Does Prolia Cause Recurrent Stroke?
No, Prolia (denosumab) does not cause recurrent stroke based on available evidence. The cardiovascular safety profile of denosumab shows no increased risk of stroke or major cardiovascular events in patients with osteoporosis.
Evidence from Cardiovascular Safety Studies
The most comprehensive meta-analysis examining denosumab's cardiovascular effects included 11 randomized clinical trials with 13,615 participants and found:
- No association with composite cardiovascular outcomes (RR 1.06,95% CI 0.88-1.28, p=0.54) 1
- No increased risk of stroke specifically (p>0.05) 1
- No increased risk of three-point major adverse cardiovascular events (3P MACE) (RR 1.01,95% CI 0.83-1.23, p=0.93) 1
- No increased risk of four-point major adverse cardiovascular events (4P MACE) (RR 0.99,95% CI 0.83-1.18, p=0.89) 1
These findings remained consistent across sensitivity analyses and subgroup analyses, demonstrating robust evidence that denosumab does not increase stroke risk 1.
Clinical Context and Mechanism
Denosumab is a fully human monoclonal antibody that targets RANKL (receptor activator of nuclear factor kappaB ligand), inhibiting osteoclast-mediated bone resorption 2. While the RANKL/RANK/OPG pathway is implicated in both osteoporosis and cardiovascular disease pathogenesis, clinical trial data do not support a causal relationship between denosumab therapy and stroke events 1.
Important Safety Considerations Unrelated to Stroke
While denosumab does not cause stroke, clinicians should be aware of other significant adverse effects:
- Rebound vertebral fractures: Multiple spontaneous vertebral fractures (median of 5 fractures) can occur 7-20 months after discontinuation if not transitioned to bisphosphonate therapy 3
- Neuropsychiatric effects: Rare cases of cognitive impairment, depression, and confusional states have been reported, particularly in patients with pre-existing neurobiological vulnerability 4
- Rebound hypercalcemia: Can occur with extended dosing intervals, requiring monitoring 5
Clinical Recommendation
Denosumab can be safely used in patients with osteoporosis without concern for causing or increasing the risk of recurrent stroke 1. The medication's cardiovascular safety profile is well-established across multiple large randomized trials. However, if denosumab is discontinued, transition to bisphosphonate therapy is essential to prevent rebound vertebral fractures 3.
For patients with prior stroke who require osteoporosis treatment, denosumab represents a safe option from a cerebrovascular standpoint, though standard stroke prevention strategies (antiplatelet therapy, blood pressure control, lipid management) should continue per established stroke prevention guidelines 6.