Bisphosphonates Linked to Short-Term Pain Reduction in Complex Regional Pain Syndrome: Study
Australia: A new systematic review and meta-analysis has revealed that bisphosphonates may reduce pain in complex regional pain syndrome (CRPS) in the short term (greater than 4 weeks up to 3 months). However, they appear less effective in the immediate (≤4 weeks) and medium-term (greater than 3 to 6 months). Treatment was also associated with an increased risk of adverse events, particularly arthralgia and myalgia.
The findings are from a comprehensive analysis published in Annals of Internal Medicine by Michael C. Ferraro of the School of Health Sciences, Faculty of Medicine and Health, University of New South Wales, and the Centre for Pain IMPACT at Neuroscience Research Australia, along with colleagues. The study addresses a key gap in evidence, as bisphosphonates are commonly recommended in clinical guidelines for CRPS despite ongoing uncertainty regarding their true effectiveness and safety profile.
CRPS is a chronic pain condition characterized by severe, persistent pain, sensory disturbances, and functional impairment, often developing after injury or surgery. Management remains challenging, and pharmacological options are limited. Bisphosphonates, drugs traditionally used to treat osteoporosis and other bone disorders, have been proposed to alleviate CRPS-related pain through their effects on bone metabolism and inflammation. However, existing trials have reported inconsistent results.
To clarify the evidence, the researchers conducted a systematic review of randomized controlled trials comparing bisphosphonates with placebo in adults diagnosed with CRPS type I or II. Major medical databases, including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, were searched from inception through September 16, 2025, along with multiple clinical trial registries. Pain intensity and adverse events were identified as the primary outcomes.
A total of 11 randomized trials involving 754 participants were included in the analysis. Most participants had CRPS type I, and the studies evaluated a range of bisphosphonates, including alendronate, clodronate, neridronate, pamidronate, and zoledronate. Using random-effects meta-analysis, the investigators assessed treatment effects across different follow-up periods.
Key Findings:
- Bisphosphonates showed little to no reduction in pain during the immediate period of four weeks or less.
- A modest decrease in pain intensity was observed in the short term, between more than four weeks and three months, which was the primary assessment time point.
- Pain relief benefits diminished in the medium term (three to six months), with no meaningful difference compared with placebo.
- Evidence on long-term pain outcomes beyond six months was highly uncertain.
- Bisphosphonate treatment was associated with a higher risk of adverse events than placebo.
- Musculoskeletal side effects, particularly joint pain and muscle pain, were among the most frequently reported adverse events.
- The overall certainty of the evidence ranged from low to moderate due to variability among studies and methodological limitations.
The authors conclude that while bisphosphonates may offer short-term pain relief for some patients with CRPS, the benefits are modest and accompanied by an increased risk of adverse effects. They emphasize the need for future research to identify which patient subgroups are most likely to respond and better to define the long-term balance between benefit and harm.
Reference:
Ferraro MC, O'Connell NE, Goebel A, Hill R, Curtis F, Wilkinson J, Center JR, Gustin SM, Cashin AG, McAuley JH. Efficacy and Safety of Bisphosphonates for Complex Regional Pain Syndrome : A Systematic Review and Meta-analysis. Ann Intern Med. 2025 Dec 16. doi: 10.7326/ANNALS-25-03693. Epub ahead of print. PMID: 41397259.
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