When is it appropriate to prescribe Prolia (denosumab) and raloxifene for osteoporosis?

When to Use Prolia (Denosumab) and Raloxifene Together

You should never use Prolia (denosumab) and raloxifene simultaneously—these medications are not prescribed in combination. Both are antiresorptive agents for osteoporosis that work through different mechanisms, but there is no evidence supporting their concurrent use, and combination therapy with multiple osteoporosis medications is not recommended. 1

Understanding the Separate Roles of Each Medication

Prolia (Denosumab) - Second-Line Therapy

Denosumab is reserved as a second-line option for patients who cannot tolerate or have contraindications to oral bisphosphonates. 1, 2

Appropriate circumstances for denosumab include:

• Postmenopausal women or men ≥40 years with moderate-to-high fracture risk who have failed oral bisphosphonates or cannot take them due to gastrointestinal intolerance, esophageal disorders, or inability to remain upright for 30-60 minutes. 1, 3

• Dosing: 60 mg subcutaneously every 6 months. 4, 5, 6

• Key advantage: Convenient twice-yearly subcutaneous injection may improve adherence compared to daily or weekly oral medications. 4, 7

Critical safety warning: Denosumab should never be discontinued abruptly without transitioning to a bisphosphonate, as this causes rapidly rising bone turnover markers and a significant risk of multiple vertebral fractures. 3, 8

Important limitation in glucocorticoid-induced osteoporosis: Denosumab has a lack of safety data in patients treated with immunosuppressive agents, making it a lower priority than IV bisphosphonates in this population. 1

Raloxifene - Last-Resort Option Only

Raloxifene should only be used in postmenopausal women when all other preferred osteoporosis medications are inappropriate. 1, 2

Raloxifene is the absolute last choice because:

• Lack of adequate fracture data: There is insufficient evidence demonstrating benefit for hip fracture reduction in glucocorticoid users or general osteoporosis populations. 1

• Serious cardiovascular risks: Raloxifene increases the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and is associated with fatal stroke, particularly in women with coronary heart disease or elevated cardiovascular risk. 1, 3

• The American College of Physicians strongly recommends against raloxifene for osteoporosis treatment due to an unfavorable benefit-harm balance. 2, 3

The only acceptable scenario for raloxifene:

• Postmenopausal women with moderate-to-high fracture risk in whom oral bisphosphonates, IV bisphosphonates, teriparatide, and denosumab are all contraindicated or not tolerated. 1

• Dosing: 60 mg orally daily. 1

• Contraindications: History of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or prolonged immobilization. 1

The Correct Treatment Algorithm

First-line therapy: Oral bisphosphonates (alendronate 70 mg weekly or risedronate 35 mg weekly) plus calcium 1,200 mg daily and vitamin D 800 IU daily. 1, 2, 3

If oral bisphosphonates fail or are contraindicated:

1. IV bisphosphonates (zoledronic acid 5 mg annually) are preferred over denosumab due to lower risk profile. 1

2. Denosumab (60 mg subcutaneously every 6 months) if IV bisphosphonates are also inappropriate. 1, 2

3. Teriparatide or other anabolic agents for very high-risk patients (recent vertebral fracture, hip fracture with T-score ≤-2.5, or multiple fractures). 2, 3

4. Raloxifene only as an absolute last resort in postmenopausal women when none of the above options are appropriate. 1

Common Pitfalls to Avoid

Never combine multiple osteoporosis medications simultaneously (such as denosumab plus raloxifene) outside of specific anabolic-to-antiresorptive sequential therapy protocols, as there is no evidence supporting combination therapy and it increases costs and potential adverse effects without proven fracture benefit. 1

Never use raloxifene in premenopausal women—it is only indicated for postmenopausal women and should not be used for breast cancer risk reduction in the osteoporosis setting. 1

Never discontinue denosumab without a transition plan to bisphosphonates, as this creates a rebound effect with increased vertebral fracture risk. 3, 8