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Bisphosphonates and risk of cardiovascular events: a meta-analysis
Dae Hyun Kim1, James R Rogers2, Lisa A Fulchino2
1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
Insights
Bisphosphonates do not impact major cardiovascular events in adults with low bone mass. However, zoledronic acid may slightly increase atrial fibrillation risk, though overall fracture benefits outweigh this concern.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Bone Metabolism
Background:
- Bisphosphonates are commonly used for osteoporosis and low bone mass.
- Existing evidence on their cardiovascular (CV) effects is conflicting, with potential benefits against atherosclerosis but concerns regarding atrial fibrillation.
- A comprehensive meta-analysis is needed to clarify these CV risks and benefits.
Purpose of the Study:
- To evaluate the impact of bisphosphonates on major adverse cardiovascular events (MACE).
- To specifically assess effects on atrial fibrillation, myocardial infarction (MI), stroke, and cardiovascular death.
- To analyze these effects in adults with or at risk for low bone mass.
Main Methods:
- Systematic search of MEDLINE and EMBASE databases up to July 2014.
- Inclusion of 58 randomized controlled trials (RCTs) with follow-up exceeding 6 months reporting CV events.
- Meta-analysis using fixed-effects models to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for various CV outcomes.
Main Results:
- Bisphosphonate treatment up to 36 months showed no significant effect on total CV events (OR 0.98), MI (OR 0.96), stroke (OR 0.99), or CV death (OR 0.88).
- No significant increase in atrial fibrillation was observed overall (OR 1.08).
- A modest elevation in atrial fibrillation risk was noted specifically for zoledronic acid (OR 1.24), but not for oral bisphosphonates. Heterogeneity was minimal across studies.
Conclusions:
- Bisphosphonates do not confer beneficial or harmful effects on atherosclerotic cardiovascular events.
- Zoledronic acid may be associated with a slight increase in atrial fibrillation risk.
- The significant fracture reduction benefits of bisphosphonates justify their continued use in osteoporosis management, irrespective of minor CV risk fluctuations.
Background And Objectives:
Some evidence suggests that bisphosphonates may reduce atherosclerosis, while concerns have been raised about atrial fibrillation. We conducted a meta-analysis to determine the effects of bisphosphonates on total adverse cardiovascular (CV) events, atrial fibrillation, myocardial infarction (MI), stroke, and CV death in adults with or at risk for low bone mass.
Methods:
A systematic search of MEDLINE and EMBASE through July 2014 identified 58 randomized controlled trials with longer than 6 months in duration that reported CV events. Absolute risks and the Mantel-Haenszel fixed-effects odds ratios (ORs) and 95% confidence intervals (CIs) of total CV events, atrial fibrillation, MI, stroke, and CV death were estimated. Subgroup analyses by follow-up duration, population characteristics, bisphosphonate types, and route were performed.
Results:
Absolute risks over 25-36 months in bisphosphonate-treated versus control patients were 6.5% versus 6.2% for total CV events; 1.4% versus 1.5% for atrial fibrillation; 1.0% versus 1.2% for MI; 1.6% versus 1.9% for stroke; and 1.5% versus 1.4% for CV death. Bisphosphonate treatment up to 36 months did not have any significant effects on total CV events (14 trials; ORs [95% CI]: 0.98 [0.84-1.14]; I2 = 0.0%), atrial fibrillation (41 trials; 1.08 [0.92-1.25]; I2 = 0.0%), MI (10 trials; 0.96 [0.69-1.34]; I2 = 0.0%), stroke (10 trials; 0.99 [0.82-1.19]; I2 = 5.8%), and CV death (14 trials; 0.88 [0.72-1.07]; I2 = 0.0%) with little between-study heterogeneity. The risk of atrial fibrillation appears to be modestly elevated for zoledronic acid (6 trials; 1.24 [0.96-1.61]; I2 = 0.0%), not for oral bisphosphonates (26 trials; 1.02 [0.83-1.24]; I2 = 0.0%). The CV effects did not vary by subgroups or study quality.
Conclusions:
Bisphosphonates do not have beneficial or harmful effects on atherosclerotic CV events, but zoledronic acid may modestly increase the risk of atrial fibrillation. Given the large reduction in fractures with bisphosphonates, changes in osteoporosis treatment decision due to CV risk are not justified.
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