Discussion
knee pain, OA
DEGENERATIVE, SECONDARY
The present study investigated cartilage-related biomarkers in serum from knee OA patients participating in either HI RT or LI RT. We assessed changes in aggrecan and type II collagen biomarker levels during training intensity programs. Our main findings were that both huARGS and C2M biomarker levels in serum increased with resistance training within the HI as well as the LI exercise groups and that huARGS levels increased more after 3 months of supervised training and after 6 months of home training in the HI RT group compared to the LI RT group. These data suggest that RT induces alterations in the cartilage tissue turnover in knee OA patients. Interestingly, the increase in huARGS and C2M levels continued from POST-XT to FU despite the transition from supervised training to unsupervised training.The cartilage turnover and degradation seem to be increased during high-intensity training, not only during the training, measurement at 3 months, but also after additional 3 months of follow-ups, which means relatively long-term elevated turnover.The increased serum levels of huARGS and C2M could be a consequence of changes in cartilage tissue turnover from training. The increased huARGS levels observed in the HI RT group may represent an additional increase in tissue turnover. This increase in turnover was also found in C2M but not differently between the HI and LI RT groups. In the current study, aggrecan degradation or remodeling appeared to be more related to training intensity than the C2M biomarker. However, the increase in C2M levels in both HI and LI RT groups from PRE-XT to FU may suggest that RT induces a catabolic or remodeling effect in type II collagen in cartilage, but that response is more resistant to the magnitude of intensity. Evidence of an interplay between aggrecan remodeling and type II collagen formation was presented in an ex vivo study investigating the recombinant form of fibroblast growth factor 18 (FGF-18), Sprifermin, on human cartilage explants [In the present study, we observed that the huARGS and C2M levels increased over time. Whether the change over time is a positive or a negative finding should be considered. It seems that high-intensity exercise has a stimulating effect on cartilage tissue turnover, but it is not clear whether these increased levels are part of a remodeling response or associated with net cartilage degradation. It is therefore difficult to draw conclusions, partly due to the design of this study in which a secondary analysis was performed in an RCT (the VIDEX study) [It is worth considering that there might not be a linear relationship between training intensity and efficacy but perhaps that exercise in OA patients functions by a goldilocks principle of a “just right” amount. This range of beneficial exercise for OA patients may be defined by lower thresholds than for healthy subjects. Two longitudinal studies investigated the general recommendations of 10,000 steps/day or 150 min/week of moderate/vigorous activity and found that ≥10,000 steps/day was associated with degenerative effects and that the threshold for moderate/vigorous exercise needed for improving function was approximately half that recommended [The large number of patients and the longitudinal design of the VIDEX study provided a good opportunity to gain more insight into the change in biomarker levels as a result of knee joint loading through the exercises. However, there are several limitations of the study. The VIDEX randomized control trial did not include a control group which did not receive exercise therapy, and therefore, a comparison of the results to a group without exercise intervention was not possible. Furthermore, it will be important to better understand how biomarker response differs between OA patients and healthy controls subjected to a similar level of physical activity or exercise intervention. An important limitation is also that actual endpoints of structural damage are yet unknown. Biomarker levels are therefore difficult to interpret. It is also difficult to bridge the clinical relevance as it is not known whether increased degradation of aggrecan leads to net loss or whether it is a sign of remodeling and reinforcement of the cartilage. Therefore, future studies should also relate changes in biomarker levels with changes in the clinical parameters as a result of exercise, for example WOMAC functionality scores, knee pain severity, and performance tests.In conclusion, cartilage tissue turnover appears to increase in response to an exercise-related joint loading training program with no evident difference in type II collagen turnover between high- and low-intensity exercises. Only aggrecan remodeling was found to increase with high-intensity resistance training. Given the absence of a favorable effect on clinical signs and symptoms in high versus low exercise-treated patients, these exploratory results indicate that the combination of clinical findings of the VIDEX study (no difference in clinical outcomes) and the findings on the biomarker analyses (more cartilage degeneration in the high-intensity group) argue against high-intensity training in knee OA patients.