Bisphosphonates may reduce short-term pain in complex regional pain syndrome 

1. In this systematic review and meta-analysis, bisphosphonates may reduce short-term (> 4 weeks to 3 months) pain in complex regional pain syndrome (CRPS) but appear less effective in the immediate (≤4 weeks) or medium-term (>3 to 6 months) periods.

2. Bisphosphonates may increase the risk of adverse events, particularly arthralgia and myalgia, but do not significantly affect the risk of serious adverse events.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Bisphosphonates have been promoted as a first-line treatment for complex regional pain syndrome (CRPS), a condition associated with substantial physical and economic burden and resistance to most therapies. They are recommended in clinical guidelines worldwide, despite evidence supporting their use being of low certainty and quality. This study aimed to synthesize available evidence on the efficacy and safety of bisphosphonates for CRPS. A systematic review and meta-analysis of 11 trials indicated that bisphosphonates show now meaningful difference in immediate pain reduction (i.e., ≤4 weeks) or the medium term (i.e. >3 to 6 months), but may reduce pain intensity in the short term (i.e., >4 weeks to 3 months). Evidence for long-term effects (>6 months) was very uncertain. Bisphosphonates were associated with an increased risk of adverse events, including arthralgia and myalgia. They did not significantly affect the risk of serious adverse events or treatment discontinuation due to adverse events. Evidence regarding their impact on disability, function, or health-related quality of life was also very uncertain. Limitations of this study include incomplete reporting in primary trials, potential errors in data synthesis, incomplete evaluation of disease-modifying effects, and possible aggregation bias. Overall, the findings suggest that while bisphosphonates may provide short-term pain relief for CRPS, their long-term effectiveness is uncertain, and their use may carry an increased risk of adverse events.

Click to read this study in AIM

Relevant Reading: Interventions for treating pain and disability in adults with complex regional pain syndrome‐ an overview of systematic reviews

In-Depth [systematic review and meta-analysis]: This systematic review and meta-analysis evaluated the efficacy and safety of bisphosphonates for treating CRPS. Randomized trials were identified from MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, the EU Clinical Trials Register, and WHO’s International Clinical Trial Registry Platform through September 16, 2025. Included trials enrolled adults (≥18 years) with CRPS (type I or II), baseline pain ≥4/10, and compared any bisphosphonate formulation or route to placebo. Primary outcomes were pain intensity and adverse events; secondary outcomes included disability, CRPS severity, quality of life, serious adverse events, treatment discontinuation, and specific adverse events. Eleven trials with 754 participants were included (median sample 57; 38–79% women; 87–93% White in four trials reporting race/ethnicity). At immediate-term follow-up (≤4 weeks), bisphosphonates may have little-to-no effect on pain (0-to-100 scale; mean difference [MD], -9.1; 95% confidence interval [CI], -19.2 to 1.1; 4 trials). At short-term follow-up, bisphosphonates likely reduce pain (MD, -10.0; CI, -18.9 to -1.1; 10 trials), with ≥50% pain reduction in 75 of 236 participants versus 33 of 153 on placebo (risk ratio [RR], 1.8; CI, 1.2–2.9). Subgroup effects were observed for bisphosphonate formulation, CRPS diagnostic criteria, and bone metabolism inclusion, but not route of administration. Medium- and long-term effects (>6 months) are very uncertain. Bisphosphonates likely increase overall adverse events (RR, 1.1; CI, 1.0–1.2; 8 trials), arthralgia (RR, 1.7; CI, 1.0–2.9), and myalgia (RR, 3.9; CI, 1.5–9.8), but reduce nausea (RR, 0.4; CI, 0.3–0.7). Effects on vomiting, dizziness, headache, fatigue, fever, bone pain, hypocalcemia, and renal dysfunction were minimal. Bisphosphonates likely do not affect serious adverse events (odds ratio [OR], 1.1; CI, 0.3–4.0; 6 trials) or treatment discontinuation (OR, 2.2; CI, 0.5–9.9; 8 trials). Evidence on disability, function, and quality of life was very uncertain. Overall, bisphosphonates may reduce short-term CRPS pain but show uncertain long-term benefit and may increase risk of adverse events.

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