Discussion

This study investigated the longitudinal association between changes in TMV, structural progression of KOA, and functional outcomes over 48 months in a large cohort with individuals at risk of or with mild KOA. Our findings show that changes in muscle volume are associated with progression of structural damage in the knee joint and functional impairment, especially with the progression of BMELL and WOMAC pain.

The WORMS analyses demonstrated distinct associations between muscle gain and muscle loss with structural progression over 48 months. Muscle gain was significantly associated with reduced progression of ligament abnormalities and BMELL, whereas muscle loss was significantly associated with greater progression of tendon abnormalities. These findings suggest that preservation or gain of muscle volume may be associated with reduced progression of specific structural features of KOA, while muscle loss may particularly contribute to tendon deterioration. Although the observed regression coefficients were modest in absolute terms, the association with BMELL corresponded to approximately 13% of the average baseline BMELL score. As no established minimal clinically important differences are available for individual WORMS subscores, the clinical relevance of these findings should be interpreted with caution and confirmed in future studies. Furthermore, the sensitivity analysis including participants with extreme TMV changes demonstrated that the association with ligament progression remained stable, whereas the association with BMELL progression was attenuated. This suggests that the BMELL findings may be more sensitive to extreme TMV values and should therefore be interpreted with caution. The WORMS cartilage outcome showed a statistical trend for the difference between the muscle gain and muscle loss groups, suggesting less cartilage progression in the muscle gain compared to the muscle loss group, which may indicate slowed degenerative changes in individuals with muscle gain over 4 years. Conversely, muscle loss was associated with greater progression in tendon WORMS scores, highlighting the detrimental effects of muscle decline on joint structures. These findings are consistent with prior studies linking muscle characteristics to KOA progression [14]. Our results build on previous studies by demonstrating associations between longitudinal changes in multi-slice-based thigh muscle volume and structural as well as functional outcomes in knee osteoarthritis. Although volumetric assessment may be less susceptible to slice-positioning variability than slice-slice approaches, this study did not directly compare the two methods.

The relationship between thigh muscle and KOA is likely bidirectional, as worsening KOA may impair physical activity through pain and joint dysfunction, leading to muscle loss, while muscle decline may exacerbate KOA progression through reduced joint stability and altered biomechanics [30]. The association between muscle gain and lower WOMAC pain scores may reflect a stabilizing effect on the joint, though the observational design precludes causal inference. Pain reduction is a critical outcome for KOA patients, as it not only improves physical function but also enhances overall well-being [31,32]. However, the absence of significant associations between muscle volume changes and WOMAC functional limitation and stiffness subscores indicates that muscle gain alone may not fully address all dimensions of functional impairment. Interestingly, WOMAC scores showed a slight improvement across all muscle groups despite the overall progression of structural abnormalities observed on MRI. This apparent discordance between structural progression and symptomatic improvement has been reported previously in KOA and likely reflects the well-recognized imperfect relationship between structural joint damage and patient-reported symptoms. In addition, regression to the mean, treatment uptake during follow-up, and selective attrition may have contributed to the observed improvement in WOMAC scores despite worsening structural disease.

The decline in CST performance observed in the muscle loss group further underscores the functional consequences of muscle decline. Physical performance tasks require both strength and coordination, and muscle loss may impair the ability to perform these activities, thereby exacerbating functional limitations. This finding is particularly concerning given the association between CST performance and broader measures of physical function and independence in KOA patients. Maintaining or increasing muscle volume appears critical for preserving physical performance, though interventions specifically designed to improve neuromuscular function may also play a role in mitigating declines.

The results of this study may have important implications for KOA management, particularly in the context of preventive and rehabilitative strategies. Although the present findings are observational and do not establish causality, they suggest that muscle loss, whether due to aging, inactivity, sarcopenia, or muscle wasting from weight [33,34], may represent a potentially modifiable risk factor associated with worsening KOA progression and impaired functional outcomes. Consequently, interventions aimed at preserving or increasing muscle volume, such as resistance training and physical activity programs, may be beneficial, consistent with current recommendations for KOA management [35]. Such interventions not only improve muscle strength and mass but also promote joint stability, reduce pain, and enhance mobility [36]. Moreover, addressing sarcopenia in older adults with KOA may be particularly beneficial, as this population is at increased risk for both muscle loss and joint damage. Additionally, dietary strategies, including protein-rich diets, may support muscle health and complement exercise-based interventions, particularly in populations at risk for muscle wasting [[37], [38], [39]]. However, whether interventions that increase muscle volume translate into slower structural progression of KOA remains to be established in prospective randomized intervention studies. A key strength of this study is the use of multi-slice-based volumetric muscle quantification, which provides a particularly robust approach for assessing longitudinal changes in muscle health [20] and extends prior single-slice cross-sectional area approaches [14] and may better reflect overall muscle morphology. In addition, the use of detailed MRI-based WORMS subscores allowed for a more granular assessment of structural changes, enabling the identification of tissue-specific associations, particularly for ligaments, tendons, and BMELL. However, MRI-based muscle assessment in KOA is increasingly moving toward multiparametric approaches that integrate for an example muscle volume and fat infiltration [20]. In this context, volumetric measures represent only one aspect of muscle health, and future studies should incorporate compositional MRI measures to provide a more comprehensive assessment.

Despite its strengths, this study has some limitations. The observational design precludes causal inference regarding the relationships between muscle volume changes and structural or functional outcomes. Furthermore, because of the observational design, the temporal relationship between changes in muscle volume and KOA progression cannot be established. Muscle decline may be both a cause and a consequence of KOA-related changes, and therefore reverse causation cannot be excluded. Additionally, while MRI-based WORMS scores provide detailed structural assessments, they do not account for dynamic biomechanical changes during movement that may contribute to joint instability and damage. Incorporating gait analysis or other biomechanical measures into future studies could provide a more comprehensive understanding of the interplay between muscle and joint health. Participants in the muscle loss group had higher baseline cartilage WORMS scores than the muscle gain group. Although the primary analyses were based on change scores rather than follow-up scores adjusted for baseline, we cannot exclude that baseline structural differences contributed to the observed progression patterns. Alternative analytical approaches, such as ANCOVA adjusting for baseline WORMS scores, may provide complementary insights [40,41]. Although baseline characteristics differed moderately between the participants that were excluded because of missing WORMS data and those that were included, with respect to BMI, whereas differences in physical activity were negligible. Nevertheless, some degree of selection bias due to missing outcome data cannot be excluded. Consequently, the present findings are most directly generalizable to OAI participants with available longitudinal WORMS assessments and should not automatically be extrapolated to the entire OAI cohort. The analysis was restricted to the right knee and right thigh. Consequently, our findings may not fully generalize to bilateral disease patterns or side-specific differences in muscle morphology and structural KOA.

In summary, this study underscores the critical role of muscle in mitigating KOA progression and improving functional outcomes. Muscle gain appears to protect against structural damage in ligaments, tendons, and BMELL while alleviating pain, whereas muscle loss exacerbates tendon damage and functional decline. These findings highlight the importance of preserving muscle volume in KOA management and suggest that targeted interventions to improve muscle health should be integral to comprehensive treatment strategies.