OsteoArthritis and Cartilage (26) 14, A14eA18 ª 26 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi:116/j.joca.26.2.22 Assessment of joint space narrowing with conventional standing antero-posterior radiographs: relief in mild-to-moderate pain is not a confounder in recent osteoarthritis structure-modifying drug trials L. C. Rovati M.D.y*, K. Pavelka M.D., Ph.D.zx, G. Giacovelli Ph.D.y and J.-Y. Reginster M.D., Ph.D.k{#yy y Department of Clinical Pharmacology, Rotta Research Laboratorium, Monza, Italy z Department of Medicine and Rheumatology, Charles University, Prague, Czech Republic x Institute of Rheumatology, Prague, Czech Republic k Department of Public Health and Epidemiology, University of Liege, Liege, Belgium { WHO Collaborating Center for Public Health Aspects of Osteoarticular Disorders, Liege, Belgium # Bone and Cartilage Research Unit, University of Liege, Liege, Belgium yy Georgetown University Medical Center, Washington, DC, USA Summary International Cartilage Repair Society Objective: Knee pain relief has been suggested to potentially alter radioanatomic positioning in conventional standing antero-posterior knee radiographs. This study was performed to determine whether this is always the case and in particular if it applied to two recent randomised, placebo-controlled trials showing both symptom- and structure-modification with glucosamine sulfate in knee osteoarthritis. Design: Patients in the two studies were selected if they completed the 3-year evaluations and, irrespectively of treatment, (1) were pain-improvers in that they underwent Western Ontario and McMaster Universities (WOMAC) osteoarthritis index (WOMAC) pain decrease at least equal to the mean improvement observed with glucosamine sulfate, or (2) if their baseline standing knee pain (item #5 of the WOMAC pain scale) was severe or extreme and improved by any degree at the end of the trials. Changes in minimum joint space width were then compared between treatments. Results: Knee pain was of mild-to-moderate severity in the two original studies and in all patient subsets identified here. Obviously, there were more pain-improvers in the glucosamine sulfate than in the placebo subsets (N ¼ 76 vs 57 in pooling the two studies), but WOMAC pain scores improved to the same extent (over 5% relative to baseline). Notwithstanding such a major pain relief, patients in the placebo subsets of both studies suffered a definite mean (SE) joint space narrowing, that was of ÿ.22 (5) mm in the pooled analysis, and that was not observed with glucosamine sulfate: þ5 (.7) mm; P ¼.3. Similar evidence was found in the smaller subsets with at least severe baseline standing knee pain improving after 3 years. Conclusions: Knee pain relief did not bias the report of a structure-modifying effect of glucosamine sulfate in two recent long-term trials, possibly due to the mild-to-moderate patient characteristics. Consensus deliverables should acknowledge that the potential limitations of conventional standing antero-posterior radiographs should not be overestimated since they may not apply to all patient populations and to all studies using this gold standard technique. ª 26 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Key words: Osteoarthritis, Glucosamine sulfate, Radiographic measurement, Joint space width. Introduction Assessment of changes in joint space width by plain radiography is the best available surrogate marker of articular cartilage loss and it is therefore the primary outcome measure for the efficacy of possible Disease Modifying Drugs, as recommended by scientific organisations and regulatory agencies 1e4. At the level of the knee joint, and in particular of the femorotibial compartment, the gold standard radiographic protocol is the standing antero-posterior fully extended knee view, as reported in the Osteoarthritis Research *Address correspondence and reprint requests to: Professor Lucio C. Rovati, Rotta Research Laboratorium, Via Valosa di Sopra 7, 252 Monza (Milano), Italy. Tel: 39-39-739318; Fax: 39-39-739371; E-mail: lucio.rovati@rotta.com Received 26 February 26; revision accepted 26 February 26. Society guidelines published in 1996 5. However, investigations have recently suggested potential problems of this gold standard technique, mainly concerning standardisation of the knee radioanatomic position 6e8. While none of the recent semi-flexed views proposed to overcome some of the theoretical limitations of conventional standing antero-posterior films has been sufficiently validated in longitudinal studies so far 9, as also confirmed during this Workshop, several studies have been in the meantime reported that used the gold standard radiographic protocol and significantly increased our knowledge about the progression of osteoarthritis in general and of joint structure changes in particular 1e13. In this regard, we have very recently reported two prospective, 3-year, randomised, placebocontrolled clinical trials that suggested, for the first time with any therapeutic intervention, the effect of glucosamine sulfate as a Disease Modifying agent in osteoarthritis 14,15. A14
Osteoarthritis and Cartilage Vol. 14, Supplement A Designed in 1994, these two studies obviously adopted the conventional standing radiographic view. Indeed, the two trials independently observed that glucosamine sulfate was able to significantly prevent the joint space narrowing occurring in the patients receiving placebo throughout the 3 years of treatment. Interestingly, this finding has been criticised 9,16 for the potential confounding factor that might have been introduced by the other major effect detected 17, i.e., the significant improvement of symptoms in the glucosamine sulfate-treated patients compared with placebo. It has been in fact hypothesised that the concomitant reduction in joint pain seen in the glucosamine sulfate arm relative to placebo may have altered the positioning of the knee (in particular favouring a better knee full extension), resulting in a change in joint space width that might have confounded the estimate of joint space narrowing and exaggerated the differences between treatment groups 9,16,as