Osteoarthritis (OA) and other rheumatic conditions comprise the leading cause of disability among adults. The cost of this public health burden is expected to increase as the population ages. Increased intervention efforts, including early diagnosis and appropriate clinical and self-management (e.g., physical activity, patient education, and maintaining appropriate weight) are needed to reduce the impact of arthritis and chronic joint symptoms (1). Moderate exercise is effective in reducing pain and improving function in knee and hip OA (2). However, exercise is underutilized as a therapy for OA, and more than 60% of US adults with arthritis do not satisfy the recommendations for physical activity (3, 4).
The hallmark of structural changes occurring in the OA joint is cartilage loss. Since OA is considered a wear and tear disease, one identified barrier to exercise is the belief that exercise will not improve or may even be harmful to joint cartilage (5, 6). In studies of exercise in animals that develop OA, it has been shown that exercise may protect against cartilage degeneration (7–9). The effects of exercise on human cartilage are largely unknown because, until recently, investigators have been unable to examine the biochemical properties of cartilage tissue in vivo.
Radiography, currently used to define the presence of OA in the joints, identifies disease only in the later stages, when severe cartilage damage has occurred (10). To study cartilage alterations earlier in the disease process, magnetic resonance imaging (MRI) techniques have been developed (11). Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) estimates cartilage quality by measuring the fixed-charge density of tissue, comprising glycosaminoglycans (GAGs) (12–14). GAGs are building blocks of proteoglycans and are crucial for the important viscoelastic properties of cartilage (15).
To test the hypothesis that moderate exercise improves the quality of knee cartilage in patients with early joint disease, we designed a randomized trial involving middle-age patients who previously underwent meniscectomy because of a degenerative meniscus tear, a group who are considered at high risk of developing radiographic OA (16). We used dGEMRIC to evaluate the effects of 4 months of exercise intervention on the GAG content of knee cartilage.
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- PATIENTS AND METHODS
This study shows compositional changes in adult joint cartilage as a result of increased exercise, which confirms the observations made in prior animal studies (7, 8) but has not previously been shown in humans. The changes imply that human cartilage responds to physiologic loading in a way similar to that exhibited by muscle and bone, and that previously established positive symptomatic effects of exercise in patients with OA may occur in parallel to or even be caused by improved cartilage properties.
The unpredictable and individually different progression rate of OA may be explained partly by subjects' differences in matrix integrity, due to differences in, for example, physical stimulation. Animal and cartilage-explant studies have shown increased cartilage GAG metabolism and content and improved indentation stiffness according to increased degree of dynamic joint loading (30–32). The use of dGEMRIC as an estimate of GAG content and assessment of cartilage quality has shown in humans that those participating in a high level of exercise have a higher T1(Gd), and this is the likely means by which higher mechanical demands are withstood (18). Furthermore, recent dGEMRIC studies have shown a high correlation between GAG distribution and biomechanical properties of cartilage (33, 34). It is notable that dGEMRIC, which is presumably more sensitive to disease because it is sensitive to biochemical changes in the tissue, allows the significance of the outcomes to be determined with a smaller number of study participants than is feasible with clinical outcome measures.
A state of prestress in the joint, due to the balance between the swelling that arises from the presence of proteoglycans and the rigid collagen network, is crucial for the function of healthy cartilage (35). In the present study, the higher mean change in the T1(Gd) in the intervention group suggests that cartilage responded to exercise by increasing its GAG content. It may be that increased cartilage GAG content improves the viscoelasticity, which, in turn, protects the collagen network from compressive forces, as has been suggested in canine studies (36). In a cartilage matrix with low GAG content, as in cartilage disease, insufficient viscoelasticity may cause progressive denaturation of collagen molecules, collagen loss, and subsequent development of OA (37).
It is possible that the susceptibility of joint cartilage to OA is related to its quality, specifically to its molecular content of GAGs with high fixed-charge density (38). Among patients with joint disease, dGEMRIC indicates a decreased cartilage GAG content in those with arthroscopic cartilage fibrillations, ligament injury, meniscus tear, and hip dysplasia (19, 39, 40). Furthermore, analysis of proteoglycans from healthy and diseased human cartilage and joint synovial fluid indicates increased proteolytic activity in diseased joints and increased release of proteoglycan fragments that differ from those released in normal joints (41–44).
The potential limitations of this study include, but are not limited to, the limited applicability of the results to other groups at risk of OA, the loss to followup, the methodologic issues related to dGEMRIC, the clinical significance of the results, and the short followup time. The present results are applicable to middle-age patients who have undergone meniscectomy. Meniscectomized knee joints have an increased risk of developing OA (45). In addition, the radiographic and clinical outcome is worse in patients with a degenerative tear, in whom the meniscus injury is suggested to be an early signal of OA (16). In the present study, 25 of 30 patients had such a meniscal tear. The possible association of meniscectomy with hand OA suggests that our results may also be applicable to other groups at risk of developing OA (46).
The primary outcome in this trial was cartilage GAG content measured as the T1(Gd). An objective MRI parameter is not subject to bias in the way that a patient-relevant outcome such as pain would be, and thus the loss to followup does not seem likely to have any influence on the results. Repeated dGEMRIC examinations or ROI drawings were not included in our protocol. However, the issues of T1(Gd) reproducibility in repeated examinations and the T1(Gd) variability between repeated drawings of the ROI are not probable biases. First, these possible biases would likely occur in both groups. Second, dGEMRIC T1(Gd) has been shown to be reproducible with 10–15% variation in repeated examinations within patients, and the intraobserver variation in T1(Gd) in repeated ROI drawings is lower than 2.5% (20, 21). The baseline T1(Gd) values of the patients lost to followup did not differ from those in the patients available for followup.
We suggest that the difference of 40 msec found in the T1(Gd) values at followup between the exercise group and the nonintervention control group is clinically significant. It is comparable with the T1(Gd) differences of 52 msec and 40 msec previously found between sedentary and moderately active healthy adults and between moderately active healthy adults and elite runners, respectively (18). It is not possible to extrapolate the results of this study to any long-term effects of exercise on cartilage. Most likely, the effect is dependent on compliance, in accordance with the effects of exercise on muscle and bone.
We conclude that moderate, supervised exercise improves knee-cartilage GAG content in patients at risk of OA. Improvements in pain and function are observed in parallel with the structural improvement. Exercise may have important implications for disease prevention in patients at risk of developing knee OA.
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We thank Ylva Ericsson, PT, MSc, for help with the data collection, and Inge Dahlberg, PT, BSc, and his coworkers for supervising and carrying out the exercise sessions. We also thank Jon Tjörnstrand, MD, and Carl Johan Tiderius, MD, PhD, for help with the MRI analysis, and Jan Åke Nilsson for statistical advice.