Can Prolia (denosumab) and bisphosphonates be taken together?

Concurrent Use of Prolia (Denosumab) and Bisphosphonates

Prolia (denosumab) and bisphosphonates should not be used concurrently as there is no evidence supporting additional benefit from combination therapy, while potentially increasing risk of adverse effects. 1

Rationale for Not Combining These Medications

• Bisphosphonates are recommended as first-line treatment for osteoporosis due to their favorable balance of benefits, harms, patient preferences, and lower cost 1, 2
• Denosumab is specifically recommended as a second-line pharmacologic treatment for patients who have contraindications to or experience adverse effects from bisphosphonates 1, 2
• Both medications work as antiresorptive agents that inhibit osteoclast activity, though through different mechanisms, making their combination potentially redundant 1, 3
• The European Society for Medical Oncology (ESMO) guidelines indicate that based on current knowledge of pharmacodynamics, denosumab appears to require continuous monthly therapy for metastatic bone disease, not combination therapy 1

Comparative Effectiveness

• Denosumab achieves greater suppression of bone turnover and greater increases in bone mineral density (BMD) at all skeletal sites compared to bisphosphonates, both in treatment-naïve and previously treated patients 3, 4
• In patients previously treated with oral bisphosphonates, transitioning to denosumab resulted in significantly greater BMD increases at all measured skeletal sites compared to zoledronic acid (3.2% vs 1.1% at lumbar spine) 4
• Sequential treatment from bisphosphonate to denosumab (not concurrent use) has shown positive effects on lumbar spine bone density in postmenopausal women 5

Safety Considerations

• Both bisphosphonates and denosumab are associated with rare but serious adverse events:
  • Osteonecrosis of the jaw (ONJ) 1, 6
  • Atypical femoral fractures 1, 4
• The risk of ONJ increases with time and reaches approximately 5% when denosumab is continued beyond 3 years 1
• Zoledronic acid is associated with more episodes of acute phase response and renal dysfunction than denosumab 1
• Hypocalcemia is more frequent and more likely to be symptomatic with denosumab, requiring calcium and vitamin D supplementation 1

Appropriate Therapeutic Approach

• For patients requiring osteoporosis treatment:

  1. Start with bisphosphonates as first-line therapy 1, 2
  2. If bisphosphonates are contraindicated or poorly tolerated, switch completely to denosumab 1, 2
  3. If transitioning from bisphosphonates to denosumab, discontinue the bisphosphonate before starting denosumab 4, 5

• For patients discontinuing denosumab:

  • Consider transitioning to a bisphosphonate to prevent rebound bone loss and increased fracture risk 2, 7
  • Do not stop denosumab without planning for alternative therapy, as its discontinuation rapidly reverses its effects on bone markers and BMD 3, 7

Special Considerations

• In cancer patients with bone metastases, both bisphosphonates and denosumab reduce skeletal-related events (SREs), including bone pain 1
• For glucocorticoid-induced osteoporosis, oral bisphosphonates are first-line therapy, with denosumab considered only when bisphosphonates are not appropriate 1
• Monitoring bone mineral density during treatment with either medication is not supported by evidence 1, 2

Remember that while sequential therapy (switching from one medication class to another) may be appropriate in certain clinical scenarios, concurrent use of denosumab and bisphosphonates is not recommended based on current clinical guidelines.