OP0002 FIRST EVIDENCE OF STRUCTURAL BENEFIT FROM A BISPHOSPHONATE, ZOLEDRONIC ACID, IN RHEUMATOID ARTHRITIS (RA)
S. Jarrett, P. O'Connor, P. Conaghan, V. Sloan, P. Papanastasiou, A. Grainger, C. Ortmann, P. Emery

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Fri0053 PROFOUND EFFECT OF ZOLEDRONIC ACID ON BONE MINERAL DENSITY IN RHEUMATOID ARTHRITIS
S. Jarrett, P. Conaghan, P. Papanastasiou, V. Sloan, B. Rees-Evans, S. Stewart, P. Mesenbrink, P. Richardson, P. Emery

Activated osteoclasts (OCs) are responsible for bone erosions in RA, and bisphosphonates inhibit OCs. Jarrett et al conducted a 6 month, proof-of-concept, placebo-controlled trial investigating the benefit of the bisphosphonate, zolendronic acid (ZA), on progression of joint erosions and bone mineral density (BMD) in RA patients.

Methods: 39 patients, aged 20 to 75 year old, with RA for less than 2 years and clinical synovitis in the wrist MCP and/or PIP joints were randomized to receive either 5mg of ZA or placebo at baseline and week 13. Methotrexate (7.5-20 mg. per week) and folic acid were allowed. No other DMARDs were allowed, and corticosteroid use was restricted. The primary endpoint was a reduction in the progression of bone erosions as measured by magnetic resonance imaging (MRI). Secondary endpoints were bone edema by MRI, bone erosion by x-ray, and bone mineral density (BMD) using DEXA scans and serum bone markers.

Results: Measurements were done at baseline and week 26. At week 26, the MRI analysis revealed a 61% decrease in mean change in hand and wrist erosions in the ZA group, compared with the placebo group, (0.9 + 1.6 versus 2.3 + 3.1, respectively; p=0.18). This reduction was due primarily to reduced erosion progression in the wrist. Likewise, the mean increase in hand/wrist erosions was higher in the placebo group, compared to the ZA group (1.4 + 1.8 versus 0.3 + 0.8, respectively; p=0.03). Patients developed less bone edema in the ZA group (33.3%) then the placebo group (57.9%). X-ray data showed similar trends.

At all major sites measured (hip, wrist, hand and distal radius), a statistically significant increase in BMD was observed in the ZA group compared to a decrease in BMD in the placebo group, with exception to the spine. Additionally, serum biomarkers for bone turnover, CTx (c-telopeptide), BSAP (bone specific alkaline phosphatase), and OC (osteoclacin), decreased markedly in the ZA group compared to the placebo group. The difference in percent change for the ZA group vs. the placebo group were as follows: CTx (-69.85), BSAP (-33.38) and DC (-48.10).

Conclusion: ZA appears to have a statistically significant beneficial effect on bone erosion, edema, BMD, and serum biomarkers for bone turnover, thereby warranting further investigation of its use in RA patients.

Editorial Comments: This is a very promising and important study that argues for more aggressive use of bisphosphonates in RA patients. However, it is important to note that the difference in primary endpoint between the treatment groups did not reach statistical significance. Consequently, the authors results will need to be confirmed in a larger study or after longer duration of treatment. Also, the improvements and worsening in BMD for some of the anatomical sites may not have exceeded limits of detection of DEXA technology. Finally, MRI has not yet been fully validated in large clinical trials as a substitute for xray as an outcome for progression of bone lesions. Nonetheless, these results are of considerable interest and will hopefully be followed by larger confirmatory trials.

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