Inspired by Bandak et al 2022.
IA – intra-articularkey to acronyms
OA – osteoarthritis
OAK – OA knee
GLA:D – Good Life with osteoArthritis in Denmark
US – ultrasound
KOOS – Knee injury and Osteoarthritis Outcome Score
SMD – standardised mean difference (a measure of effect size used in meta-analyses)
EA – electroacupuncture
MCID – minimum clinically important difference
I am very grateful to a young man from Inverness (Henry) who showed me the abstract of this paper on a course recently. I was getting side-tracked and animated about NICE recommendations and the differing levels of evidence that support them – particularly when comparing exercise and acupuncture. He thought I might be interested by the paper, and I certainly am.
I’m still getting over the shock of finding out that this trial got funded in the first place since what is perceived by some to be the open-label placebo is not entirely risk free. I am referring here to intra-articular saline injections every 2 weeks for 8 weeks. These were compared in a two-arm open RCT with an 8-week programme of group education and supervised exercise following the GLA:D protocol. This programme consisted of two 1.5-hour education sessions and twelve 1-hour supervised group exercise sessions over an 8-week period. The injection group received US-guided injection of 5 ml saline every 2 weeks.
206 adults aged 50 or over with symptomatic and radiologically confirmed OAK were randomly assigned to each group, and the primary outcome was the change from baseline to week 9 in KOOS.
I had not come across KOOS before, and the sound of saying it makes me think of my veterinary surgeon colleague Sam talking about her experiences in large animal practice in Scotland when she was a newly qualified vet. I looked up the original paper describing KOOS and was amused to find that the first two authors were both Roos, giving us Roos, Roos and KOOS. Sam would chuckle at that one, but then a recent paper studying the effects of GLA:D also included hip OA as well as knee OA and had the same first author… giving us the wonderful combination of Roos, KOOS and HOOS.
Getting back to the paper at hand, the results demonstrated equivalence of the GLA:D programme with the 2 weekly US-guided saline injections.
Bandak et al comment:
These findings raise important questions about mechanisms of action as well as the continued widespread recommendation of exercise and education in the management of knee OA.
It is somewhat ironic that I have just seen the latest draft NICE guideline on osteoarthritis and sure enough exercise is at the top of the list.
Bandak et al also refer to ‘inert’ intra-articular saline injections. But what is the evidence that IA saline is inert? In 2016, Altman et al performed a meta-analysis of trials including IA saline to examine the effect size of this control intervention in knee OA pain. Of 40 studies included, 32 with 1709 patients gave a pain reduction of 0.68 (SMD) associated with IA saline in the short-term, and 19 trials with 1445 patients gave a pain reduction of 0.61 (SMD) in the long-term. Those effect sizes would be big enough to interest NICE if they were measured against a placebo of course. What placebo should we use to test IA saline? I guess we need to know how it works. Is it the saline, the needling, or the context that has the main effect? You can probably guess what I think.
The authors of the editorial that accompanied this paper in Annals of the Rheumatic Diseases, clearly are advocates of exercise and education. They argue that in this open trial the placebo effects of the interventions may be different and thus we cannot estimate the specific effect of GLA:D. That is true, but it does rather suggest that the effect is small. For comparison, the effect size for my favoured treatment, EA to muscle points around the knee, against sham EA, is 1.21 to 2.27 (see Figure 3 from Vickers et al 2018).
The Cochrane review of exercise for knee OA estimates a pain reduction of 0.49 (SMD) immediately after the end of the exercise program, which dropped to 0.24 (SMD) at 2 to 6 months. Note that the comparison here is no exercise.
The equivalent figure for IA corticosteroid is 0.40 (SMD) dropping to 0.22 at 13 weeks, but this is in comparison to IA saline. Of course I am not really advocating steroid, since we know that it is not good for the cartilage in the long-term (see the previous blog: Why not needles for OA – no steroid, just the needles!)
Now I probably sound as if I am against exercise at this point, but no, my issue is simply the double standard in terms of evidence. Exercise is consistently recommended by NICE with effect sizes over no exercise that are below the MCID applied to acupuncture over sham. I have note the same thing for back pain here.
