A new systematic review and meta-analysis published in Annals of Internal Medicine evaluated the efficacy and safety of bisphosphonates for complex regional pain syndrome (CRPS), a chronic primary pain disorder that usually occurs distally, in a single limb, after fracture, sprain, or surgery.
The reviewers note the condition carries substantial personal, societal, and economic burdens, with two thirds of patients experiencing long-term work incapacity and treatment costs that are 13 times greater than those associated with non-CRPS injuries.
The analysis synthesized evidence from 11 trials involving 754 adult participants, most of whom had CRPS type I, to determine the efficacy and safety of bisphosphonates compared with placebo for CRPS. The data were derived from MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and 3 trial registries from inception to September 16, 2025.
According to the reviewers, the primary outcomes were pain intensity and adverse events, and data were synthesized with random-effects meta-analyses. The review included randomized trials that enrolled adults with CRPS without (type I) or with (type II) nerve injury, and with average baseline pain intensity of at least 4 of 10. The duration of treatment ranged from a single administration to an 8-week course.
Data Synthesis
According to the reviewers, 11 trials with 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. What they found was that 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). Also, in the short term (>4 weeks to 3 months; primary time point), while 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). Therefore, the reviewers concluded that 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]), and that bisphosphonates probably increase risk for adverse events (risk ratio, 1.1 [CI, 1.0 to 1.2]; moderate certainty).
Breaking it Down Further
The reviewers identified low-certainty evidence suggesting that bisphosphonates may reduce pain intensity at short-term follow-up. Moderate-certainty evidence indicated that bisphosphonates probably increase the risk for at least 1 adverse event and arthralgia; while high-certainty evidence showed an increased risk for myalgia and decreased risk for nausea; and moderate-certainty evidence of little to no difference in fatigue, influenza-like symptoms, or treatment discontinuations due to adverse events.
What remains unclear, the reviewers pointed out, are the effects on pain intensity in the immediate, medium, and long term; disability; and health-related quality of life, because of limited data and low to very low certainty of evidence.
According to the reviewers, future research should resolve uncertainty around which patients with CRPS are most likely to benefit from bisphosphonates.
Source: Annals of Internal Medicine