| July, 2006 - CRA Journal Club Review by Dr. LORI ALBERT | Preliminary Evidence for a Structural Benefit of the New Bisphosphonate Zoledronic Acid in Early Rheumatoid Arthritis
Jarrett SJ et al. Arthritis and Rheumatism, Vol 54, No. 5, May 2006 pp1410-1414.
Lori Albert
M.D., FRCPC |
Editorial:
By Dr. Lori Albert
There is evidence from both animal models and human studies that osteoclasts play an important role in the development of erosions and bone damage in rheumatoid arthritis. Bisphosphonates, which are commonly used to manage osteoporosis, have been shown in animal models to reduce the development of erosions. However, support from human studies is lacking. Thus, this study was undertaken to test the hypothesis that zoledronic acid, a potent third-generation aminobisphosphonate (thought to act by inhibiting the osteoclast lifespan), would prevent the development of new bone erosions, detected by MRI, in patients with early RA.
| In this industry sponsored, double-blind randomized, placebo-controlled trial, patients with RA of less than two years’ duration were given an intravenous infusion of either 5 mg of zoledronic acid (ZOL)or placebo along with methotrexate (range of 7.5-20mg/week).The primary efficacy variable was the change from baseline in the number of MRI erosions, evaluated at week 26, with the predefined primary outcome being a >50% reduction in the number of new erosions.
In this small study of 39 patients, the baseline characteristics of the two treatment groups were fairly comparable, although those in the ZOL group had more severe disease at baseline. Mean dosage of MTX at baseline and at study completion was comparable between the two groups. However, concomitant intraarticular/intramuscular corticosteroid (allowed after randomization) was reported by 72% of patients in the ZOL group vs 43% of patients in the placebo group.
At week 26, the mean +/- SD change from baseline in the number of hand and wrist MRI erosions was 61% lower in the ZOL group compared with placebo. However, the confidence intervals were large and this did not reach statistical significance. The mean increase in the number of eroded sites was significantly less in the ZOL group vs placebo group. The mean increase in the number of newly eroded joints/bones (i.e. erosion-free at baseline) was lower in the ZOL group but did not quite reach significance. There was no significant difference between groups in the development of new bone edema (a precursor of erosions), although the trend favoured the ZOL group. There was no difference in the mean change in the number of erosions seen on plain radiographs.
With regard to secondary efficacy measures, there was a significant increase from baseline in the mean percent change in bone mineral density at all sites for the ZOL group. There was a significant decrease in the mean levels of bone biomarkers (both for bone resorption and bone formation). As well, the mean improvement in patient’s global assessment of disease activity was greater for the ZOL group compared with placebo and was maintained throughout the study. The physician’s global assessment favoured patients in the ZOL group at week 13, but this was not sustained through week 26. No statistically significant differences were observed for the number of tender and swollen joints or the CRP level. The medication was tolerated well, although 3 patients did experience an influenza-like syndrome with ZOL.
Unfortunately, this small study failed to show a statistically significant reduction in number of erosions with use of a potent bisphosphonate. However, there were some interesting trends observed, which lend support to the concept that inhibition of the osteoclast may mitigate development of erosions in RA. Not surprisingly, there were no differences seen in clinical synovitis, as bisphosphonates are not thought to act as anti-inflammatory agents. However, the improvement observed in the patient global assessment of disease activity warrants further exploration. It might be important to dissect out the role played by corticosteroid (which saw greater use in the ZOL group than in the placebo group) in both MRI and clinical outcomes.
The role of this well-tolerated drug in the management of RA clearly warrants further study, and it will be important to learn whether true benefits, if observed, are seen only with ZOL, or whether they are class effects of bisphosphonates (thus allowing for substitution of less expensive agents).
For an interesting review of the role of the osteoclast in RA and the complex interactions with immune cells, see Sato, K and Takayanagi, H. Osteoclasts, rheumatoid arthritis and osteoimmunology.Curr Opin Rheumatol ,18:419-426,2006.
Learning Objectives:
Appreciate a possible role for bisphosphonates in modifying the development of damage in patients being treated for rheumatoid arthritis
ABSTRACT
Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis.
Jarrett SJ, Conaghan PG, Sloan VS, Papanastasiou P, Ortmann CE, O'Connor PJ, Grainger AJ, Emery P.
University of Leeds, Leeds, UK.
OBJECTIVE: Bisphosphonates inhibit osteoclast activity, which is central to the development of bone damage in rheumatoid arthritis (RA). The aim of this study was to assess whether treatment with zoledronic acid, compared with placebo, could achieve a > or = 50% reduction in the development of new erosions on magnetic resonance imaging (MRI) in patients with early RA.
METHODS: In this proof-of-concept study, 39 patients with early RA and clinical synovitis of the hand/wrist were randomized to receive infusions with either zoledronic acid (5 mg) or placebo, administered at baseline and week 13. Patients in both groups received methotrexate (MTX) at a dosage of 7.5-20 mg/week. MRI and plain radiography were performed at baseline and week 26.
RESULTS: At week 26, the mean +/- SD change in MRI hand and wrist erosions was 61% lower in the zoledronic acid group compared with the placebo group (0.9 +/- 1.63 versus 2.3 +/- 3.09; P = 0.176). The mean +/- SD increase in the number of hand and wrist bones with erosions was 0.3 +/- 0.75 for zoledronic acid compared with 1.4 +/- 1.77 for placebo (P = 0.029). The proportion of patients in whom new MRI-visualized bone edema developed was smaller in the zoledronic acid group compared with the placebo group (33% versus 58%; P = 0.121). The zoledronic acid group had a mean change in the number of radiographic erosions of 0.1 compared with 0.5 for the placebo group (P = 0.677). The safety profile of zoledronic acid was similar to that of placebo.
CONCLUSION: The results of this study suggest a structural benefit associated with zoledronic acid therapy in patients with RA, as demonstrated by consistent results in structural end points in favor of zoledronic acid plus MTX compared with MTX alone.
PMID: 16645968 [PubMed - in process]
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CRA Forum : Review by Dr. LORI ALBERT - July
Topic: Review by Dr. LORI ALBERT
