OBJECTIVES: Several studies found that biphosphonates counteract locally increased bone resorption and associated pain in patients with complex regional pain syndrome I (CRPS I). We performed a systematic review of all randomised controlled trials to assess the benefit of biphosphonates in the treatment of CRPS I patients with bone loss. DATA SOURCES: We searched Medline, Embase (April 2007) and the Cochrane Library and screened bibliographies of included studies. REVIEW METHODS: We selected randomised trials comparing biphosphonates with placebo, with the goal of improving pain, function and quality of life in patients with CRPS I. Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, conflicts were resolved with discussion and/or trial authors were contacted for further details. We calculated the study size weighted pooled mean reduction of pain intensity (measured with a visual analogue scale (VAS)). RESULTS: Four trials of moderate quality fulfilled our inclusion criteria. In respect to function and quality of life there was a trend in favour of biphosphonates but differences in outcome assessment impeded pooling of results. Two trials provided sufficient data to pool pain outcomes. Biphosphonates reduced pain intensity by 22.4 and 21.6mm on a VAS after 4 and 12 weeks of follow-up. Data on adverse effects were scarce. CONCLUSIONS: The very limited data reviewed showed that bisphosphonates have the potential to reduce pain associated with bone loss in patients with CRPS I. However, at present there is not sufficient evidence to recommend their use in practice.