What are the guidelines for sequential therapy in osteoporosis management?

Sequential Therapy for Osteoporosis Management

Sequential therapy is mandatory after discontinuing denosumab, romosozumab, and PTH/PTHrP analogs (teriparatide, abaloparatide) to prevent rebound bone loss and vertebral fractures, while bisphosphonates and raloxifene can be stopped without requiring sequential therapy. 1

Critical Principle: Which Medications Require Sequential Therapy

Medications That MUST Be Followed by Sequential Therapy:

• Denosumab: Strongly requires transition to bisphosphonate or romosozumab 6-9 months after the last dose to prevent rebound vertebral fractures 1
• Romosozumab: Must be followed by bisphosphonate or denosumab after completing the 12-month course 1, 2
• PTH/PTHrP analogs (teriparatide, abaloparatide): Should be followed by bisphosphonate or denosumab to prevent gradual bone loss over 12-18 months 1

Medications That Do NOT Require Sequential Therapy:

• Bisphosphonates (oral or IV): Can be discontinued without sequential therapy 1
• Raloxifene: Can be discontinued without sequential therapy 1

Specific Sequential Therapy Algorithms

After Denosumab Discontinuation:

Start bisphosphonate 6-9 months after the last denosumab dose 1

• Duration: Treat for at least 1 year with oral bisphosphonate OR 1-2 years with IV bisphosphonate 1
• Alternative: Romosozumab can be used, but must then be followed by bisphosphonate 1
• Critical timing: The 6-9 month window is essential to prevent rebound vertebral fractures 1

After PTH/PTHrP Discontinuation:

Transition to bisphosphonate or denosumab immediately after completing the course 1

• If denosumab is chosen: Must subsequently transition to bisphosphonate when denosumab is stopped 1
• Rationale: Anti-fracture efficacy may persist for 18 months, but bone loss begins gradually without antiresorptive therapy 1

After Romosozumab Discontinuation:

Transition to bisphosphonate or denosumab after the 12-month romosozumab course 1, 2

• Duration of romosozumab: Limited to 12 monthly doses as the anabolic effect wanes after this period 2
• If denosumab is chosen: Must subsequently transition to bisphosphonate when denosumab is stopped 1
• If romosozumab is used after denosumab: Must still be followed by bisphosphonate 1

Treatment Failure Requiring Sequential Change

When to Switch Medication Classes:

If osteoporotic fracture occurs ≥12 months after starting therapy OR significant BMD loss (greater than least significant change) after 1-2 years, switch to a different medication class 1

Switching Algorithm Based on Initial Therapy:

• From oral bisphosphonate (if poor adherence/absorption suspected): Switch to IV bisphosphonate, denosumab, romosozumab, or PTH/PTHrP 1
• From denosumab: Do NOT switch to PTH/PTHrP as this causes transient bone loss in hip and spine 1
• From PTH/PTHrP: Can switch to denosumab (leads to continued BMD increases) 1
• After long-term bisphosphonate: PTH/PTHrP has blunted anabolic response but still increases BMD 1

Special Considerations for Glucocorticoid-Induced Osteoporosis

Very High Fracture Risk Patients:

Anabolic agents (PTH/PTHrP) are conditionally recommended as initial therapy over antiresorptives for very high fracture risk 1

• Very high risk defined as: Prior osteoporotic fracture(s) OR BMD t-score ≤-3.5 OR FRAX 10-year risk of major osteoporotic fracture ≥30% or hip ≥4.5% OR high glucocorticoid dose ≥30 mg/day for >30 days or cumulative doses ≥5 g/year 1
• Rationale: Anabolic agents provide superior vertebral fracture prevention compared to antiresorptives in very high-risk patients 1

When Discontinuing Glucocorticoids:

If BMD t-score ≥-2.5 and no new fragility fracture: Stop osteoporosis therapy (except denosumab, PTH/PTHrP, romosozumab which require sequential therapy) 1

If BMD t-score ≤-2.5 or history of fragility fracture after ≥12 months of therapy: Continue current therapy or switch to another medication class 1

Common Pitfalls to Avoid

• Never stop denosumab without planning sequential bisphosphonate therapy - this is associated with rapid bone loss and vertebral fractures 1
• Never transition from denosumab to PTH/PTHrP - this causes transient bone losses 1
• Never use romosozumab beyond 12 months - the anabolic effect wanes 2
• Never forget that if denosumab is used after any anabolic agent, bisphosphonate must follow when denosumab is stopped 1

Optimal Treatment Sequence for Severe Osteoporosis

For patients with severe osteoporosis and high fracture risk, start with bone-building drugs (teriparatide, abaloparatide, or romosozumab) followed by antiresorptive therapy 3, 4, 5, 6

• Rationale: This sequence provides maximal BMD gains and better fracture risk reduction compared to the opposite sequence 4, 6
• Evidence: Anabolic agents followed by antiresorptives afford better and earlier fracture risk reduction than antiresorptive-first approaches 4
• Long-term management: Osteoporosis requires lifelong treatment with sequential therapy adapted to fracture risk and comorbidities 7