysiology is starting to appear intelligible, we are yet to have a cure for the disorder. OA is typically managed with traditional palliative measures, such as topical and systemic analgesics, including non-steroidal anti-inflammatory drugs, therapeutic exercise, and braces. Sometimes, intra-articular glucocorticoids, viscosupplementation, or regenerative interventions provide short-term pain relief and functional improvement; some may require arthroplasty. Researchers continue their efforts to unveil a new therapeutic target to be effective in OA that modifies symptoms and arrests disease progression as well. In the present literature review, insights into new therapeutic strategies in OA, for example, liposome-based dexamethasone, microspore-based triamcinolone, nerve growth factor antagonist, anti-ADAMTS-5 (A Disintegrin And Metalloproteinase Thrombospoidin Motifs - 5), pentosan polysulfate sodium, allogeneic stem cells, C-C chemokine receptor type-4 (CCR4) ligand 17 inhibitor, Wnt-signaling inhibitor, and anti-obesity medications are provided.

Comparison of ultrasound guidance with landmark guidance for symptomatic benefits in knee, hip and hand osteoarthritis: Systematic review and meta-analysis of randomised controlled trials.

Introduction: More than half of the patients with moderate and severe osteoarthritis (OA) report unsatisfactory pain relief, requiring consideration of intra-articular (IA) injections as the second-line management. Ultrasound-guided IA injection has proven evidence of higher accuracy in administering IA injectates into the joints than landmark-guided or blind IA injections. However, questions remain about translating higher accuracy rates of ultrasound-guided injection into better clinical improvements. Therefore, we examined the symptomatic benefits (pain, function and patient satisfaction) of ultrasound-guided injection in knee, hip and hand OA compared with blind injections by synthesising a systematic review and meta-analysis of randomised controlled trials (RCT). Methods: PubMed, Medline and Embase databases were searched for eligible studies from their inception to August 28, 2023. Results: Out of 295 records, our meta-analysis included four RCTs (338 patients with knee OA), demonstrating significant improvement in procedural pain [-0.89 (95% CI -1.25, -0.53)], pain at follow-up [-0.51 (95% CI -0.98, -0.04)] and function [1.30 (95% CI 0.86, 1.73)], favouring ultrasound guidance. One single study showed higher patient satisfaction with ultrasound guidance. Conclusion: Ultrasound-guided IA injection provided superior clinical outcomes compared with landmark-guided IA injection.

Exploring antidiabetic drug targets as potential disease-modifying agents in osteoarthritis.

BACKGROUND: Osteoarthritis is a leading cause of disability, and disease-modifying osteoarthritis drugs (DMOADs) could represent a pivotal advancement in treatment. Identifying the potential of antidiabetic medications as DMOADs could impact patient care significantly. METHODS: We designed a comprehensive analysis pipeline involving two-sample Mendelian Randomization (MR) (genetic proxies for antidiabetic drug targets), summary-based MR (SMR) (for mRNA), and colocalisation (for drug-target genes) to assess their causal relationship with 12 osteoarthritis phenotypes. Summary statistics from the largest genome-wide association meta-analysis (GWAS) of osteoarthritis and gene expression data from the eQTLGen consortium were utilised. FINDINGS: Seven out of eight major types of clinical antidiabetic medications were identified, resulting in fourteen potential drug targets. Sulfonylurea targets ABCC8/KCNJ11 were associated with increased osteoarthritis risk at any site (odds ratio (OR): 2.07, 95% confidence interval (CI): 1.50-2.84, P < 3 × 10-4), while PPARG, influenced by thiazolidinediones (TZDs), was associated with decreased risk of hand (OR: 0.61, 95% CI: 0.48-0.76, P < 3 × 10-4), finger (OR: 0.50, 95% CI: 0.35-0.73, P < 3 × 10-4), and thumb (OR: 0.49, 95% CI: 0.34-0.71, P < 3 × 10-4) osteoarthritis. Metformin and GLP1-RA, targeting GPD1 and GLP1R respectively, were associated with reduced risk of knee and finger osteoarthritis. In the SMR analyses, gene expression of KCNJ11, GANAB, ABCA1, and GSTP1, targeted by antidiabetic drugs, was significantly linked to at least one osteoarthritis phenotype and was replicated across at least two gene expression datasets. Additionally, increased KCNJ11 expression was related to decreased osteoarthritis risk and co-localised with at least one osteoarthritis phenotype. INTERPRETATION: Our findings suggest a potential therapeutic role for antidiabetic drugs in treating osteoarthritis. The results indicate that certain antidiabetic drug targets may modify disease progression, with implications for developing targeted DMOADs. FUNDING: This study was funded by the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (2022), the Shanghai Municipal Health Commission Health Industry Clinical Research Project (Grant No. 20224Y0139), Beijing Natural Science Foundation (Grant No. 7244458), and the Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation (Grant No. GZC20230130).

Efficacy and safety of pentosan polysulfate sodium in people with symptomatic knee osteoarthritis and dyslipidaemia: protocol of the MaRVeL trial.

INTRODUCTION: Knee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain relief; growing evidence suggests pentosan polysulfate sodium (PPS) is chondroprotective and could have anti-inflammatory effects in knee OA. This study aims to explore the efficacy and safety of oral PPS in symptomatic knee OA with dyslipidaemia. METHODS AND ANALYSIS: MaRVeL is a phase II, single-centre, parallel, superiority trial which will be conducted at Royal North Shore Hospital, Sydney, Australia. 92 participants (46 per arm) aged 40 and over with painful knee OA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) will be recruited from the community and randomly allocated to receive two cycles of either oral PPS or placebo for 5 weeks starting at baseline and week 11. Primary outcome will be the 16-week change in overall average knee pain severity measured using an 11-point Numeric Rating Scale. Main secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life and other structural changes. A biostatistician blinded to allocation groups will perform the statistical analysis according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The protocol has been approved by the NSLHD Human Research Ethics Committee (HREC) (2021/ETH00315). All participants will provide written informed consent online. Study results will be disseminated through conferences, social media and academic publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trial Registry (ACTRN12621000654853); U1111-1265-3750.

Efficacy, Safety, and Accuracy of Intra-articular Therapies for Hand Osteoarthritis: Current Evidence.

The lifetime risk of symptomatic hand osteoarthritis (OA) is 39.8%, with one in two women and one in four men developing the disease by age 85 years and no disease-modifying drug (DMOAD) available so far. Intra-articular (IA) therapy is one of the options commonly used for symptomatic alleviation of OA disease as it can circumvent systemic exposure and potential side effects of oral medications. The current narrative review focuses on the efficacy and safety profiles of the currently available IA agents in hand OA (thumb-base OA or interphalangeal OA) such as corticosteroids and hyaluronic acid (HA), as well as the efficacy and safety of IA investigational injectates in phase 2/3 clinical trials such as prolotherapy, platelet-rich plasma, stem cells, infliximab, interferon-? and botulinum toxin, based on the published randomized controlled trials on PubMed database. The limited published literature revealed the short-term symptomatic benefits of corticosteroids in interphalangeal OA while long-term data are lacking. Most of the short-term studies showed no significant difference between corticosteroids and hyaluronic acid in thumb-base OA, usually with a faster onset of pain relief in the corticosteroid group and a slower but greater (statistically insignificant) pain improvement in the HA group. The majority of studies in investigational agents were limited by small sample size, short-term follow-up, and presence of serious side effects. In addition, we reported higher accuracy rates of drug administrations under imaging guidance than landmark guidance (blind method), and then briefly describe challenges for the long-term efficacy and prospects of IA therapeutics.