PADUA, Italy—A study that randomized 150 knee osteoarthritis (OA) patients to intra-articular (I-A) hyaluronic acid injections or to I-A injections of 0.5mg-2mg of clodronate concluded that clodronate was “at least as good” as hyaluronic acid, but the study design did not enable researchers to rule out the possibility that results with either drug were basically just placebo responses.¹

Maurizio Rossini, MD, and colleagues report in Rheumatology the results of a phase 2 randomized “partially blind” clinical trial that randomized knee OA patients aged 50-75 years to one of 5 arms: 1 injection of 0.5 mg clodronate/week for 4 weeks, 1 injection of 1.0 mg clodronate/week for 4 weeks, 1 injection of 2 mg clodronate/week for 4 weeks, 2 injections of 0.1 mg clodronate/week for 4 weeks, or 1 injection of 20 mg HA/week for 4 weeks.

The researchers found no significant differences in visual analogue scores (VAS) for different types of pain or in the Lequesne index, all of which improved in all groups of subjects. Joint extension and mobility scores improved similarly at all time points in all groups. Dr. Rossini reported that “non-significant differences were detected among the four clodronate treatment regimens, even though a significant dose-response relationship for the three doses of clodronate was found for active movement pain and a trend for extension and mobility scores and paracetamol consumption.”

The researchers, who are in the Rheumatology Unit at the University of Verona in Padua, Italy, concluded, “This study indicates that IA clodronate provides symptomatic and functional improvements at least as good as those obtained with HA.”

Is this a placebo response?

Just how good those improvements are is open to question, however.

Eric Matteson, MD, Chair of Rheumatology at the Mayo Clinic in Rochester, MN, told Musculoskeletal Report that the key problem with this study is that there was no placebo control.

“The lack of a dose effect means either that the lowest dose works as well as the highest, or that the drug might not be better than placebo,” Dr. Matteson said. “There is among experts considerable controversy about whether HA really works better than placebo, especially in terms of long term benefit, or whether it works better than conventional glucocorticosteroid treatment. In my view, this study would have been much stronger with a placebo arm, and further studies should have a placebo arm.”

Hard to do placebo control for HA studies

Dr. Rossini tackled that problem head-on in the discussion.

“To what extent these results might be related to the well-recognized placebo response after aspiration of the knee remains unclear. Such a placebo effect is still advocated for HA, since in randomized placebo-controlled trials ensuring adequate blinding during the study is considered impossible due to the high viscosity of the hyaloronan solutions, which makes the drug easily recognizable,” Dr. Rossini wrote. “Recent reviews, guidelines and meta-analysis consistently attribute an appreciable therapeutic effect to HA. These position papers made and are still making a placebo arm for IA injections ethically unacceptable, despite the clinically minimal effect of HA as compared to placebo....[I]f we agree that HA is an effective treatment for KOA, they this study provides strong evidence that clodronate should be considered as a new agent with an extraordinary potential for management of KOA.”

Reference

1. Rossini M, Viapiana O, Ramonda R, et al. Intra-articular clodronate for the treatment of knee osteoarthritis: dose ranging study vs hyaluronic acid. Rheumatology 2009;48:773-778.