Is Evenity (romosozumab) appropriate for a patient with severe osteoporosis who has a history of myocardial infarction or other major adverse cardiovascular events?

Evenity and MACE: Cardiovascular Risk Considerations

Evenity (romosozumab) should NOT be initiated in patients with a history of myocardial infarction or stroke within the preceding year, and must be discontinued if MI or stroke occurs during treatment. 1

FDA Black Box Warning

The FDA mandates a boxed warning stating that romosozumab may increase the risk of myocardial infarction, stroke, and cardiovascular death 1. This is the highest level of safety alert and takes precedence in clinical decision-making.

Absolute Contraindications:

• MI or stroke within the past 12 months - do not initiate 1
• Active MI or stroke during therapy - discontinue immediately 1

Relative Contraindications Requiring Risk-Benefit Assessment:

• Other cardiovascular risk factors (hypertension, hyperlipidemia, diabetes, smoking, family history)
• The FDA explicitly states: "Consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors" 1

Evidence Behind the Warning

The cardiovascular signal emerged from the ARCH trial, which compared romosozumab to alendronate and showed higher cardiovascular event rates in the romosozumab arm 2, 3. This finding led to FDA analysis of the Adverse Event Reporting System suggesting elevated MACE risk 4.

However, recent real-world evidence presents a more nuanced picture:

• In patients WITHOUT prior cardiovascular history, romosozumab was associated with lower risks of 3-point MACE at 3-year (HR 0.645) and 5-year follow-up (HR 0.755) compared to denosumab 5

• In patients WITH preexisting cardiovascular disease, romosozumab showed consistently higher cardiovascular risks across all follow-up periods 5

• Compared to teriparatide, romosozumab demonstrated lower MACE (HR 0.441) and improved survival in general osteoporosis populations 6

• In CKD patients, romosozumab showed lower MACE (HR 0.82) and MI risk (HR 0.77) versus teriparatide 7

Clinical Algorithm for Decision-Making

Step 1: Screen for Absolute Contraindications

• Recent MI/stroke (< 1 year)? → Do not use romosozumab 1
• Hypocalcemia? → Do not use (also contraindicated) 1

Step 2: Assess Cardiovascular Risk Profile

For patients without recent MI/stroke, stratify:

Low CV Risk (no or minimal risk factors):

• Romosozumab is appropriate for severe osteoporosis at high fracture risk 1, 8

Moderate CV Risk (controlled hypertension, mild hyperlipidemia, age > 65):

• Carefully weigh fracture risk versus potential CV risk
• Recent data suggest safety may be acceptable in this group 5, 6
• Consider alternative agents (teriparatide, denosumab) if fracture risk permits

High CV Risk (multiple uncontrolled risk factors, established CAD without recent events):

• Strongly consider alternative therapies 3
• If romosozumab chosen due to very high fracture risk, ensure intensive CV monitoring

Very High CV Risk (prior MI/stroke > 1 year ago, unstable angina):

• The evidence shows increased harm in this population 5
• Avoid romosozumab - use alternative anabolic (teriparatide) or potent antiresorptive (denosumab, zoledronate)

Step 3: If Romosozumab Is Used

• Monitor for MI/stroke symptoms throughout the 12-month treatment course 1
• Instruct patients to seek immediate medical attention for chest pain, shortness of breath, neurological symptoms
• Discontinue immediately if cardiovascular event occurs 1

Critical Caveats

The cardiovascular data remain conflicting - the ARCH trial showed increased risk, but multiple real-world studies suggest neutral or even protective effects in patients without preexisting CVD 2, 5, 6. This discrepancy may reflect:

• Selection bias in real-world data
• Differences in comparator agents (alendronate vs. denosumab vs. teriparatide)
• Unmeasured confounding

Despite newer reassuring data, the FDA black box warning remains in effect and must guide clinical practice 1. The regulatory stance prioritizes safety in the absence of definitive prospective data.

Treatment Duration and Sequencing

• Limit romosozumab to exactly 12 monthly doses (210 mg subcutaneously monthly) 1
• The anabolic effect wanes after 12 months 4, 1
• Must transition to antiresorptive therapy (denosumab or bisphosphonate) to maintain gains 1, 8

Bottom Line for Practice

For a patient with severe osteoporosis and history of MI or stroke: romosozumab is contraindicated if the event occurred within the past year 1. If the event was more remote, the recent real-world evidence showing increased harm in patients with preexisting CVD 5 strongly argues against its use. Choose teriparatide or potent antiresorptive therapy instead 8, 3.