suggested by recent experimental studies conducted on patients different than those in the glucosamine sulfate trials 18. For the purpose of this Consensus Workshop, the conventional standing antero-posterior protocol has not been further evaluated, in view of its potential limitations especially in multicenter studies (where standardisation may be a problem). However, such limitations have probably been overestimated 9,16,18 relative to the validity of previous studies and in particular of the glucosamine sulfate long-term trials. The present re-analysis of our data in these two trials 14,15 has been therefore undertaken in light of the recent criticisms and in order to finally assess whether improvement in knee pain was really a confounder in the assessment of joint space width in our study populations and whether it biased the structure-modifying effect reported for glucosamine sulfate. Methods The general methodology of the trials and patient inclusions/exclusions are described in detail in the two original study reports 14,15. In brief, patients with knee osteoarthritis 19 were randomly assigned to receive a 3-year continuous treatment with either placebo, or crystalline glucosamine sulfate (Dona, Viartril-S, Xicil, or other trademarks by the Rotta Research/Rottapharm Group, Monza, Italy) at the oral dose of 15 mg once-a-day as a soluble powder formulation, in a double-blind fashion. Radiographs were obtained at baseline and at yearly intervals according to the gold standard standing (weightbearing) antero-posterior fully extended knee view. The radiographic protocols were remarkably similar in the two studies 14,15. In particular, the focus to film distance was fixed, as well as all other radiographic parameters and settings. In addition, the posterior aspect of the knee was in contact with the X-ray cassette to avoid variation in the distance between the knee and the cassette throughout the study. Finally, fluoroscopy was used to direct the X-ray beam to the centre of the joint space, to control for joint rotation and to maintain the same degree of alignment with the tibial plateau in subsequent radiographs. In both trials, patient repositioning was guided by the baseline film and aided by foot maps in the Reginster s study and by placing the feet together in the Pavelka s study. Joint space width of the medial femorotibial compartment was assessed at the joint narrowest point by chondrometry 2. Among symptom assessment measures, the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index 21 was used throughout the studies. The visual analogue scale (VAS) version of the index (VA-3.) was used in one trial 14 and the Likert scale version (LK-3.) in the other 15 : changes relative to baseline are therefore reported here as % changes, for uniformity reasons. The aim of the present re-analysis was to assess whether improvement in knee pain in the glucosamine sulfate arms of the studies resulted in an artifactual increase in joint space width, possibly by improving the ability of knee full extension. Two different approaches were adopted to assess this hypothesis. In the first approach, patients completing the 3-year treatment course and the study evaluations were selected on the basis of a major global knee pain improvement at the end of the trial relative to baseline values, regardless of treatment with glucosamine sulfate or placebo (i.e., both drug and placebo responders). The cut-off of pain improvement was set to a decrease in the WOMAC pain subscale equal to the mean intention-to-treat improvement observed in the glucosamine sulfate groups in the two original trials 14,15. Changes in joint space width in this subset of pain-improvers were then compared by analysis of variance to see if there was still any difference between the glucosamine sulfate and placebo groups: the working hypothesis was that if major pain relief leads to artifactual increase in joint space width, no joint space narrowing should be detected in either of these patient subgroups, irrespectively of treatment with glucosamine sulfate or placebo. In the second approach, 3-year completers were selected if they had a higher chance not to be able to fully extend their knee at baseline due to severe pain while standing, and if this pain had improved by any degree at the end of the trials, again regardless of treatment. For this purpose we used the flaring knee definition described by Mazzuca et al. 18, and selected patients if they had reported at baseline that standing knee pain (i.e., item #5 of the WOMAC pain subscale) was severe or extreme, i.e., score 3 or 4 on the e4 WOMAC Likert scale adopted in the study by Pavelka et al. 15 or, by analogy, >6 mm out of 1 in the WOMAC VAS scale used by Reginster et al. 14 In addition, for patients to be selected for this subset analysis, this standing pain should have improved by at least 1 point on the Likert scale, or >2 mm on the VAS scale. Changes in joint space width were then again compared between treatment groups by analysis of variance. Results A15 A total of 212 and 22 patients (414 overall) were enrolled in the two studies, respectively, and their characteristics have already been described 14,15. Patients had knee osteoarthritis of mild-to-moderate severity, both from the point of view of symptoms and in terms of baseline joint space. There were obviously more patients (76 vs 57 in the two studies combined) in the glucosamine sulfate pain-improver subsets (drug responders) than in the placebo subsets (placebo responders) according to our first approach, but the mean (SE) baseline WOMAC pain scores were similar between treatments and only slightly higher compared to the two original full study populations, but still in the mildto-moderate severity range: 228 (16) and 236 (18) sum of VAS scores (mm) in the subsets from the Reginster s study, or 7.3 (.4) and 8. (.6) points in the Pavelka s subsets, in the glucosamine sulfate and placebo groups, respectively. Joint space width in these pain-improver subsets was also similar to that of the respective full study populations: 3.9 (5) mm in the glucosamine sulfate pooled subset and 3.94 (7) mm in the placebo subset.
