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• Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al. (2022)
  Jessica Stanhope, Amy Salter and Philip Weinstein
  Published on: 14 July 2022
• Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al.
  Yang Li, Yiying Mai, Changhai Ding and Zhaohua Zhu
  Published on: 22 April 2022

• Published on: 14 July 2022

  Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al. (2022)

  • Jessica Stanhope, Lecturer in Physiotherapy The University of Adelaide
  • Other Contributors:
    • Amy Salter, Associate Professor in Biostatistics
    • Philip Weinstein, Professorial Research Fellow in Public Health

  Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.

  Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studi...

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  Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.

  Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studies of knee OA.[3] Bandak et al.’s[1] use of saline intra-articular injections as a placebo intervention was inappropriate.
  Although Bandak et al.[1] argued that by using an open-label placebo they controlled for the placebo effect, this is not the case. In addition to the abovementioned concerns regarding the real therapeutic effect of a saline intra-articular injection, by design the placebo intervention would have been perceived as different by participants who would be aware of the two treatments by the provision of their informed consent. Furthermore, researchers told participants that saline injections were “inert, yet with potential beneficial effects that may compare to those of exercise and education”, and that “investigators had no treatment preference”[1] in an attempt to make the placebo effect comparable. These statements may have negatively influenced the patient-reported outcomes for those in the education and exercise intervention group, as the researchers implied they anticipated no real effect. As a result, the open-label placebo has not controlled for the placebo effect, as implied by the authors.

  The findings of Bandak et al.’s[1] study must be considered with caution, and we should not be swayed by the inappropriate use of the term ‘placebo’. Placebo-controlled trials are often considered the ‘gold standard’ when the aim is to compare an intervention with no intervention. However, if the chosen ‘placebo intervention’ does not meet the necessary criteria for a placebo, such studies provide misleading evidence that could lead to inappropriate management recommendations for knee OA, including negative perceptions about the value of education and exercise programs.

  Bandak et al.[1] concluded that the pain and function results were equivalent between their treatment and placebo groups, stating that their “findings raise important questions about … the continued widespread recommendation of exercise and education in the management of knee OA.” We do not find their conclusion valid. Instead of aiming for (potentially invalid) placebo controls, we should be making meaningful comparisons that can guide therapy: for instance, studies that compare different education and exercise programs, compare such programs with treatment as usual or in addition to treatment as usual, would more directly inform positive case management.
   
  References
  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(4):537-43. doi: 10.1136/annrheumdis-2021-221129
  2. Fitzgerald GK, Hinman RS, Zeni Jr J, et al. OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of rehabilitation interventions for osteoarthritis. Osteoarthritis Cartilage 2015;23(5):803-14. doi: 10.1016/j.joca.2015.03.013
  3. Fazeli MS, McIntyre L, Huang Y, et al. Intra-articular placebo effect in the treatment of knee osteoarthritis: a survey of the current clinical evidence. Ther Adv Musculoskelet Dis 2022;14: 1759720X211066689. doi: 10.1177/1759720X211066689

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  Conflict of Interest:
  None declared.

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• Published on: 22 April 2022

  Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al.

  • Yang Li, postgraduate student Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
  • Other Contributors:
    • Yiying Mai, postgraduate student
    • Changhai Ding, professor
    • Zhaohua Zhu, principal investigator

  Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al.

  Yang Li1, MD; Yiying Mai1, MD; Changhai Ding1, Prof; Zhaohua Zhu1,2, PhD

  Author Affiliations:
  1. Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, 510280
  2. Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, 510280

  Corresponding Author: Zhaohua Zhu, PhD. Clinical Research Centre, Zhujiang Hospital, Southern Medical University. No.253 Industrial Avenue, Haizhu District, Guangzhou, Guangdong Province, China, 510280 (Email: zhaohua.zhu@utas.edu.au).

  Word count: 415

  We read with great interest the article by Bandak et al 1. The authors conducted an open-label, single centre randomised controlled trial involving 206 knee osteoarthritis (OA) patients in an attempt to discriminate the effect of exercise and education from a placebo control on joint symptoms. They reported that an 8-week exercise and education programme provided equivalent efficacies for improving OA symptoms and function to 4 intra-articular saline injections over 8 weeks. The findings question the recommendation of exercise and education as OA symptoms management strategies. However, we believe the effect of exercise and education cannot be negated, as some p...

