Using a panel of biochemical indices of bone, cartilage, and synovial tissue turnover, we found that a single measurement of serum hyaluronic acid or short term changes in urine CTX‐II could identify the patients at greatest risk of osteoarthritis progression.
Biochemical markers of bone, cartilage, or synovial remodelling have the potential to serve as diagnostic tools for osteoarthritis. Increases in serum or urine levels of COMP,10,11,12
have been described previously in osteoarthritis patients compared with controls. On the other hand, very few studies have assessed the relation between the structural severity of osteoarthritis and biochemical markers.13,15,16,18
In this study, we showed no significant correlation at baseline between the level of any of the various biochemical markers and any single MRI feature (volume and thickness of cartilage of the medial tibia, the lateral tibia and the femur). However, when using a validated global MRI score, a significant association was found between damage severity score and two biochemical markers (COMP and CTX‐II, p
0.03 and p
0.0002, respectively). To the best of our knowledge, the only other study using MRI assessment of joint damage showed that YKL‐40, measured in synovial fluid, correlated with synovial membrane and the joint effusion volumes determined by MRI.19
Using standard x
ray, we previously reported the absence of significant associations, at baseline, between biochemical markers (serum keratan sulphate, serum hyaluronic acid, urine pyridinoline and deoxypyridinoline, serum osteocalcin, and COMP) and femoro‐tibial joint space width in more than 200 patients with knee osteoarthritis.18
Garnero et al
reported that an increased CTX‐II and glucosyl‐galactosyl pyridinoline levels were significantly correlated with cartilage loss.10
However, no significant associations were reported between joint space width and other biochemical markers (COMP, CTX‐I, YKL‐40, hyaluronic acid, and C reactive protein).10
Obviously, joint space narrowing on standard x
rays only produces an indirect assessment of cartilage damage. However, pathologically, osteoarthritis is an episodical inflammatory disorder of synovial joints characterised by the focal deterioration and abrasion of articular cartilage, with sclerosis and cyst formation in the underlying bone, as well as the formation of osteophytes at the joint surface.20
Thickening of the joint capsule and chronic synovitis are also commonly reported features. In this study, we showed a significant association between global joint damage severity score and CTX‐II and COMP levels. Our results corroborate the hypothesis that, because hyaluronic acid and COMP are not cartilage specific and because these biochemical markers levels were not correlated with knee cartilage volume or thickness, the pathogenesis of osteoarthritis not only involves cartilage but also bone and synovium.21,22,23
Our results obtained with COMP and hyaluronic acid may suggest that synovial inflammation plays a central role in the pathogenesis of osteoarthritis. The key role of inflammation in osteoarthritis is supported by histological evidence of severe inflammation, raised levels of biomarkers related to synovitis, and heightened levels of pro‐inflammatory cytokine expression in osteoarthritic chondrocytes. Moreover, MRI and ultrasonography have demonstrated synovitis in early osteoarthritis.
Another field of interest for biochemical markers is the identification of patients at increased risk of rapid disease progression. Some studies found a predictive value of hyaluronic acid,13,24
C reactive protein,25
procollagen of type II collagen (PIINP),28
and Coll 2‐1 NO229
for radiographic progression. To the best of our knowledge, our study is the first to assess the value of biochemical markers for predicting the progression of osteoarthritis using MRI. We found that a single measurement of serum hyaluronic acid could predict a one year progression of the validated whole‐organ MRI score of the knee in patients with osteoarthritis. Our results are in accordance with previous reports of the predictive value of hyaluronic acid13,24
for joint space narrowing, assessed on x
rays. Recently, Pavelka et al
reported that osteoarthritis patients with high basic serum level of hyaluronic acid had a rapid radiological progression (r
In our study, we used a validated global joint score to assess structural severity. WORMS combines individual scores for articular cartilage, osteophytes, bone marrow abnormality, subchondral cysts, and bone attrition in 14 locations. It also incorporates scores for the medial and lateral menisci, anterior and posterior cruciate ligaments, medial and lateral collateral ligaments, and synovial distension.6
Our results suggest that hyaluronic acid level predicts global damage in patient with knee osteoarthritis, and not only cartilage loss. This seems reasonable because, as a major product of synovial cells, hyaluronic acid is considered to be a marker of synovial inflammation4
and so is not cartilage specific. This study suggests that short term changes in CTX‐II identify patients at greatest risk of losing tibial cartilage after one year. These results are in accordance with our previous report that, when using x
ray to assess joint damage severity, 12 month changes in CTX‐II correlated with the changes in joint space width (on x
ray assessment) observed after 36 months (r
Garnero et al
reported that an increased level of U‐CTX‐II was correlated with the one year progression of knee joint damage in 67 patients with knee osteoarthritis (though the significance was borderline: r
A recent study showed that, in an osteoarthritis cohort of 1235 men and women followed for a mean of 6.6 year, subjects with CTX‐II levels in the highest quartile had a sixfold increased risk for progression of radiographic osteoarthritis in the knee.20
It should be noted that the correlation coefficients were low (0.32 and 0.38) and account for little of the variance of cartilage lost. However, the association between biological markers and cartilage volume were stronger when the analysis was adjusted for age, sex, and body mass index, suggesting that the variance accounts for more than is apparent. It should also be noted that the importance of changes in thickness of less than 1 mm is not yet established. Several large ongoing studies such as the Osteoarthritis Initiative will be able to address this question. Our study, however, does clearly show a significant association between CTX‐II and thickness loss. We must also acknowledge that the matrix of acquisition for the cartilage volume sequences might not be adequate to pick up small changes in volume. However, other studies have shown important results using a similar matrix size. In our present study, the size was chosen to minimise the time taken for the investigation, and thereby patient discomfort.
These results suggest that a single measurement of serum hyaluronic acid or short term changes in urine CTX‐II may identify patients at greatest risk of osteoarthritis progression. This could be helpful for the clinician in identifying patients who should be treated with a structure modifying drug rather than with simple analgesics.