Bisphosphonates are well-established in the management of osteoporosis. These drugs retard bone resorption by targeting osteoclast cells. They encourage osteoclast apoptosis, a type of cell self-destruction. But bisphosphonates have been indulging in a bit of mission creep as they have been demonstrated to have analgesic properties. It is thought that inhibition of osteoclast proton secretion may create a less acidic tissue environment, and made lead to less sensitization of nociceptors in subchondral bone. As we blogged recently, our own Cochrane overview concluded that there is low quality evidence in favour of the efficacy of these drugs for treating pain in CRPS.
A new exploratory trial just published in Pain has investigated the efficacy of a bisphosphonate for treating chronic low back pain. This small pilot trial recruited patients with an average pain score of 4/10 or more and with MRI evidence of lumbar degenerative disk or spondylitic disease and randomly allocated them to receive one of 4 doses of intravenous pamidronate, or placebo. Groups 1, 2 and 3 received either 30, 60 or 80mg or placebo and group 4 received 180mg or placebo. This higher dose was delivered via 2 separate 90mg infusions 4 weeks apart. Participants were followed up for 6 months. It is worth taking a moment to reflect on how small and exploratory the trial was. 44 participants were randomly allocated to 4 groups (11 per group) and then within each group randomised to receive pamidronate infusion or placebo (7 got the drug, 4 got placebo in each group).
So what of the results? The authors report essentially no effect on pain above placebo at the 30, 60 and 90mg doses. However the 180mg group are reported to demonstrate statistically significant improvements in pain over both placebo and the other doses. How big are these improvements? From the study report the improvement is a meaty looking reduction from baseline in average daily pain of 4.13/10 (95%CI 2.85 to 5.4). That looks sizeable against a baseline level of pain of around 6. But within-group change from baseline is not really the comparison of interest. That change will not only reflect the active effect of bisphosphonates but also the natural course of the symptoms, placebo effects and regression to the mean. What we are really interested in is the effect size of the between group comparison after treatment between this group and placebo. That is not directly presented in the paper (something that’s rather common) though is clearly somewhat smaller since the placebo group improved by 1.53 points and the lower dose groups by a similar amount. A responder analysis, looking at the proportion of participants in each group who reported at least a 50% reduction in pain appears very positive. From the time-point of the second infusion through to the 6 month follow up, the 180mg group showed a 100% responder rate, compared with between 20 and 60% for the other doses and placebo at different time-points. Adverse events were transient and not serious in this group.
There are a number reasons to strike a note of caution. Only 7 participants received pamidronate in the 180mg group and of these one withdrew their consent. In the placebo groups 7 (out of a total 16) participants withdrew. The authors report applying an intention to treat analysis to account for drop-out (nominally a good thing) but it is not made clear how missing patient data was included. With such small numbers the method used to impute missing data might feasibly have a very important impact on the outcome. Then the secondary outcomes of disability and quality of life showed no between-group differences. As the group with the best results received 2 infusions on separate days, it is possible that multiple interventions might beef up any placebo response. Finally we know that smaller trials have a tendency to produce inflated effects for a number of reasons and are inherently unreliable.
This trial represents a first toe dipped in the water for this drug in this condition. There are positive signs here for bisphosphonates but also, as the authors themselves clearly acknowledge in the discussion, good reasons to hang back from celebration just yet. We now need bigger trials, focused on the promising high dose, to answer a number of questions. Was this positive result real? Are the effects of pamidronate really that large? Will these results replicate in a more broadly selected group? Is improvement in pain reflected in changes in disability and quality of life (and if not why not?), and what are the risks?
Neil O’Connell
As well as writing for Body in Mind, Dr Neil O’Connell, (PhD, not MD) is a researcher in the Centre for Research in Rehabilitation, Brunel University, West London, UK. He divides his time between research and training new physiotherapists and previously worked extensively as a musculoskeletal physiotherapist.
He also tweets! @NeilOConnell
Neil’s main research interests are chronic low back pain and chronic pain more broadly with a focus on evidence based practice. He has conducted numerous systematic reviews including some for the Cochrane Collaboration. He also makes a mean Yorkshire pudding despite being a child of Essex.
Link to Neil’s published research here. Downloadable PDFs here.
Reference
Pappagallo M, Breuer B, Lin HM, Moberly JB, Tai J, Noto C, Sanchez A, & Manfredi PL (2013). A pilot trial of intravenous pamidronate for chronic low back pain. Pain PMID: 24060707