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We read with great interest the recently published study ‘Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial’ by Takeuchi et al.1 This trial has shown a beneficial effect of denosumab in reducing radiographic progression (modified total Sharp score) and erosions in patients of rheumatoid arthritis (RA), in two dosing regimens, that is, 60 mg subcutaneous 6 monthly and 3 monthly.
However, there are some concerns. While there has been a significant reduction in erosion score over 12 months, the above study failed to demonstrate any beneficial effect of denosumab on joint space narrowing.1 Radiographic scores are surrogates for reflecting disability and functional limitation, and thus any reduction in these is the gold-standard for ‘disease-modification’ in RA. But, it is the joint space narrowing which is a better predictor of function than erosions.2 In that regard, it is notable that there was no improvement in function per se measured by health assessment questionnaire - disabaility index (HAQ-DI) in this study. Also, at the end of 12 months of therapy, no difference was seen in ACR20/50/70 response. Thus, the benefit in erosions may not translate into clinically meaningful improvement.
Denosumab is proven to have a beneficial effect on RA-associated osteoporosis.3 This effect was also evident on lumbar spine bone mineral density in ‘DESIRABLE’ trial.1 However, denosumab has been associated with rebound osteoporosis and increased risk of multiple fractures after withdrawal when used in osteoporosis.4 Whether a similar effect would also occur on erosions remains to be seen.
Finally, patients with RA are at a 10% increased risk for development of malignancies than the general population.5 A previous study found that malignancies in patients treated with denosumab were higher, though were not statistically significant.6 In the ‘DESIRABLE’ study, three patients in the denosumab groups developed malignancies and two developed interstitial lung disease.1 Though there was no statistically significant difference between the treatment and placebo groups, the study was not adequately powered to study adverse effects. A longer follow-up is needed to ensure the safety of denosumab.
To conclude, in the absence of clinical improvement and lack of long-term safety data, it would be still early to consider denosumab for a non-osteoporotic indication, such as reducing RA erosion scores.
Handling editor Josef S Smolen
Contributors NA, AC and VD: are responsible for conceptualisation, drafting and revising, final approval and are accountable for the work
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.