What are the potential side effects of romosozumab (generic name) in an older adult patient with a history of osteoporosis and fracture, particularly with regards to cardiovascular risk?

Romosozumab Side Effects in Older Adults with Osteoporosis

Romosozumab carries a black box FDA warning for increased cardiovascular risk and should be avoided in patients with myocardial infarction or stroke within the preceding year, while other common side effects include injection site reactions, hypocalcemia, and rare but serious complications including osteonecrosis of the jaw and atypical femoral fractures. 1

Cardiovascular Risk (Most Critical Safety Concern)

The most significant safety concern with romosozumab is cardiovascular events, which occurred at higher rates compared to both alendronate and placebo in clinical trials. 2

Evidence of Cardiovascular Risk:

• In the ARCH trial, serious cardiovascular adverse events occurred in 2.5% of romosozumab patients versus 1.9% with alendronate during the first year of treatment 3
• FDA analysis of the Adverse Event Reporting System suggested higher risk for major adverse cardiovascular events with romosozumab 2
• Romosozumab increased cardiovascular event risk compared with alendronate (hazard ratio 1.9,95% CI 1.1-3.1) 2

FDA Black Box Warning:

• Romosozumab should NOT be initiated in patients with myocardial infarction or stroke in the preceding year 1, 4, 5
• Patients should seek immediate medical attention for symptoms of heart attack (chest pain, shortness of breath, lightheadedness) or stroke (headache, numbness/weakness, difficulty talking, vision changes) 1

Conflicting Evidence:

• A 2025 Japanese study using instrumental variable analysis found no definitive evidence of increased cardiovascular risk compared with bisphosphonates (hazard ratio 1.30,95% CI 0.88-1.90), though the study may have been underpowered 6
• The cardiovascular risk remains controversial and requires further investigation 5

Common Side Effects

Injection Site Reactions:

• 4-5% of patients experience injection site reactions, which are generally mild 5
• Romosozumab is administered as two 105 mg subcutaneous injections monthly for exactly 12 months 1

Hypocalcemia:

• All patients must take daily calcium and vitamin D supplementation to prevent hypocalcemia 1, 2
• Patients should seek immediate medical attention for symptoms of low calcium 1
• Pre-existing hypocalcemia is an absolute contraindication to romosozumab 1

Serious but Rare Adverse Events

Osteonecrosis of the Jaw (ONJ):

• Patients should practice good oral hygiene and inform their dentist they are receiving romosozumab before dental work 1
• In the ARCH trial, 1 case of ONJ occurred in each treatment group during the alendronate follow-up period 3

Atypical Femoral Fractures:

• Patients should report new or unusual thigh, hip, or groin pain 1
• In the ARCH trial, 2 atypical femoral fractures occurred in the romosozumab-to-alendronate group versus 4 in the alendronate-alone group 3

Hypersensitivity Reactions:

• Serious allergic reactions including angioedema, erythema multiforme, dermatitis, rash, and urticaria have been reported 1
• Patients should seek immediate medical attention for signs of allergic reactions 1
• Allergy to romosozumab is an absolute contraindication 1

Overall Safety Profile

• Moderate-certainty evidence shows romosozumab resulted in no differences in serious adverse events or withdrawals due to adverse events compared with placebo 2
• The overall adverse event profile was balanced between romosozumab and alendronate groups in clinical trials 3

Critical Clinical Considerations

Patient Selection Based on Risk-Benefit:

• Romosozumab is recommended only for postmenopausal women at very high fracture risk (age >74 years, recent fracture, multiple osteoporotic fractures, or failure of other therapies) with LOW cardiovascular risk 2, 5
• The fracture reduction benefits must be weighed against cardiovascular risks, particularly in patients with hypertension, coronary artery disease, or prior stroke 7

Treatment Duration and Sequential Therapy:

• Treatment is strictly limited to 12 monthly doses as the anabolic effect wanes after this period 2, 8
• Patients MUST transition to an antiresorptive agent (preferably alendronate) after completing romosozumab to maintain bone density gains 2, 8