What is the prescribing information for romosozumab, including its indication, dosing regimen, contraindications, monitoring requirements, and alternative therapies for severe osteoporosis?

Romosozumab Prescribing Information

Indication

Romosozumab is reserved exclusively for postmenopausal women with primary osteoporosis at very high risk of fracture who have contraindications to, failed, or cannot tolerate bisphosphonates. 1, 2

Very high fracture risk is defined by:

• Age >74 years (mean age in pivotal trials) 2, 3
• Recent fracture within the past 12 months 2
• History of multiple clinical osteoporotic fractures 2, 3
• T-score ≤-2.5 at spine, hip, or femoral neck 3, 4
• Failure of other available osteoporosis therapy 2, 3

Bisphosphonates remain the strongly recommended first-line therapy for postmenopausal osteoporosis (high-certainty evidence), and romosozumab should never be used as initial treatment. 1, 3

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Dosing Regimen

The treatment consists of 210 mg subcutaneous injection once monthly for exactly 12 months only, as the anabolic effect wanes after this period. 2, 5, 6

Critical: Do not exceed 12 monthly doses under any circumstances. 2, 5

Patients must be on adequate calcium and vitamin D supplementation before initiating therapy. 2, 3

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Contraindications

Absolute contraindications:

• Myocardial infarction or stroke within the preceding 12 months (FDA black-box warning) 2
• Uncorrected hypocalcemia 2, 6

Relative contraindications requiring careful assessment:

• Any significant cardiovascular disease history, given the 1.9-fold increased cardiovascular event risk (HR 1.9; 95% CI 1.1-3.1) compared to alendronate 2, 3
• Cardiovascular event rate: 2.5% with romosozumab vs. 1.9% with alendronate 2, 3

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Mandatory Sequential Therapy

After completing the 12-month romosozumab course, patients MUST transition to an antiresorptive agent to maintain bone density gains and prevent rebound fractures. 1, 2, 5

Alendronate is the preferred antiresorptive for sequential therapy (moderate-certainty evidence). 2

Failure to transition to an antiresorptive will result in loss of bone density gains and potential rebound fractures. 1, 5

Timing for sequential therapy:

• Start bisphosphonate or denosumab immediately after the 12th dose 1, 2
• If denosumab was used during treatment, transition to bisphosphonate 6-7 months after the last denosumab dose 1

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Monitoring Requirements

Pre-Treatment Screening

Perform comprehensive cardiovascular evaluation including:

• ECG 2
• Detailed cardiovascular history 2
• Assess for prior MI or stroke within past year 2

Correct hypocalcemia before initiation and ensure adequate calcium/vitamin D supplementation. 2, 6

During 12-Month Treatment

• Monitor for cardiovascular events throughout the treatment period 2
• Assess for signs of hypocalcemia 2
• Monitor for osteonecrosis of the jaw and atypical femoral fractures (rare but reported) 2, 4

Post-Treatment

• Obtain BMD measurement after 12 months before transitioning to antiresorptive therapy 2
• Continue monitoring on sequential bisphosphonate therapy 2

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Efficacy Outcomes

Vertebral fracture reduction:

• 73% reduction at 12 months (0.5% vs. 1.8% with placebo; P<0.001) 4
• 75% reduction at 24 months with sequential romosozumab-to-alendronate (0.6% vs. 2.5%; P<0.001) 2, 4
• 66% reduction maintained through 36 months with sequential denosumab (1.0% vs. 2.8%; P<0.001) 7

Clinical fracture reduction:

• 36% reduction at 12 months (1.6% vs. 2.5%; P=0.008) 4
• 27% reduction at 36 months (4.0% vs. 5.5%; P=0.004) 7

Nonvertebral fracture reduction:

• No significant reduction at 12 months (1.6% vs. 2.1%; P=0.10) 4
• 21% reduction at 36 months (3.9% vs. 4.9%; P=0.039) 7

Hip fractures: No significant reduction observed in trials (moderate-certainty evidence). 2

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Safety Profile

Serious adverse events occurred at similar rates to placebo (moderate-certainty evidence). 2

Withdrawal due to adverse events showed no difference versus placebo (low-certainty evidence). 2

Romosozumab-to-alendronate did not increase serious harms compared to bisphosphonate alone over 12-36 months (moderate-to-low certainty). 2

Rare but serious adverse events:

• Osteonecrosis of the jaw (1 case reported) 4
• Atypical femoral fractures (2 cases reported) 4

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Alternative Therapies for Severe Osteoporosis

First-line therapy (strongly recommended):

• Oral bisphosphonates (alendronate, risedronate) for initial treatment (high-certainty evidence) 1, 3

Second-line therapy:

• Denosumab for patients with contraindications to or adverse effects from bisphosphonates (moderate-certainty evidence for women, low-certainty for men) 1

Third-line therapy for very high fracture risk:

• Romosozumab (conditional recommendation, moderate-certainty evidence) 1, 2
• Teriparatide (PTH) followed by bisphosphonate (conditional recommendation, low-certainty evidence) 1

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Cost Considerations

Romosozumab costs $5,574 annually per Medicare beneficiary, compared to $39-$2,700 for bisphosphonates. 3

Cost-effectiveness has not been established for sequential therapy, particularly in resource-limited settings. 2, 3

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Critical Pitfalls to Avoid

1. Never use romosozumab as first-line therapy when bisphosphonates are appropriate—cost and cardiovascular safety concerns outweigh benefits. 3

2. Never exceed 12 months of treatment—the anabolic effect diminishes thereafter. 2, 5

3. Always transition to an antiresorptive after 12 months—failure to do so results in bone density loss and rebound fracture risk. 1, 2, 5

4. Never initiate in patients with MI or stroke within the past year—FDA black-box warning. 2

5. Never start therapy with uncorrected hypocalcemia—correct calcium levels first. 2, 6

6. Do not use in moderate or low fracture-risk patients—cardiovascular risks outweigh benefits. 2