Letter to Editor

David T. Felson, ,
, ,

Other Contributors:

March 23, 2011

Dear Editor,

In a recent issue of ARD, Wildi and colleagues reported results of a randomized trial and suggested that chondroitin sulfate slowed the rate of cartilage loss in osteoarthritic knees over 6 months (1). We have a number of concerns.

The authors controlled for age and bisphosphonate use between treatment groups, but these are not known to be associated with cartilage loss. In contrast, these authors and others (2;3) have reported that meniscal damage, high BMI and malalignment do increase the risk of cartilage loss, yet the authors provide no information about the comparability of treatment groups on these factors and do not control for them in analyses. This is especially critical in such a small trial, when randomization often fails to produce a balance in prognostic factors.

Differences in cartilage loss between treatment groups were reported for the lateral but not medial femorotibial compartment, but the authors do not state whether study participants had lateral or medial disease. Generally a greater proportion of OA patients has medial disease, and therefore one wonders about the clinical value of preventing cartilage loss in a clinically likely unaffected compartment.

No significant difference in bone marrow lesion (BML) scores or synovitis was detected at the end of the randomized trial (6 months).
Difference reported at 12 months must thus be due to changes during the second 6 months, when both groups were taking chondroitin. This suggests no effect of treatment on BMLs.

In the placebo group, the authors report rates of change over 6/12 months between -1.8%/-4.0% (trochlea) and -6.8%/-9.3% (medial femoral condyle). These rates are 4-fold higher than those reported in the OA Initiative (4) and other observational studies (3;5). The authors state that the two trained readers were blinded to treatment and examination time point, except for baseline. Could partial unblinding to time sequence or treatment have affected the results?

The authors used a FISP sequence to assess BMLs (6). FISP is a Gradient Recalled Echo (GRE) sequence that is insensitive to BMLs (7) due to trabecular magnetic susceptibility or T2* effects (also see consensus statements by OMERACT (Outcome Measures in Rheumatology Clinical Trials) and OARSI (Osteoarthritis Research Society International) (8)). Why did the authors not use T2-, proton density-, or intermediate-weighted FS FSE sequences as has been recommended?

Further, the authors used non fat-suppressed T1-weighted and T2-weighted axial GRE type sequences to assess peripatellar synovitis. These sequences are prone to chemical shift artifacts that hinder accurate differentiation from other peripatellar structures, such as the retinaculae or fat (9). In figure 1 of their paper, the arrows do not depict the exact location of measurement, nor do they differentiate fluid from synovium, retinaculum or fat. Few non-enhanced MRI sequences have been described that can delineate the synovial membrane from adjacent structures, and none have been validated against a gold standard of either histology or contrast-enhanced MRI (10). Could the authors provide validation data for their method to provide evidence that what they are measuring is actually synovium?


1. Wildi LM, Raynauld JP, Martel-Pelletier J, et al. Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI. Ann Rheum Dis 2011 Mar 1.

2. Raynauld JP, Martel-Pelletier J, Berthiaume MJ, et al. Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period. Ann Rheum Dis 2008;67(5):683-8.

3. Sharma L, Eckstein F, Song J, et al. Relationship of meniscal damage, meniscal extrusion, malalignment, and joint laxity to subsequent cartilage loss in osteoarthritic knees. Arthritis Rheum 2008;58(6):1716-26.

4. Hunter DJ, Niu J, Zhang Y, et al. Change in cartilage morphometry: a sample of the progression cohort of the Osteoarthritis Initiative. Ann.Rheum Dis 2009;68(3):349-56.

5. Le Graverand MP, Buck RJ, Wyman BT, et al. Change in regional cartilage morphology and joint space width in osteoarthritis participants versus healthy controls: a multicentre study using 3.0 Tesla MRI and Lyon-Schuss radiography. Ann Rheum Dis 2010;69(1):155-62.

6. Raynauld JP, Martel-Pelletier J, Berthiaume MJ, et al. Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes. Arthritis Res Ther 2006;8(1):R21.

7. Roemer FW, Hunter DJ, Guermazi A. MRI-based semiquantitative assessment of subchondral bone marrow lesions in osteoarthritis research. Osteoarthritis Cartilage 2009;17(3):414-5.

8. Peterfy CG, Gold G, Eckstein F, et al. MRI protocols for whole-organ assessment of the knee in osteoarthritis. Osteoarthritis Cartilage 2006;14 Suppl A:A95-111.

9. McGibbon CA, Bencardino J, Palmer WE. Subchondral bone and cartilage thickness from MRI: effects of chemical-shift artifact. MAGMA 2003;16(1):1-9.

10. Hayashi D, Roemer FW, Katur A, et al. Imaging of Synovitis in Osteoarthritis: Current Status and Outlook. Semin Arthritis Rheum 2011 Feb 2.

Conflict of Interest

None declared