A16 L. C. Rovati et al.: Assessment of joint space narrowing with antero-posterior radiographs By definition, the pain-improver subsets identified in the current re-analysis had a major decrease in 3-year WOMAC pain scores irrespectively of treatment and in both studies, that was ÿ57.2 (3.1)% with glucosamine sulfate and ÿ5.9 (3.1)% with placebo (NS) in the two studies pooled. Despite major pain relief in both treatment subsets, of similar magnitude between them, Fig. 1 shows that placebo-treated patients underwent an evident joint space narrowing that was not detected in the patients who had received glucosamine sulfate for the 3 years of the trials. Interestingly, the mean degree of joint space narrowing attained with placebo in these pain-responder subsets [Fig. 1(panels B and C)] after 3 years was in the same range of the changes observed in the two original studies, similarly to the changes observed in the glucosamine sulfate subsets 14,15. By analogy, this means that patients who did not improve their knee pain or that did not reach the stipulated cut-off for pain relief behaved in the same way (data not shown). When we considered only patients with severe or extreme standing knee pain at baseline and improving by any degree after 3 years, the sample size was further reduced in these subpopulations, that consisted of only 12e15% of the total number of patients randomised in each treatment group in the two original studies. Baseline global WOMAC pain scores were still in the same mild-tomoderate range and minimum joint space width baseline values did not differ from those previously described as well. Notwithstanding improvement in severe or extreme standing knee pain, also in this case patients receiving placebo nevertheless experienced a definite joint space narrowing that was not seen in those treated with glucosamine sulfate (Fig. 2). Discussion Re-analysis of our data from two randomised, placebo-controlled, double-blind, 3-year trials showing disease-modification with glucosamine sulfate 14,15 has clearly shown that the structure-modifying effect of the drug, detected by conventional standing antero-posterior knee radiographs, was not biased by the concomitant pain relief induced by glucosamine sulfaterelativetoplacebo.thisfindingiscontrarytowhatwas unduly postulated by recent reviews 9,16 that suspected that pain relief might have selectively improved knee extension with a consequent alteration in radioanatomic positioning, jeopardising the chance of seeing a joint space narrowing with glucosamine sulfate. Indeed, our data demonstrate, with two independent methodological approaches, that patients experiencing major knee pain relief irrespectively of treatment (i.e., drug responders or placebo responders), nevertheless underwent joint space narrowing on placebo, but not when they have been treated with glucosamine sulfate over the 3 years of the trials. Conventional standing antero-posterior radiographs have been recently criticised for their poor ability to prevent longitudinal changes in medial tibial plateau alignment 8, although none of the new nonfluoroscopic semi-flexed protocols has been shown to be definitely better in this regard 7,8 (and preliminary data presented during this Workshop indicated that indeed only semi-flexed anteroposterior fluoroscopically-assisted protocols may assure satisfactory alignment). Actually, changes in alignment may derive from failure to reproduce the degree of knee extension achieved at baseline, so that changes in the knee extension/flexion pattern may alter the distance between the centre of the joint and the X-ray cassette. Several technical measures and positioning guidelines had been adopted in the studies by Reginster et al. 14 and by Pavelka et al. 15 to avoid this possibility and included the use of fluoroscopy, that minimised the effect of medial tibial plateau alignment and assured reproducibility of the radiographs serially taken during the two trials 22. In addition, the patients enrolled in the trials had baseline disease in general, and global knee pain levels in particular, of mild-to-moderate severity and thus not preventing knee full extension on the.2 - -.2 - -.4 A) Both studies pooled (N=57, 76) P=.3 Placebo Glucosamine sulfate.4.2 - -.2 - -.4 -.5 B) Reginster et al (N=3, 35) P=.19.2 - -.2 - C) Pavelka et al (N=27, 41) P=.6 Fig. 1. Mean (SE) change in joint space width after 3 years in the global knee pain-improver subsets. Panel A reports the data pooled from both studies, while panels B and C show the data from the single studies of Reginster et al. and of Pavelka et al., respectively. N stands for the number of patients that qualified for the analysis in the placebo and glucosamine sulfate groups, respectively.
