This study assesses radiographic outcomes in OA of the knee in persons using G, CS, G+CS, celecoxib, or placebo. Over two years, no treatment achieved the study’s predefined clinically important difference from placebo in terms of JSW loss. The power was limited by smaller than anticipated sample size and increased variability of measurement.
Controlled studies have reported slowing of JSW loss using G (17
). In particular, the study by Reginster and colleagues followed 106 G treated and 106 placebo patients (18
). The mean JSW losses were 0.06mm and 0.31 mm respectively. When they defined progression as loss >0.5mm, twice as many progressors were observed in the placebo treated group as in the G treated group. A randomized trial by Pavelka et al examined 101 G and 101 placebo treated patients over three years (17
). They found a mean JSW increase
of 0.04mm with G treatment and a decrease of 0.19mm on placebo therapy, respectively (17
). A meta-analysis performed by Richy summarized these studies with respect to JSW loss and found an effect size of 0.41 SD units when treated with G (25
). Our G group had 0.153mm less loss over two years as compared to placebo for a smaller effect size of 0.25 SD units (26
). In part, this may be related to the increased variability associated with multi-center trials.
Similar approaches have been used to examine the effect of CS on JSW loss (16
). A meta-analysis performed by Reichenbach summarized minimum JSW loss data from 5 trials that included treatment with CS. They found an average effect size of 0.18 SD units, a size not clearly felt to be of clinical significance (31
). In our study, the CS group had an even smaller effect size of 0.10 SD units with 0.059mm less JSW loss at two years.
No prior reports have examined the combined effects of G and CS on JSW loss, even though this is a combination commonly taken by patients. Our study observed similar JSW loss in the combination group compared to placebo, but the loss was greater than that seen with G or CS alone, raising the possibility of interference associated with their combined use. Pharmacokinetic studies have shown decreased absorption of G when given concurrently with CS (Jackson, CG-unpublished data), which could effectively lower the G blood levels obtained. Alternatively, the higher proportion of K&L 3 Grade subjects who were treated with combination therapy might have altered the results; in general K&L 3 subjects demonstrated more progression and may have had less treatment benefit ( and ). Celecoxib might have been predicted to progress more than placebo as previous nonsteroidal anti-inflammatory agent trials have suggested increased JSW loss occurs with their use (32
), however, other trials have not (33
). No significant difference between the celecoxib group and placebo was observed in this trial and the direction of the changes was in line with those seen with G or CS.
While the optimal method of documenting disease progression in OA is unknown, the standard at present remains measurement of JSW on plain radiographs (35
). Many feel that MRI may replace radiographs (40
) in the future, especially if the substantial costs of MRI can be offset by a reduction in the required sample size and trial duration due to enhanced precision and sensitivity. When this study was designed, it was felt that weight-bearing PA based films had the best overall performance characteristics. Fluoroscopic guidance for placement was not used due to cost and the difficulty of standardization in a multi-center trial. The non-fluoroscopic MTP view of Buckland-Wright was chosen to balance these issues and was considered adequate to detect a clinically important difference at two years of follow-up (10
). In the time since the initiation of this trial, fluoroscopic methods have been tested, validated and (35
) may now be considered more advantageous, (45
) even in multi-center trials, as they allow increased sensitivity to detection of JSW loss due to better alignment of the tibial plateau (6
In this study, the rate of JSW loss over 2 years was less than the conservative estimate of 0.20mm loss per year using the radiographic technique available at the time of study design (9
). Other recent large studies have also demonstrated significantly less loss. For example, Michel et al found JSW losses close to 0.1mm/year (16
) and the risedronate trial using a fluoroscopically aligned MTP view demonstrated a placebo group loss of only 0.088mm per year in the European and 0.13 in the North American arms, respectively (21
). These results are even less than the 0.14mm annual loss observed in our placebo treated arm. It is likely that the expected rate of loss differs due to radiographic technique and is affected by quality of alignment of the tibial plateau, with better alignment associated with improved detection of JSW loss (39
). Overall, it appears that a rate of progression of 0.1mm/year should be used for planning of future OA radiographic progression studies.
Since a substantial number of individuals may experience little or no JSW loss, mean loss may not even be the best measure to compare treatment groups (35
). As with other trials (18
), we defined progressors as those who lost more than three times the average SD of error of measurement. Although we had a greater proportion of progressors using this definition (22.4%) than reported in the placebo group of the risedronate study (14%), this was not statistically different from placebo in our study. Overall, the order of effect was similar to that observed for the mixed-model mean JSW loss results.
Although the use of state of the art statistical methodology allowed us to utilize all the collected data to obtain the most robust estimates of treatment effect possible, the power of this study was limited by several factors. First, the number of qualifying individuals with acceptable follow-up films was less than expected (14.1%. loss to this effect rather than the expected of 3–10%) (35
). Second, the magnitude of JSW loss in the placebo group was less than anticipated from the literature at the time (0.14mm/year versus 0.2mm/year)(9
). Third, the variability of JSW measurement was larger than expected (0.16 versus 0.09 from available literature) (11
). The standard deviations of JSW measurement for the MTP view were 2–3 times the measured JSW difference in this study which compares favorably to other examinations of this technique (12
) but is higher than the data available at the time the study was designed. Although these factors limit the power of the present study, the results do provide valuable information for future OA study design.
In summary, no therapy reached predefined thresholds for either statistical or clinically meaningful structural modification. The combination of G + CS may be less active compared to their individual effects. The validity and mechanism of this novel observation is uncertain but could be related to altered G absorption. In future OA trials evaluating structural modification, K&L Grade 2 knees may represent a more potentially responsive population, however, a larger sample size, longer study duration, and/or improved methods of measurement will be required as the rate of JSW loss seen on plain radiographs is much slower than previously appreciated.