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Response to: ‘Effectiveness of low-dose radiation therapy on symptoms in patients with knee osteoarthritis’ by Wu et al
  1. Elien A M Mahler1,
  2. Michiel J M Minten1,
  3. Mathilde M Leseman-Hoogenboom2,
  4. Philip M P Poortmans2,3,
  5. Jan Willem H Leer2,
  6. Simone S Boks4,
  7. Frank H J van den Hoogen5,
  8. Alfons A den Broeder1,
  9. Cornelia HM van den Ende1
  1. 1 Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands
  2. 2 Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
  3. 3 Department of Radiation Oncology, Institut Curie, Paris, France
  4. 4 Department of Radiology, Sint Maartenskliniek, Nijmegen, The Netherlands
  5. 5 Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
  1. Correspondence to Elien A M Mahler, Department of Rheumatology, Sint Maartenskliniek, Nijmegen 6500 GM, The Netherlands; e.mahler{at}

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We thank Wu et al for their interest in and encouragement of our randomised studies in which we found no substantial beneficial effect on symptoms and inflammatory signs of low-dose radiation therapy (LDRT) in patients with knee and hand osteoarthritis (OA).1–3 The authors emphasise that our results inevitably force involved clinicians to re-examine the true effectiveness of LDRT on OA in real-world clinical practice. However, they addressed two constructive concerns related to our work, to which we will reply hereby.

The first point addresses the heterogeneity of the participants reflecting a real-world population, that is, patients with clinical diagnosis of knee OA after failure of conservative treatment options. Wu et al suggest that randomisation stratified by an objective measure for severity of knee OA (eg, K&L scores) might be preferable to the numeric rating scale for pain to stratify patients. We do not agree on this point because we hypothesised that LDRT would primarily improve clinically relevant OA symptoms including pain and disfunctioning. Accordingly, the primary outcome was the proportion of the OMERACT-OARSI responders, including pain, function and patient global assessment. To prevent bias due to an unbalanced randomisation of a very severe pain score, stratification was performed for pain intensity. Of note, the proportion of patients with K&L score ≥2 in the LDRT and sham group was comparable between groups (LDRT group: 56%; sham group: 61%) as were radiographic scores for joint space narrowing and osteophytes. Additional analyses adjusting for these different kinds of radiographic scores did not modify our results. In conclusion, stratification for pain intensity is in line with the aim of our study to evaluate the effect on symptoms in patients with knee (and hand) OA.

The second concern risen relates to the potential confounding effect of use of analgesics and the ability to perform daily physical activities. We agree that a possible influence of those potential confounders cannot be ruled out due to a potential unbalanced randomisation of these variables considering the limited sample size. However, we think the influence of those two potential confounders is limited. First, analgesic use was allowed, but patients were encouraged not to change it during the study period. Absolute numbers of participants using analgesics at baseline and at all follow-up moments were very low, that is, 36% at baseline and 35% at 3 months did use paracetamol a few days a week or almost daily; for non-steroidal anti-inflammatory drugs this was 20% at baseline and 11% at 3 months, and for tramadol 2% versus 2%, respectively. In addition, these proportions were comparable between the LDRT and sham groups at all time points. Moreover, with regard to daily physical activities as potential confounder in evaluating the relationship between LDRT/sham treatment and symptoms, we argue that we assessed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscale physical function that assesses a diversity of important activities of daily living. At baseline, we did not find an imbalance in this measure between groups. Moreover, sensitivity analysis taking into account the baseline WOMAC subscale physical function as potential confounder yielded similar results. In summary, we think that our conclusion is valid and we do not have any reasons to assume that differences between groups in use of analgesics and physical activities jeopardise the results. However, we agree with the conclusion of the authors that future research with replication of our studies is desirable.

It is disappointing that the 2018 update of the German recommendations for LDRT for benign conditions (DEGRO) continues to advise LDRT for patients with knee OA after failure of non-surgical options and without indication for knee replacement. These criteria mirror the eligibility criteria of our randomised controlled trial. Notwithstanding this, the authors of the guidelines question the validity of our results considering that about half of the patients had duration of symptoms ≤5 years. Sensitivity analysis taking into account the duration of symptoms as potential confounder yielded similar results. Remarkably, by refuting the high-level evidence of absence of clinically significant effect of LDRT on OA from our trials and our previous systematic review,2–5 the authors of the DEGRO recommendation reverse the burden of proof as they base their recommendation on studies of lower quality, that is, the results of methodologically weaker studies (uncontrolled, retrospective design) and a survey among centres for radiation therapy in Germany. This illustrates that significant efforts are needed to change current beliefs of both patients and involved clinicians into accepting scientific evidence and subsequently to deimplement the use of LDRT for knee and hand OA.


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  • Handling editor Josef S Smolen

  • Contributors The authors declare the following contributions to the preparation of the response: drafting of the manuscript (EAMM, MLMM, CHvdE); critical revision of the manuscript for important intellectual content (all authors); final approval of the manuscript (all authors). All authors take responsibility for the integrity of the work and agreed to submit the response for publication.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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