Osteoarthritis and Cartilage Vol. 14, Supplement A A17.4.2 - -.2 - -.4 -.5 -.6 A) Both studies pooled (N=26, 31) P=.14 Placebo Glucosamine sulfate.4.2 - -.2 - -.4 -.5 -.6 -.7 B) Reginster et al (N=1, 17) P=.55.5.4.2 - -.2 - -.4 -.5 C) Pavelka et al (N=16, 14) P=1 Fig. 2. Mean (SE) change in joint space width after 3 years in the subset of patients with standing knee pain (item #5 in WOMAC pain scale) at least severe at baseline and improving by any degree after 3 years. Panel A reports the data pooled from both studies, while panels B and C show the data from the single studies of Reginster et al. and of Pavelka et al., respectively. N stands for the number of patients that qualified for the analysis in the placebo and glucosamine sulfate groups, respectively. entry radiograph. The results of the present re-analysis are therefore not in contrast with those of Mazzuca et al. 18.In fact, they showed that in patients with extreme severity knee pain, joint space width artifactually increased with pain relief 18, but such severe patients are inadequate for long-term, placebo-controlled Disease Modifying Drug trials and, definitely, they did not enter the Reginster s or the Pavelka s trial 14,15. In fact, even when in the present reanalysis we selected patients with extreme standing knee pain at enrolment, their global WOMAC pain score was in any case in the mild-to-moderate severity range. This was therefore far from the extreme global knee pain severity that can be deducted from the small sample in the study by Mazzuca et al. 18. A bias in patient repositioning may therefore be operative only in patients with extreme severity global knee pain scores and not in those with mild-to-moderate severity enrolled in our long-term trials, that rather seem to be more similar to those indicated by Mazzuca et al. as nonflaring and in which pain relief did not bias the assessment of joint space width 18. The changes in joint space width we detected in the subsets of patients with major pain relief are similar to those reported for the global patient populations of the two original studies 14,15, as well as to those of the opposite subset of patients in which pain was not relieved to the same extent or worsened. This confirms that changes in knee pain did not affect radiographic joint space narrowing assessment in either way and that glucosamine sulfate protective effects on joint structure changes were independent of the drug symptomatic effect. The conventional standing antero-posterior radiographic protocol may have other inherent limitations in the assessment of joint space width, including accuracy errors in measurement due to parallax and to transmission of body weight to a region of the joint which is not involved in normal locomotion 6,7. However, none of these can affect the difference in joint space narrowing we have observed between glucosamine sulfate and placebo that can be only attributed to a difference in the loss of articular cartilage between treatments. Sensitivity to change in joint space width and precision errors are also issues that have been raised 23, whose improvement may favour detection of a difference between placebo and an active drug with a smaller sample size. However, they were not major problems in the two glucosamine sulfate trials, since the drug was able to prevent the natural (placebo) rate in joint space narrowing assessed by the radiographic technique adopted and the sample size calculated a priori proved to be large enough to detect a significant difference between treatments in both independent studies 14,15. In addition, we have now confirmed a similar joint space narrowing rate, with a similar precision, irrespectively of knee pain behaviour. In conclusion, major relief in mild-to-moderate global knee pain is not a confounder in the evaluation of joint space narrowing on standing antero-posterior knee radiographs taken in full extension. Misleading information 9,16,18 has been released in this regard relative to the validity of the structure-modifying effects of glucosamine sulfate in two recent independent long-term trials 14,15. Conversely, these structure-modification results are valid and were not biased by the concomitant symptom-modification observed with the drug, nor by any other limitations in the conventional radiographic technique adopted. While acknowledging the inherent limitations of conventional standing antero-posterior radiographic protocols, that may suggest adoption of more efficient techniques in the future, care should be taken in verifying whether real biases occurred in previous studies using such gold standard, prior to raising unjustified warnings. Consensus deliverables from this Workshop should acknowledge these data and rectify previous misleading information released on the extent of the limitations of conventional standing anteroposterior radiographs and on the validity of the glucosamine sulfate long-term trials.
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