Objectives: We aimed to examine whether metformin (MET) use is associated with a reduced risk of total knee arthroplasty (TKA) and low severity of knee pain in patients with knee osteoarthritis (OA) and diabetes and/or obesity. Methods: Participants diagnosed with knee OA and diabetes and/or obesity from June 2000 to July 2019 were selected from the information system of a local hospital. Regular MET users were defined as those with recorded prescriptions of MET or self-reported regular MET use for at least 6 months. TKA information was extracted from patients’ surgical records. Knee pain was assessed using the numeric rating scale. Log-binomial regression, linear regression, and propensity score weighting (PSW) were performed for statistical analyses. Results: A total of 862 participants were included in the analyses. After excluding missing data, there were 346 MET non-users and 362 MET users. MET use was significantly associated with a reduced risk of TKA (prevalence ratio: 0.26, 95% CI: 0.15 to 0.45, p < 0.001), after adjustment for age, gender, body mass index, various analgesics, and insurance status. MET use was significantly associated with a reduced degree of knee pain after being adjusted for the above covariates (β: −0.48, 95% CI: −0.91 to −0.05, p = 0.029). There was a significantly accumulative effect of MET use on the reduced risk of TKA. Conclusion: MET can be a potential therapeutic option for OA. Further clinical trials are needed to determine if MET can reduce the risk of TKA and the severity of knee pain in metabolic-associated OA patients.

Previous studies have consistently revealed that both local and systemic inflammations are the key to the onset and progression of osteoarthritis (OA). Thus, anti-inflammatory biologic agents could potentially attenuate the progression of OA. We conducted this meta-analysis to examine the efficacy and safety of ant-inflammatory biologic agents among OA patients. Methods: Five databases were searched for randomized controlled trials (RCTs) comparing biologics with placebo or each other in OA patients. Data of pain, physical function, stiffness, and adverse events (AEs) were extracted for a conventional and a Bayesian network meta-analysis. Results: 15 studies with data for 1566 patients were analyzed. In the conventional meta-analysis, etanercept (SMD −0.47; 95% CI −0.89, −0.05) and infliximab (SMD −2.04; CI −2.56, −1.52) were superior to placebo for knee pain. In the network meta-analysis, infliximab was superior to all the other biologic agents in improving pain (vs. hyaluronic acid (SMD −22.95; CI −34.21, −10.43), vs. adalimumab (SMD −21.71; CI −32.65, −11.00), vs. anakinra (SMD −24.63; CI −38.79, −10.05), vs. canakinumab (SMD −32.83; CI −44.45, −20.68), vs. etanercept (SMD −18.40; CI −29.93, −5.73), vs. lutikizumab (SMD −25.11; CI −36.47, −14.78), vs. naproxen (SMD −30.16; CI −41.78, −17.38), vs. tocilizumab (SMD −24.02; CI −35.63, −11.86) and vs. placebo (SMD −25.88; CI −34.87, −16.60)). No significant differences were observed between biologics and placebo regarding physical function, stiffness, and risk of AEs. Conclusions: The findings suggest that infliximab may relieve pain more than other biological agents in OA patients. No significant differences were observed between biologics and placebo regarding physical function, stiffness, and risk of AEs. The results must be interpreted cautiously; therefore, further randomized controlled trials are warranted.

Objective: This study aims to demonstrate the cellular composition and underlying mechanisms in subchondral bone marrow lesions (BMLs) of knee osteoarthritis (OA). Methods: BMLs were assessed by MRI Osteoarthritis Knee Score (MOAKS)≥2. Bulk RNA-sequencing (bulk-seq) and BML-specific differentially expressed genes (DEGs) analysis were performed among subchondral bone samples (including OA-BML=3, paired OA-NBML=3; non-OA=3). The hub genes of BMLs were identified by verifying in independent datasets and multiple bioinformatic analyses. To further estimate cell-type composition of subchondral bone, we utilized two newly developed deconvolution algorithms (MuSiC, MCP-counter) in transcriptomic datasets, based on signatures from open-accessed single-cell RNA sequencing (scRNA-seq). Finally, competing endogenous RNA (ceRNA) and transcription factor (TF) networks were constructed through multiple predictive databases, and validated by public non-coding RNA profiles. Results: A total of 86 BML-specific DEGs (up 79, down 7) were identified. IL11 and VCAN were identified as core hub genes. The “has-miR-424-5p/lncRNA PVT1” was determined as crucial network, targeting IL11 and VCAN, respectively. More importantly, two deconvolution algorithms produced approximate estimations of cell-type composition, and the cluster of heterotopic-chondrocyte was discovered abundant in BMLs, and positively correlated with the expression of hub genes. Conclusion: IL11 and VCAN were identified as the core hub genes of BMLs, and their molecular networks were determined as well. We profiled the characteristics of subchondral bone at single-cell level and determined that the heterotopic-chondrocyte was abundant in BMLs and was closely linked to IL11 and VCAN. Our study may provide new insights into the microenvironment and pathological molecular mechanism of BMLs, and could lead to novel therapeutic strategies.

