Clinical Science (42)
Authors: Varenna Massimo , Zucchi Francesca , Ghiringhelli Daniel 
Published: September 2010

Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome: a randomized, double blind, placebo‐controlled study. (Istituto Ortopedico Gaetano Pini, Milan, Italy) J Rheumatol 2000;27:1477–1483.

This study evaluated the efficacy of intravenous (IV) clodronate in patients with reflex sympathetic dystrophy syndrome (RSDS) and assessed the urinary excretion of type 1 collagen crosslinked N‐telopeptide (NTx) before and after treatment. Thirty‐two patients with RSDS were randomized to receive either IV Clodronate 300 mg daily for 10 consecutive days or placebo. Forty days later, the placebo treated patients received the clodronate treatment. Outcome measures included as a primary endpoint the visual analog scale of pain (VAS, range 0–100); secondary endpoints were a clinical global assessment (CGA, range 0–3) and an efficacy verbal score (EVS, range 0–3). Clinical and biochemical assessments were performed before the treatment, 40 (T40), 90 (T90), and 180 (T180) days later. At T40 the 15 patients randomized to clodronate treatment showed significant decreases of VAS and CGA (P = 0.002, P = 0.001, respectively). Compared with the placebo group (17 patients), significant differences were found in all clinical variables. A further clinical improvement was observed throughout the study. Pooling the results of all 32 patients after clodronate treatment, at T180 the overall percentage decrease of VAS was 9.32 ± 15.6% with 30 patients significantly improved or asymptomatic. Significant inverse correlations between baseline NTx values and decreases of VAS were found at T90 (P = 0.03) and T180 (P = 0.01). No adverse events related to treatment occurred. Conclude that a 10‐day IV clodronate course is better than placebo and effective in the treatment of RSDS. NTx seems to be a predictive factor for clodronate efficacy.

Comment by Susan Anderson, MD.

This is a randomized double blind placbo controlled study to evaluate the efficacy of intravenous clodronate in patients with reflex sympathetic dystrophy syndrome (RSDS) or complex regional pain syndrome type I. It is also to assess the urinary excretion of type I collogen crosslink N‐telopeptide (NTx) before and after the treatment. Thirty‐two patients with complex regional pain syndrome type I were randomized to receive either a placebo or IV clodronate 300mg daily for 10 consecutive days. At the end of 40 days, the placebo group was then treated with the clodronate. The primary endpoint measures with the visual analog scale (VAS, range 0–100) and a secondary endpoint was the clinical global assessment (CGA, range 0–3), and an efficacy vocal score (EVS, range 0–3). In addition, the patient had clinical and biochemical assessments performed before the treatment at 40 days, at 90 days, and at 180 days later. The purpose of the study was valued at the efficacy of the IV clodronate in pain relief. The second purpose was to evaluate the possibility of using NTx as a predicting factor for evaluating complex regional pain syndrome type I or the clodranate efficacy. On day 40, 15 patients that were randomized to the clodronate treatment showed significant decreases in their VAS and CGA when compared with the placebo group with 17 patients.

In addition, the patients who had originally received placebo infusions showed decreased VAS and CGA scores after 40 days of treatment with the clodronate when compared to their VAS and CGA scores after placebo. At 180 days, the patients continued to show significant improvement or were asymptomatic. Bisphosphonates have been proposed since 1988 for the treatment of CRPS type I. The most frequently used is pamidronate, which is given intravenously showing varied results. The pamidronate did not seem to be well tolerated. Alendronate is also given intravenously demonstrating good efficacy. It, however, has a high relapse rate. Clodronate was chosen for this study because it was efficacious in treatment of various painful skeletal disorders and was more tolerable and safe than the pamidronate. The length of the time of the study was chosen to be 10 consecutive days so that it followed the study with successful use of pamidronate. These results suggest that a 10‐day IV clodronate course is better than placebo and is an effective complex regional pain syndrome type I treatment that may induce prompt and long lasting improvement. This study also attempted to demonstrate NTx as a predictive factor for clodranate efficacy. While NTx has shown to be a specific and sensitive marker of bone resorption, in this study, they found a low association between high NTx values and the complex regional pain syndrome type I. This finding could weaken the relationship between NTx baseline values and the responsiveness to clodronate treatment. It should be noted, however, that there were significant immerse correlations found between the baseline NTx values and in the pain improvement measured on the percentage change of VAS at 90 days and 180 days. Therefore, while significant inverse correlations may have been determined, and the NTx may be a promising tool, it is not yet possible to determine the predictive rolls of NTx as a marker.