PAIN+ CPN

BACKGROUND: Clinical guidelines recommend bisphosphonates for complex regional pain syndrome (CRPS) despite limited evidence of efficacy.

PURPOSE: To determine the efficacy and safety of bisphosphonates compared with placebo for CRPS.

DATA SOURCES: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and 3 trial registries from inception to 16 September 2025.

STUDY SELECTION: Randomized controlled trials enrolling adults with CRPS (type I or II) to bisphosphonate treatment or placebo.

DATA EXTRACTION: Primary outcomes were pain intensity and adverse events. Data were synthesized with random-effects meta-analyses. Risk of bias and certainty of evidence were assessed using the Cochrane Risk of Bias 2 Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation).

DATA SYNTHESIS: Eleven trials (754 participants; CRPS type I, 97%), evaluating alendronate (n = 2), clodronate (n = 1), neridronate (n = 5), pamidronate (n = 1), and zoledronate (n = 2), were included. Bisphosphonates may result in little to no difference in pain intensity in the immediate term (=4 weeks; 0-to-100 scale; mean difference [MD], -9.1 [95% CI, -19.2 to 1.1]; low certainty). In the short term (>4 weeks to 3 months; primary time point), bisphosphonates may reduce pain intensity (MD, -10.0 [CI, -18.9 to -1.1]; low certainty), and in the medium term (>3 to 6 months), they may result in little to no difference in pain intensity (MD, 8.0 [CI, -15.4 to 31.4]; low certainty). The evidence is very uncertain about the effects of bisphosphonates on pain intensity in the long term (>6 months; MD, -2.5 [CI, -19.6 to 14.6]). Bisphosphonates probably increase risk for adverse events (risk ratio, 1.1 [CI, 1.0 to 1.2]; moderate certainty).

LIMITATIONS: High heterogeneity and uncertain medium- and long-term effects. Evidence mostly applies to CRPS type I and includes non-U.S.-approved formulations (neridronate, clodronate).

CONCLUSION: Bisphosphonates may reduce CRPS pain intensity in the short term, but treatment is accompanied by adverse events. Future research should resolve uncertainty around which patients with CRPS are most likely to benefit from bisphosphonates.

PRIMARY FUNDING SOURCE: None. (PROSPERO: CRD42024559783).

Physician rater

This systematic review highlights the uncertainties of the effects of biphosphonates on pain intensity in the immediate, medium, and long term, disability, and health-related quality of life in CRPS due to limited data and low- to very low-certainty evidence. Unfortunately, data were insufficient to explore the moderating effect of symptom duration, with 4 of 10 trials not reporting mean or median values. From the clinical experience, patients can benefit from biphosphonates in the early ("hot") phase of CRPS. Unfortunately (again), the certainty of evidence of subgroup analysis of 4 trials with positive findings that restricted participation to patients with metabolic bone changes was downgraded to low due to imprecision.

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