Are Bisphosphonates Effective in Treating Ankylosing Spondylitis?

Nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy have been the standard of treatment for ankylosing spondylitis (AS) for several decades but neither stops or slows the progression of disease. Pamidronate, a bisphosphonate, has been shown to be effective in animal models of established arthritis. Moreover, pamidronate has appeared to be beneficial in patients with NSAID-refractory AS in two previous studies (1,2). These studies were non-controlled, however, and a large placebo effect was expected (3,4). Maksymowych et al (Arthritis Rheum 46:766-773, 2002) therefore investigated the efficacy of pamidronate treatment in AS patients.

Methods:

Designing a placebo-controlled study was found to be problematic; however, as myalgia and transient postinfusion arthralgias are very common after administration of intravenous pamidronate. Such a phenomenon could significantly interfere with patient blinding. To preserve the blind, a dose-response design was chosen over a placebo-controlled trial.

Eighty-four patients were randomized to receive either 10 mg (the lowest dose of pamidronate shown to induce the postinfusion response) or 60 mg of intravenous pamidronate. The drug was given monthly in a six-month randomized, double-blind, controlled trial. Patients had active disease according to one or more of the following criteria: a Bath AS Disease Activity Index [BASDAI] score of > 4 or morning stiffness of > 45 minutes despite stable NSAID therapy. Patients were allowed to remain on NSAIDs and second-line therapy such as sulfasalazine or methotrexate.

Results:

Both groups were well matched at baseline for demographics, disease activity and functional indices. By six months, the mean BASDAI had decreased by 2.22 (34.5%) in the 60-mg group and by 0.93 (15%) in the 10-mg group (P = 0.002). Dose-dependent reductions were also observed for the Bath AS Functional Index (BASFI) (P<0.001), the Bath AS Global Index (BASGI)(P=0.01), and the Bath AS Metrology Index (BASMI) (P=0.03). More patients in the 60-mg group (63.4%) achieved a reduction of > 25% in the BASDAI than in the 10-mg group (30.2%) (P=0.004). No significant differences were found in the laboratory measurements of disease activity (ESR/CRP). Transient arthralgias and myalgias occurred after the first IV infusion in 68.3% of the 60-mg group and 46.5% of the 10-mg group. No other adverse events were noted.

Monthly intravenous administration of pamidronate is a well-tolerated therapy that can effect clinical improvement in patients with ankylosing spondylitis in a dose-dependent manner.

Editorial Comment:

The rationale for use of bisphosphonates in AS is somewhat vague. To the extent that bisphosphonates promote osteoclast apoptosis, these agents may be helpful in suppressing bone erosion/destruction. However, in this study, the main outcome was improvement in clinical and inflammation indices. Although there was statistically significant clinical improvement in the high dose pamidronate group, it was very modest at best. In addition, ESR and CRP did not improve. By way of comparison, anti-TNF agents have a much more profound effect both on clinical and inflammatory indices in AS.(see prior news: etanercept in AS and infliximab in AS) Without more mechanistic information and /or more impressive clinical or radiological data to support the use of bisphosphonates in AS, its application to this disease seems limited.

1Maksymowych WP, Jhangri GS, LeClercq S, Skeith K, Yan A, Russell AS. An open study of pamidronate in the treatment of refractory ankylosing spondylitis. J Rheumatol 1998; 25: 714-7.

Maksymowych WP, Lambert R, Jhangri GS, LeClercq S, Chiu P, Wong B, et al. Clinical and radiological amelioration of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy. J Rheumatol 2001; 28: 144-55.

Dougados M, van der Linden S, Leirisalo-Repo M, Huitfeldt B, Juhlin R, Veys E, et al. Sulfasalazine in the treatment of spondylarthropathy: a randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995; 38: 618-27.

Clegg DO, Reda DJ, Weisman MH, Blackburn WD, Cush JJ, Cannon GW, et al. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. Arthritis Rheum 1996; 39: 2004-12.

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