Exercise does have consistent small effects over no exercise, and we probably don’t need more trials on this, and the good news is that, unlike corticosteroid, it does not seem to degrade cartilage or increase inflammatory markers (IA corticosteroid degrades cartilage but does not, of course, increase inflammatory markers).[11,12]
In the long-term (~1 year) the effect of physical therapy has been shown to outperform that of a single IA glucocorticoid injection, but given that IA steroid is no better than IA saline in the long-term, and probably degrades the joint faster, it is not so impressive to modestly outperform an intervention with potentially deleterious effects at this time point.
Finally, I have to comment that I have some patients coming to me for EA for their knees so that they can do the exercises they have been prescribed! If they do not get the EA, the exercise causes their knees to swell up and become more painful.
1 Bandak E, Christensen R, Overgaard A, et al. Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial. Ann Rheum Dis 2022;81:537–43. doi:10.1136/annrheumdis-2021-221129
2 Roos EM, Roos HP, Lohmander LS, et al. Knee Injury and Osteoarthritis Outcome Score (KOOS)–development of a self-administered outcome measure. J Orthop Sports Phys Ther 1998;28:88–96. doi:10.2519/jospt.19220.127.116.11
3 Roos EM, Grønne DT, Skou ST, et al. Immediate outcomes following the GLA:D® program in Denmark, Canada and Australia. A longitudinal analysis including 28,370 patients with symptomatic knee or hip osteoarthritis. Osteoarthritis Cartilage 2021;29:502–6. doi:10.1016/j.joca.2020.12.024
4 Altman RD, Devji T, Bhandari M, et al. Clinical benefit of intra-articular saline as a comparator in clinical trials of knee osteoarthritis treatments: A systematic review and meta-analysis of randomized trials. Semin Arthritis Rheum 2016;46:151–9. doi:10.1016/j.semarthrit.2016.04.003
5 Kloppenburg M, Rannou F, Berenbaum F. What evidence is needed to demonstrate the beneficial effects of exercise for osteoarthritis? Ann Rheum Dis 2022;81:451–3. doi:10.1136/annrheumdis-2021-221685
6 Vickers AJ, Vertosick EA, Lewith G, et al. Acupuncture for Chronic Pain: Update of an Individual Patient Data Meta-Analysis. J Pain 2018;19:455–74. doi:10.1016/j.jpain.2017.11.005
7 Fransen M, McConnell S, Harmer AR, et al. Exercise for osteoarthritis of the knee. Cochrane Database Syst Rev 2015;1. doi:10.1002/14651858.CD004376.pub3
8 Jüni P, Hari R, Rutjes AWS, et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev 2015;:CD005328. doi:10.1002/14651858.CD005328.pub3
9 Goh S-L, Persson MSM, Stocks J, et al. Efficacy and potential determinants of exercise therapy in knee and hip osteoarthritis: A systematic review and meta-analysis. Ann Phys Rehabil Med 2019;62:356–65. doi:10.1016/j.rehab.2019.04.006
10 Verhagen AP, Ferreira M, Reijneveld-van de Vendel E a. E, et al. Do we need another trial on exercise in patients with knee osteoarthritis?: No new trials on exercise in knee OA. Osteoarthritis Cartilage 2019;27:1266–9. doi:10.1016/j.joca.2019.04.020
11 Bricca A, Juhl CB, Steultjens M, et al. Impact of exercise on articular cartilage in people at risk of, or with established, knee osteoarthritis: a systematic review of randomised controlled trials. Br J Sports Med 2019;53:940–7. doi:10.1136/bjsports-2017-098661
12 Bricca A, Struglics A, Larsson S, et al. Impact of Exercise Therapy on Molecular Biomarkers Related to Cartilage and Inflammation in Individuals at Risk of, or With Established, Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Arthritis Care Res 2019;71:1504–15. doi:10.1002/acr.23786
13 Deyle GD, Allen CS, Allison SC, et al. Physical Therapy versus Glucocorticoid Injection for Osteoarthritis of the Knee. N Engl J Med 2020;382:1420–9. doi:10.1056/NEJMoa1905877
14 Ayub S, Kaur J, Hui M, et al. Efficacy and safety of multiple intra-articular corticosteroid injections for osteoarthritis-a systematic review and meta-analysis of randomized controlled trials and observational studies. Rheumatology 2021;60:1629–39. doi:10.1093/rheumatology/keaa808
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