Is initial treatment with Evenity (Romosozumab-aqqg) 210 mg subcutaneously (SQ) every 4 weeks appropriate and necessary for a 33-year-old female patient with general osteoporosis, who is not postmenopausal?

Evenity (Romosozumab) is NOT Appropriate as Initial Treatment for This Patient

Evenity should not be approved for this 33-year-old premenopausal woman because it is FDA-approved exclusively for postmenopausal osteoporosis, and the patient does not meet criteria for off-label use that would justify the significant safety risks and costs. 1

Critical Issues with This Request

1. Off-Label Use Without Supporting Evidence

• Evenity is FDA-labeled only for postmenopausal osteoporosis in patients at high fracture risk or who have failed other therapies 1
• The patient is a 33-year-old premenopausal woman, making this use explicitly off-label
• All major clinical trials establishing romosozumab's efficacy and safety were conducted exclusively in postmenopausal women 2, 3
• No high-quality evidence exists supporting romosozumab use in premenopausal women, even those with secondary osteoporosis 1

2. Bisphosphonates Are the Appropriate First-Line Treatment

The American College of Physicians strongly recommends bisphosphonates as first-line therapy for osteoporosis, with romosozumab reserved only for very high fracture risk patients who have failed or cannot tolerate bisphosphonates. 1, 4

• This patient discontinued Fosamax (alendronate) in May 2024, but there is no documentation of treatment failure, intolerance, or adverse effects that would justify bypassing bisphosphonates
• The clinical note states only that she "stopped taking Fosamax" without providing medical justification [@case presentation]
• Bisphosphonates have high-certainty evidence for fracture reduction with 6 fewer hip fractures, 18 fewer clinical vertebral fractures, and 56 fewer radiographic vertebral fractures per 1000 patients compared to placebo [@9@]

3. Patient Does Not Meet "Very High Fracture Risk" Criteria

The patient lacks the defining characteristics of very high fracture risk that would warrant anabolic therapy:

• No history of fragility fractures (explicitly documented: "No recent falls or new fractures or injuries") [@case presentation]
• No multiple vertebral fractures 1
• While her T-scores are low (femoral neck -3.5, total hip -3.6), T-scores alone do not define very high risk without accompanying fractures 1
• She is only 33 years old, not elderly or frail 1

4. Glucocorticoid-Induced Osteoporosis Context

This patient has secondary osteoporosis from her 2017 kidney-pancreas transplant with chronic glucocorticoid use:

• For glucocorticoid-induced osteoporosis, oral bisphosphonates are strongly recommended as first-line therapy in high or very high fracture risk adults 1
• Anabolic agents like romosozumab are conditionally recommended only for adults with very high fracture risk (which requires fracture history or multiple severe risk factors) 1
• The 2023 ACR guidelines for glucocorticoid-induced osteoporosis do not support romosozumab as initial therapy in patients without prior fractures 1

5. Significant Safety Concerns

• Romosozumab carries a black box warning for cardiovascular events, including myocardial infarction and stroke 5, 2
• The FDA explicitly recommends avoiding romosozumab in patients at high cardiovascular risk 1
• This patient has chronic kidney disease (eGFR 68, history of peritoneal dialysis) and is a transplant recipient—populations with elevated cardiovascular risk [@case presentation]
• Hypocalcemia must be corrected before initiation, which is particularly relevant in transplant patients on immunosuppression [@11@, 2]

6. Sequential Therapy Requirements

• Romosozumab requires mandatory sequential therapy with an antiresorptive agent after the 12-month treatment course to prevent rebound bone loss [@1@, 1, @10@]
• The anabolic effect wanes after 12 doses, necessitating transition to bisphosphonates or denosumab [@8@, @14@]
• This creates a more complex treatment pathway when bisphosphonates could be used effectively as initial monotherapy [@9@, @10@]

7. Cost-Effectiveness Considerations

• Bisphosphonates are significantly less expensive than romosozumab and available as generics [@2@, 1,4]
• The American College of Physicians specifically cites cost-effectiveness as a key factor favoring bisphosphonates as first-line therapy [1, @6@]
• Romosozumab should be reserved for patients who truly cannot use less expensive, equally effective alternatives [@9@]

Recommended Treatment Approach

Immediate Actions Required

1. Clarify why Fosamax was discontinued in May 2024—was there documented intolerance, adverse effects, or treatment failure? [@case presentation]
2. Restart oral bisphosphonate therapy (alendronate or risedronate) as first-line treatment unless contraindications exist 1, 4
3. Ensure adequate calcium (1000-1200 mg/day) and vitamin D (600-800 IU/day) supplementation 1, 4
4. Assess and correct any hypocalcemia before any osteoporosis therapy, particularly important in transplant patients 5

Alternative Options If Bisphosphonates Are Truly Contraindicated

• Intravenous zoledronic acid if oral bisphosphonates cause GI intolerance 4
• Denosumab as second-line therapy if bisphosphonates are contraindicated or ineffective 1
• Teriparatide could be considered for very high fracture risk, but this patient lacks fracture history 1

When Romosozumab Might Be Appropriate for This Patient

Romosozumab could potentially be reconsidered only if:

• She sustains a fragility fracture while on adequate bisphosphonate therapy 1
• She develops documented bisphosphonate intolerance or contraindications (esophageal disorders, severe renal impairment) 4
• She fails bisphosphonate therapy with continued bone loss or fractures after at least 1 year of treatment 1
• Cardiovascular risk is thoroughly assessed and deemed acceptable 5, 2

Medical Necessity Determination

This treatment plan does NOT meet criteria for medical necessity because:

1. The patient does not have the FDA-labeled indication (postmenopausal osteoporosis) 1
2. First-line therapy (bisphosphonates) has not been adequately trialed or documented as failed/contraindicated 1, 4
3. The patient lacks very high fracture risk features (no fracture history) that would justify anabolic therapy 1
4. The Aetna policy requires either fragility fracture history OR very low T-scores with indicators of very high fracture risk OR failed prior therapy—this patient meets none of these criteria definitively [@case presentation]

Standard of Care Assessment

This treatment plan is NOT considered standard of care and represents experimental/investigational use because:

• All major guidelines (ACP, ACR) recommend bisphosphonates as first-line therapy 1, 4
• Romosozumab is reserved for very high-risk patients or those who have failed first-line therapy [1, @6