In an 87-year-old woman with severe aortic stenosis and severe mitral regurgitation, is it safe to administer denosumab and romosozumab (Evenity 320) for osteoporosis?

Romosozumab (Evenity) Should NOT Be Used; Denosumab May Be Considered with Extreme Caution

In an 87-year-old woman with severe aortic stenosis (AS) and severe mitral regurgitation (MR), romosozumab is contraindicated due to cardiovascular risk, while denosumab may be used cautiously if osteoporosis treatment cannot be deferred.

Romosozumab (Evenity) - CONTRAINDICATED

The FDA label for Evenity carries a boxed warning for major adverse cardiac events (MACE) including myocardial infarction, stroke, and cardiovascular death 1. This is particularly critical in your patient's context:

• Severe valvular disease represents very high cardiovascular risk. The ACC/AHA perioperative guidelines explicitly state that severe symptomatic AS carries approximately 10% mortality risk even for noncardiac procedures 2, 3. Your patient has TWO severe valvular lesions, compounding this risk.

• ACR guidelines specifically recommend AGAINST romosozumab in patients with cardiovascular risk factors. The 2023 ACR guideline conditionally recommends against using romosozumab "due to risk of myocardial infarction, stroke, or death" in multiple patient populations 4.

• Recent real-world evidence confirms heightened cardiovascular risk in patients with preexisting cardiovascular disease. A 2026 multinational study found romosozumab was associated with "significantly higher risks of 4P-MACE, 5P-MACE, stroke, mortality, and chronic ischemic heart disease" in patients with prior cardiovascular history 5.

• The drug label explicitly states romosozumab may increase cardiovascular risk and advises against use in patients who have had a myocardial infarction or stroke within the preceding year 1.

Denosumab - May Be Used with Caution

Denosumab does NOT carry the same cardiovascular contraindications and may be the safer choice for this patient 6:

• No cardiovascular signal in osteoporosis trials. The Endocrine Society guidelines note denosumab showed no increased cardiovascular risk in meta-analyses (HR 1.06 for composite CV outcomes, p=0.54) 7.

• Specifically studied in severe AS without adverse effects. A 2021 randomized controlled trial evaluated denosumab in patients with calcific aortic stenosis and found it safe, though it did not slow valve disease progression 8.

• Not contraindicated in renal insufficiency, which may be relevant given her age and potential hemodynamic compromise from valvular disease 9.

• Recommended as alternative initial treatment by the Endocrine Society for high-risk osteoporosis patients 6.

Critical Management Considerations

Before Starting ANY Osteoporosis Therapy:

1. Assess cardiovascular stability: Is she symptomatic from her valvular disease? Severe symptomatic AS or MR may require valve intervention BEFORE osteoporosis treatment 2, 10, 3.

2. Correct hypocalcemia: Both agents require adequate calcium/vitamin D, but this is especially critical with denosumab in elderly patients with potential renal impairment 9, 6.

3. Dental evaluation: Screen for dental disease before initiating therapy due to osteonecrosis of jaw risk 1.

If Denosumab Is Chosen:

• Dosing: 60 mg subcutaneously every 6 months 6
• No drug holidays permitted - stopping denosumab causes rebound bone loss and vertebral fracture risk 6
• Must transition to bisphosphonate if discontinuation is ever needed 6
• Monitor calcium closely, especially in first weeks after injection 9

Alternative Approach:

If osteoporosis treatment can be deferred, consider addressing valvular disease first. The ESC/EACTS and ACC/AHA guidelines indicate that severe symptomatic valvular disease warrants intervention, and hemodynamic stabilization may improve overall prognosis 11, 12, 13. Once cardiovascular status is optimized (whether through medical management or valve intervention), osteoporosis therapy can be reconsidered with potentially lower risk.

Common Pitfall to Avoid

Do not assume "osteoporosis treatment is urgent" in all cases. While fracture risk is real, the immediate mortality risk from severe AS/MR likely exceeds the short-term fracture risk. Coordinate with cardiology to determine if valve intervention is indicated before committing to long-term osteoporosis therapy that cannot be safely interrupted (denosumab) or carries significant cardiovascular risk (romosozumab).