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  Correspondence on ‘Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial’ by Bandak et al.

  Yang Li1, MD; Yiying Mai1, MD; Changhai Ding1, Prof; Zhaohua Zhu1,2, PhD

  Author Affiliations:
  1. Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, 510280
  2. Department of Joint and Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China, 510280

  Corresponding Author: Zhaohua Zhu, PhD. Clinical Research Centre, Zhujiang Hospital, Southern Medical University. No.253 Industrial Avenue, Haizhu District, Guangzhou, Guangdong Province, China, 510280 (Email: zhaohua.zhu@utas.edu.au).

  Word count: 415

  We read with great interest the article by Bandak et al 1. The authors conducted an open-label, single centre randomised controlled trial involving 206 knee osteoarthritis (OA) patients in an attempt to discriminate the effect of exercise and education from a placebo control on joint symptoms. They reported that an 8-week exercise and education programme provided equivalent efficacies for improving OA symptoms and function to 4 intra-articular saline injections over 8 weeks. The findings question the recommendation of exercise and education as OA symptoms management strategies. However, we believe the effect of exercise and education cannot be negated, as some points of this article require further discussion.

  First, for delivering placebo treatment, the use of intra-articular injection, a procedure that can increase pain-relieving effect of inert substance 2, may have leaded to significant unbalanced potential placebo responses in two groups. Even if an open-label design could diminish the contextual effects, as described by the authors, it is still difficult to conclude the isolated effect of exercise and education with new biases arising from the discrepancies between the two arms (e.g., varying contact time with clinicians). A significant favour to the exercise and education group in participants’ global assessment outcome in Table 2 is a hint of poor comparability. Therefore, using a low intensity exercise or an attention control, which shares similar procedure with exercise and education, may be a better placebo control design 3,4.

  Second, an 8-week exercise and education programme may be too short to observe the significant effects as most previous trials examining the effect of excise and education intervention for OA have reported long-lasting and significantly superior effect over non-surgical interventions for at least 16 weeks 5.

  Third, the efficacy of exercise for OA can be affected by various factors, especially comorbid diseases 6. We notice that 24.5% participants in the intervention group and 29.8% in the control group were obese (BMI ≥ 30), who were likely to suffer from cardiovascular and metabolic disorders at the same time. It is reasonable to assume that different subgroups of participants would react differently to exercise and education intervention. Thus, more details of demographic characteristics and subgroup analysis should be provided.

  Finally, it is worth presenting the results of both within and between groups differences for the primary and secondary outcomes, as they would give additional information for a more comprehensive conclusion.

  To sum up, we believe that the effect of exercise and education in OA management would be confirmed by better-designed randomised controlled trials.

  Ethics statements: Not required.

  Patient consent of publication: Not required.

  Conflict of Interest Disclosure: None reported.

  Contributors: YL, YM and ZZ draft this correspondence. CD and ZZ were involved in revising and editing the correspondence.

  Funding: The present study was supported by the National Natural Science Foundation of China (32000925).

  Patient and public involvement: Patients and/or public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  Provenance and peer review: Not commissioned; internally peer reviewed.

  References

  1. Bandak E, Christensen R, Overgaard A, et al. Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial. Annals of the Rheumatic Diseases 2022;81:537-543.
  2. Zhang W, Robertson J, Jones AC, et al. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008;67(12):1716-1723.
  3. Messier SP, Mihalko SL, Beavers DP, et al. Effect of high-intensity strength training on knee pain and knee joint compressive forces amoung adults with knee osteoarthritis: the START randomized clinical trial. JAMA. 2021;325(7):646-657.
  4. Henriksen M, Klokker L, Graven-Nielsen T, et al. Association of exercise therapy and reduction of pain sensitivity in patients with knee osteoarthritis: a randomized controlled trial. Arthritis Care Res (Hoboken). 2014;66(12):1836-1843.
  5. Kechichian A, Lafrance S, Matifat E, et al. Multimodal interventions including rehabilitation exercise for older adults with chronic musculoskeletal pain: a systematic review and meta-analyses of randomized controlled trials. J Geriatr Phys Ther. 2022;45(1):34-49.
  6. de Rooij M, Steultjens MPM, Avezaat E, et al. Restrictions and contraindications for exercise therapy in patients with hip and knee osteoarthritis and comorbidity. Phys Ther Rev 2013;18:101-11.

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  Conflict of Interest:
  None declared.

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