Is it best to begin anabolic therapy or Prolia (denosumab) after completing bisphosphonate therapy with Fosamax (alendronate) in a patient with osteoporosis?

Transitioning After Bisphosphonate Therapy: Direct to Denosumab vs. Anabolic Therapy First

For patients completing 5 years of bisphosphonate therapy (Fosamax/alendronate), you can proceed directly to Prolia (denosumab) without requiring anabolic therapy first, unless the patient is at very high fracture risk or has experienced treatment failure. 1

Risk Stratification Determines the Optimal Pathway

Very High-Risk Patients: Anabolic Therapy First

For patients at very high fracture risk, anabolic agents (teriparatide or romosozumab) are conditionally recommended over antiresorptive agents like denosumab. 1

Very high-risk features include:

• Multiple vertebral fractures 1
• Fracture occurring after ≥18 months of bisphosphonate treatment 1
• Significant bone loss (≥10% per year) despite bisphosphonate therapy 1
• T-score ≤ -3.0 with additional risk factors 1
• Age >80 years with multiple risk factors 2
• Ongoing high-dose glucocorticoid use (≥7.5 mg prednisone daily) 1

High-Risk Patients: Either Denosumab or Anabolic Therapy

For adults ≥40 years at high risk of fracture, denosumab or anabolic agents (PTH/PTHrP) are conditionally recommended over continuing bisphosphonates. 1

High-risk features include:

• History of hip or vertebral fracture 2
• T-score ≤ -2.5 at the femoral neck after 5 years of treatment 2
• Multiple non-spine fractures 2

Moderate-Risk Patients: Denosumab is Appropriate

For patients at moderate fracture risk who have completed 5 years of bisphosphonate therapy, denosumab is conditionally recommended as a reasonable continuation option. 1

Moderate-risk patients can transition directly to denosumab without requiring anabolic therapy first. 1

Why Direct Transition to Denosumab is Often Appropriate

Efficacy Evidence

• Denosumab demonstrates superior BMD increases compared to bisphosphonates (3.5% vs 2.6% at the hip) and provides sustained fracture risk reduction. 2
• In registry-based real-world data, denosumab showed significantly greater vertebral fracture risk reduction than alendronate (adjusted HR 0.47) or ibandronate (adjusted HR 0.70). 3
• The American College of Physicians recommends denosumab as second-line therapy for patients with contraindications to bisphosphonates (moderate-certainty evidence). 1

When Anabolic Therapy is NOT Required First

The 2023 ACP guidelines explicitly state that anabolic agents are reserved for "females with primary osteoporosis at very high risk of fracture," not for all patients completing bisphosphonate therapy. 1

The 2022 ACR guidelines for glucocorticoid-induced osteoporosis recommend anabolic agents over antiresorptives only in very high-risk patients, while conditionally recommending either denosumab or anabolic therapy for high-risk patients. 1

Critical Considerations Before Starting Denosumab

The Rebound Fracture Risk

The most important caveat with denosumab is that it CANNOT be discontinued without immediate transition to bisphosphonate therapy. 2, 4, 5

• Multiple vertebral fractures can occur as early as 7 months after denosumab discontinuation (average 19 months). 5
• If denosumab must be stopped, bisphosphonate therapy must be initiated within 6 months to suppress rebound osteolysis. 2, 4
• This is a permanent commitment unless the patient transitions back to bisphosphonates—there is no safe "drug holiday" from denosumab. 2, 5

Dental Evaluation is Mandatory

A routine oral examination should be performed before initiating denosumab, with completion of any invasive dental procedures prior to starting therapy. 5

• Risk of osteonecrosis of the jaw (ONJ) increases with duration of denosumab treatment. 5
• Patients with risk factors (invasive dental procedures, cancer diagnosis, concomitant corticosteroids, poor oral hygiene) require dental examination with preventive dentistry before treatment. 5

Algorithmic Approach to Decision-Making

Step 1: Assess fracture risk after 5 years of bisphosphonate therapy

• Obtain current BMD (especially femoral neck T-score)
• Document any fractures during treatment
• Calculate FRAX score (if ≥40 years old)
• Assess for ongoing risk factors (glucocorticoid use, age >80, multiple comorbidities)

Step 2: Categorize patient risk level

• Very high risk → Anabolic therapy (teriparatide or romosozumab) followed by denosumab or bisphosphonate 1
• High risk → Either denosumab OR anabolic therapy (shared decision-making based on patient preference, cost, injection tolerance) 1
• Moderate risk → Denosumab is appropriate; alternatively consider bisphosphonate drug holiday with close monitoring 1, 2
• Low risk → Consider drug holiday with reassessment in 2 years 2

Step 3: If choosing denosumab, complete pre-treatment requirements

• Dental examination and completion of invasive dental work 5
• Ensure adequate calcium (1000-1200 mg/day) and vitamin D (800 IU/day) 5
• Counsel patient about permanent commitment (no safe discontinuation without transition therapy) 2, 5
• Assess renal function (denosumab preferred if CrCl <60 ml/min) 2

Step 4: If choosing anabolic therapy first

• Plan for 1-2 years of anabolic treatment 1
• Mandatory transition to antiresorptive (denosumab or bisphosphonate) after anabolic therapy to preserve gains 1

Common Pitfalls to Avoid

Do not assume all patients need anabolic therapy before denosumab—this is only for very high-risk patients. 1

Do not start denosumab without counseling about the rebound fracture risk—patients must understand this is not a medication they can simply stop. 2, 5

Do not initiate denosumab without dental clearance in high-risk patients—ONJ risk increases with treatment duration and is highest with recent dental procedures. 5

Do not continue bisphosphonates indefinitely without reassessment—after 5 years, the risk of rare adverse events (ONJ, atypical femoral fractures) increases while additional fracture benefit is limited to vertebral fractures only. 1, 6, 2

If the patient later discontinues denosumab, do not allow a gap in therapy—bisphosphonate must be started within 6 months to prevent rebound vertebral fractures. 2, 4, 5