Background: Osteoarthritis (OA), the most common joint disease in the elderly, has no cure. Macroelements are vital in human health and their relationships with OA are not clear. Clarifying the relationships between macroelements and OA may assist knee OA management. Methods: This study was a post-hoc analysis using data from a two-year randomized controlled trial among 392 participants with knee OA. Dietary macroelements, including calcium, magnesium, potassium, and phosphorus were computed-based on a semi-quantitative food frequency questionnaire at baseline. Knee joint structures (including cartilage volume, cartilage defect, bone marrow lesions, and effusion-synovitis volume), OA symptoms, quality of life, and OA comorbid conditions (including lower limb muscle strength and depressive symptoms) were assessed at baseline and month 24. Western Ontario and McMaster Universities (WOMAC) Index and depressive symptoms were assessed at baseline and months 3, 6, 12, and 24. Quality of life and lower limb muscle strength were assessed at baseline and months 6, 12, and 24. All analyses were conducted using mixed-effects models. Results: Higher dietary magnesium and potassium were associated with fewer OA symptoms, higher quality of life, greater lower limb muscle strength, and fewer depressive symptoms, but not with knee joint structures. Higher dietary calcium and phosphorus was not associated with any of the OA-related outcomes, except that dietary phosphorus was associated with greater lower limb muscle strength. Conclusions: In the longitudinal analyses, higher dietary magnesium and potassium intake are associated with fewer OA symptoms, higher quality of life, and milder comorbid conditions in patients with knee OA, suggesting dietary magnesium and potassium may have beneficial effects on OA and could be used for knee OA management.

Individuals with osteoarthritis (OA) often experience significant changes in their metabolic status and have a higher risk of mortality compared to the general population. However, no study has quantified the metabolic status of OA patients. Moreover, the association between metabolic status and risk of mortality among OA patients remains unclear. The analysis included baseline populations with OA from the UK Biobank (UKBB) study and the National Health and Nutrition Examination Survey (NHANES) 1999–2018. Metabolic status was assessed using composite scores based on body mass index, waist-hip ratio, blood pressure, fasting plasma glucose, hemoglobin A1c, C-reactive protein, triacylglycerols, and lipoproteins. Restricted cubic splines were used to define healthy ranges for each indicator regarding mortality risk. Factors received 1 if within a healthy range, else 0. Total scores ranged from 0 to 7, with 3+ indicating good metabolic health. The traditional metabolic syndrome criteria (ATP III) and the Strict definition were used for comparison. Associations between metabolic unhealth and mortality were examined using Cox proportional hazards models. Integrated Discrimination Improvement (IDI) evaluated discriminatory capacity, and Net Reclassification Improvement (NRI) assessed reclassification performance in predicting ten-year mortality. Among 44,302 UKBB OA participants, 36.0 % were metabolically unhealthy (scores: 0–2), while in 5233 NHANES OA participants, 39.1 % were metabolically unhealthy based on our newly-established definition. After adjustment for covariates, metabolically unhealthy individuals had significantly higher all-cause mortality risk (HR: 1.36; 95 % CI: 1.26–1.47 in UKBB; HR: 1.16; 95 % CI: 1.03–1.30 in NHANES) compared to metabolically healthy individuals. In UKBB, compared to ATP III definition, the changes in IDI and NRI for our newly-established definition were 0.10 % (0.01 %, 0.20 %) and 10.60 % (1.8 %, 13.60 %), respectively. When the comparison was made with the Strict definition, the newly-established definition showed changes in IDI and NRI of 0.18 % (0.10 %, 0.20 %) and 12.10 % (10.30 %, 13.80 %), respectively. results. A new definition for quantifying metabolic unhealth in OA was proposed. It identified a significant mortality risk with poorer metabolic status and outperformed general definitions in predictive accuracy. conclusion. OA is the leading joint disease worldwide, carrying a heavy health burden. Our newly established definition, evaluating metabolic health through waist-to-hip ratio, BMI, blood pressure, glucose, lipids, and C-reactive protein, identified 36.0 % OA patients in UK Biobank and 39.1 % OA patients in NHANES as having poor metabolic status, which is applicable in clinical and research settings. This study also showed that poor metabolic status, as classified by these criteria, is significantly correlated with an elevated risk of all-cause mortality in OA patients. It further highlights the importance of maintaining a holistic approach to care for OA patients, emphasizing the need to address both joint and metabolic health.