A RANDOMIZED, CROSS-OVER STUDY TO INVESTIGATE THE EFFECT OF WEIGHT-BEARING VS NON-WEIGHT-BEARING EXERCISE AND CARDIOVASCULAR STRESS ON TYPE II COLLAGEN TURNOVER IN KNEE OSTEOARTHRITIS PATIENTS – BIOMARKER DATA FROM THE EFEX-OA-02 STUDY

Background: Biomechanical stress is a prerequisite for OA development and studies have shown a difference in the effect of impact- and shear stress , although studies of the direct impact of exercise on cartilage turnover have not demonstrated clear trends . Objectives: Exploring how weight-bearing (WB), non-weight-bearing (NWB) exercise and cardiovascular stress influence circulating biomarkers of cartilage extracellular matrix turnover in OA. Methods: EFEX-OA-02 was a randomized, cross-over, clinical study investigating the direct effect of exercise on joint biomarkers in knee OA. Subjects were randomized to an order of cycling and running followed by adrenaline infusion and finally resting one week apart. Exercise and infusion sessions were multiphasic, consisting of 4x5-minute intervals. Peak cardiorespiratory stress (PCS) per interval was set to ≥80% of the heart rate reserve during exercise. Blood samples were obtained before, during, at five time points after and 24 h post exercise/infusion. For adrenaline infusion, 0.06 mg/kg of adrenaline was prepared in a 50 mL saline solution and administered intravenously. At rest, samples were collected at corresponding time points, except for the 24 h sample, which was omitted. Levels of serum C2M, T2CM (type II collagen degradation) and PRO-C2 (type II collagen formation) were measured using ELISA-assays (Nordic Bioscience). Coll2-1 and Coll2-1NO2 (type II collagen degradation) were measured using ELISA (Artialis). Changes in biomarker concentrations after activity were compared to baseline (BL) and the corresponding resting samples. We used ANCOVA and Dunnett’s test with geometric means of change from BL up to 240 min as the dependent variable and subject and activity as covariates. Paired t-test was used to compare values at 24-hour to BL. Results: Forty subjects were included. Mean age was 60.4 years (SD: 8.7), 24 (60%) were females, mean BMI was 27.0 kg/m (SD: 3.5), 18 had cumulated KL grade of 2 or 3 (45%) and 22 (55%) had KL 4, 5 or 6. and mean KOOS pain at BL was 67.5 (SD: 15.2) corresponding to mild-moderate pain. All subjects reached minimum PCS during exercise, but only an average of 70% (SD: 8.7) of that during infusion. Cycling induced a small reduction in C2M (peak: -5.3%, 95%CI: -7.8 to -2.7%). PRO-C2 increased rapidly in response to cycling (peak: 11.7%, 95%CI: 4.3 to 19.1%) and running (peak: 12.9%, 95%CI: 3.54 to 22.2%). T2CM decreased up to one hour after cycling (peak: -10.8%, 95%CI: -15.1 to -6.5%) and running (peak: -9.5%, 95%CI: -15.5 to -3.6%), similar to adrenaline, then increased. Coll2-1NO2 increased rapidly following cycling (peak: 12.5%, 95%CI: 2.8 to 22.2%) and running (peak: 9.8%, 95%CI: 0.26 to 19.6%). Trends of increase was found in Coll2-1 (21.3%, 95%CI: 2.9 to 39.6) and Coll2-1NO2 (11.6%, 95%CI: -7.9 to 31.1%) in response to running at 240 min ( Figure 1 – Error bars: SE, *Change to resting, † Change from BL, */ † : P < 0.05, **/ †† : P < 0.01 ***/ ††† : P<0.001). Figure 1. At 24h PRO-C2 reduced -9.4% (95%CI: -18.2 to -0.5%) after cycling, Coll2-1NO2 reduced -8.33% (95%CI: -17.0 to 0.3%) after running and T2CM elevated by 6.0% (95%CI: -0.8 to 12.8%) after running and 7.1% (95%CI: 0.5 to 13.7%) after cycling. Conclusion: Running, cycling and adrenaline infusion induced rapid small-to-moderate changes in circulating biomarkers reflecting type II collagen turnover. Changes after adrenaline-infusion suggests a cardiovascular contribution to exercise-induced changes. This model could potentially be used to evaluate treatment effects on collagen turnover. REFERENCES: [1]Bjerre-Bastos JJ, Karsdal MA, Boesen M, Bliddal H, Bay-Jensen A, Andersen JR, Bihlet AR: The acute and long-term impact of physical activity on biochemical markers and MRI measures in osteoarthritis—Perspectives for clinical osteoarthritis research. Transl Sport Med, 2020. [2]Vincent TL: Mechanoflammation in osteoarthritis pathogenesis. Semin Arthritis Rheum, 2019. Disclosure of Interests: Jonathan Bjerre-Bastos: None declared, Casper Sejersen: None declared, Henning Bay Nielsen: None declared, Mikael Boesen Speakers bureau: Speaker for Novartis and Eli Lilly, Niels Secher: None declared, Gregorio Distajo: None declared, Vincent Flood: None declared, Yves Henrotin Employee of: Founder and President of Artialis SA, Melanie Uebelhoer Employee of: Employee of Artialis, Abigail Mackey: None declared, Peter Krustrup: None declared, Carl-Christian Kitchen: None declared, Ema Petersen: None declared, Christian Thudium Shareholder of: Shareholder Nordic Bioscience A/S, Employee of: Full-time employee at Nordic Bioscience A/S, Jeppe Ragnar Andersen Employee of: Full-time employee of NBCD/Sanos Group A/S, Asger Reinstrup Bihlet Employee of: Full-time employee of NBCD/Sanos Group A/S Citation: , volume 81, supplement 1, year 2022, page 884Session: Osteoarthritis (POSTERS only)