The present pilot study provides, for the first time, evidence of the structure protective effect of CS in knee OA patients as early as 6 months into treatment. In addition, the pronounced reduction in cartilage loss found in the lateral tibiofemoral compartment was also associated with a reduction in the size of BML. This finding is interesting as BML are believed to be associated with the progression of cartilage lesions.46–51
This study is the first to use quantitative MRI to assess the DMOAD potential of CS in knee OA patients, bringing important information to a field in which the results have been contradictory in the past. The positive results are in line with a number of studies using x-ray technology5–8
and with a recent meta-analysis that reported CS to be effective in reducing JSN.52
However, another recent meta-analysis including x-ray trials of glucosamine and CS,53
as well as a structural analysis of the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT)54
in which a non-fluoroscopically guided x-ray technique was used and sample sizes were small, came to the conclusion that there is no treatment effect of CS. In general, the effect size was reported to be small to moderate, demonstrating the need for further trials that may confirm the positive findings of the present trial and shed light on this controversial field.
In the present study, the shorter time (6 months) needed to obtain significant difference demonstrated the superiority of MRI in such studies. MRI has been shown to reliably and quantitatively assess cartilage volume and its changes over time in knee OA in longitudinal15 23
studies. With regard to this study, as age was significantly different in the two groups the results were adjusted where appropriate and no relevant change overall was found. Of note, the observed rate of cartilage loss found in this study lies within the upper range of previous reports.14 43 55 56
Here, CS treatment was found to significantly reduce the cartilage volume loss at 6 months in the global knee, mainly in the lateral tibiofemoral compartment and tibial plateaus. These findings are in accordance with those of a previous MRI multicentre trial14
in which a protective effect with the DMOAD licofelone was also detected as early as 6 months into the study, and was found predominantly in the lateral compartment. Data from x-ray studies showed a protective effect of CS mainly in the medial compartment. These findings are probably related to the design of these studies, as in those trials the JSW was measured only in the medial compartment.5 6 8
A number of hypotheses could explain the predominant positive effect of CS treatment in the lateral compartment, including: (1) lesions are generally less severe in the lateral compartment than in the medial compartment and may be more responsive to treatment; (2) the effect of CS on the medial compartment could also take place at a later time during the treatment schedule (eg, 2 years).7 8
The non-significant effect of the drug seen on the trochlea could reflect the distinct biomechanical environment of the femoropatellar compartment. Our system did not allow for the detection of the cartilage in the patella, which could be considered a limitation of the findings. The significant reduction in cartilage volume loss in the CS group was found to persist until the end of the open phase at the 12-month follow-up. The reduction in the difference of the rate of cartilage loss between the two groups in the double-blind phase () could probably be explained by the fact that the placebo group started CS treatment at 6 months. Treatment with CS was effective at reducing both BML and cartilage volume loss in the same anatomical regions; however, a decrease in BML occurred only in the open phase (at 12 months). This finding could suggest that BML are consequential to cartilage degradation and thus reducing cartilage lesions could lead to fewer BML. Alternatively, BML were shown to be involved in an inflammatory/catabolic process57
on which CS could act directly, leading to structural repair. The latter hypothesis is supported by in vitro data showing that CS increases the ratio of osteoprotegerin/receptor activator of nuclear factor-κB ligand, suggesting a positive effect on OA subchondral bone structural changes.31
Data also showed that CS treatment alone did not reduce the synovial membrane thickness (primary endpoint). This finding contrasts with those from animal models26 58–61
and the GAIT,62
in which CS treatment was associated with a significant decrease in the incidence of joint swelling, effusion, or both upon clinical examination. The relatively small number of patients in the present pilot study could have been the limiting factor explaining the data.
The effect of the combination of CS with NSAIDs on the synovial membrane thickness and the incidence of joint swelling is interesting with practical clinical impact, and definitely needs future exploration. The absence of differences in disease symptoms between the placebo and CS groups could be explained by the use of rescue medication (paracetamol) as well as NSAIDs, which are strong confounding factors, and this may have masked an underlying symptom-relieving effect of CS. Moreover, as the severity of femoropatellar OA was not assessed, this might have been an additional confounding factor. The impact of the structure-modifying effect of CS on disease symptoms may also become clinically significant only after an extended period of treatment. That question can only be answered by a long-term study. The study design included a double-blind phase (6 months) followed by an open-label phase (6 months) with CS treatment in both groups. This design does not allow for any conclusion regarding the symptom-relieving effects of CS, especially in the open-label phase, as the dropouts after unblinding occurred only in the placebo group resulting in a possible selection bias. The second phase was primarily chosen to gather additional information on the effects of CS on structural change.
The use of multiple analyses to compare the different structural changes has limitations, including the risks of finding significant results only by chance. Because of a relatively small study sample size, imbalances in baseline characteristics between the treatment groups may have had an impact on our results. For instance, even if there is a numerical difference (without statistical significance) between treatment groups for variables such as BML scores and the presence of knee swelling and effusion, adding these additional variables in the ANCOVA model would not yield any additional significant information. Therefore, a confirmation of these results in a larger trial is mandatory.
The safety profile of CS was excellent and confirms the findings of previous reports.5–8 62 63
No SAE were found to be related to CS.
In summary, this pilot study demonstrates with the use of quantitative MRI a significant reduction in cartilage volume loss as early as 6 months into treatment with CS and, for the first time, a significant reduction in BML size. These data underline not only the importance of the crosstalk between cartilage and subchondral bone in OA, but also their potential role in the disease process and response to DMOAD treatment. The anti-inflammatory effect of the combination of CS with NSAIDs is a new and interesting finding that deserves confirmation in a definitive study. In conclusion, CS has been shown to be a safe drug with a positive global effect on OA joint structural changes.