In an 88‑year‑old woman with breast cancer, nine years of alendronate (Fosamax) followed by a drug holiday and two years of denosumab (Prolia), who now has a supracondylar femoral fragility fracture and a declining DXA T‑score of –2.5, what is the next management step?

Management of Osteoporosis After Atypical Femoral Fracture on Denosumab

This patient must immediately transition to intravenous zoledronic acid (4–5 mg as a single dose) to prevent catastrophic rebound vertebral fractures, and should then be considered for anabolic therapy with teriparatide given the treatment failure on denosumab. 1, 2, 3

Critical Understanding: Denosumab Cannot Be Safely Stopped

Denosumab fundamentally differs from bisphosphonates—it does not incorporate into bone matrix, and discontinuation triggers rapid rebound bone turnover with a marked increase in vertebral fracture risk beginning 3–7 months after the missed dose. 1, 2, 3 This patient has already experienced an atypical femoral fracture (AFF) while on denosumab, which represents a rare but serious complication requiring drug cessation 1, 4, 5, yet stopping denosumab without immediate bisphosphonate transition would expose her to an even greater risk of multiple spontaneous vertebral fractures 1, 2, 3.

The Rebound Phenomenon

• Bone turnover markers rise above baseline within 3–6 months of the last denosumab dose 2
• Bone mineral density returns to pretreatment levels within 12–18 months 2
• Multiple vertebral fractures have been documented in clinical trials and case series, occurring on average 19 months (range 7–24 months) after discontinuation 1, 2, 3
• This rebound effect occurs in both osteoporosis patients and cancer patients, regardless of bone metastases status 1, 2

Immediate Management Algorithm

Step 1: Urgent Bisphosphonate Transition (Within 6–7 Months of Last Denosumab Dose)

Administer a single dose of intravenous zoledronic acid 4–5 mg immediately to suppress the rebound osteolysis 1, 2. This is the most widely recommended post-denosumab regimen by osteoporosis specialists, though the optimal protocol remains incompletely defined 1, 2.

• Do not apply bisphosphonate "drug holiday" concepts—the pharmacology is fundamentally different and requires continuous antiresorptive coverage 6, 2
• Ensure adequate calcium (≥1000 mg daily) and vitamin D (≥800 IU daily) supplementation before zoledronic acid administration to prevent hypocalcemia 1, 3
• Check serum calcium, creatinine, and vitamin D levels before infusion 1, 3

Step 2: Address the Atypical Femoral Fracture

The supracondylar femoral fracture requires orthopedic evaluation for surgical fixation 1. Atypical femoral fractures are characterized by transverse fracture lines, periosteal callus formation, and minimal comminution—features resembling stress fractures 1.

• AFFs occur in 3.2–50 cases per 100,000 person-years with antiresorptive therapy, rising to ~100 per 100,000 person-years with long-term use (median 7 years) 1, 6
• This patient received 9 years of alendronate plus 2 years of denosumab (11 years total antiresorptive exposure), placing her in the higher-risk category 1, 6, 5
• Evaluate the contralateral femur with imaging, as AFFs can be bilateral 1

Step 3: Transition to Anabolic Therapy After Fracture Healing

Once the femoral fracture has healed (typically 3–6 months post-operatively), initiate teriparatide 20 mcg subcutaneously daily for up to 24 months 4, 7, 8. This represents the most appropriate next step for several reasons:

• Anabolic therapy is indicated after antiresorptive treatment failure, particularly in patients who fracture despite adequate therapy 4, 8
• Teriparatide reduces vertebral fractures by ~70% and non-vertebral fractures by ~45% in postmenopausal women 8
• The patient's declining bone density (T-score –2.5) and fragility fracture while on therapy indicate high fracture risk requiring the most potent available treatment 1, 9, 4
• Discontinuing all antiresorptives without anabolic replacement would leave this 88-year-old with severe osteoporosis unprotected 4

Alternative Anabolic Approach

If teriparatide is not tolerated or contraindicated, consider cyclic teriparatide or abaloparatide (3 months on, 3 months off) as an off-label strategy to minimize potential AFF recurrence risk while maintaining bone formation 4. However, this approach lacks FDA approval and fracture outcome data 4.

Step 4: Sequential Therapy After Anabolic Treatment

After completing 24 months of teriparatide, transition back to an antiresorptive agent to maintain BMD gains 8. Given this patient's history:

• Denosumab 60 mg every 6 months is the preferred option after teriparatide, as combination and sequential data show superior BMD increases compared to either agent alone 7, 8
• The prior AFF occurred after 11 years of cumulative antiresorptive exposure; resuming denosumab after a 2–3 year anabolic "reset" may carry lower AFF risk 4
• If denosumab is restarted, the patient must understand it cannot be stopped again without bisphosphonate transition 6, 2, 3
• Alternative: Resume zoledronic acid 5 mg annually if denosumab is declined 1

Maximize Non-Pharmacologic Management

While pharmacologic therapy is being optimized, implement comprehensive fall and fracture prevention 4:

• Home safety assessment to remove tripping hazards, improve lighting, and install grab bars 4
• Physical therapy for gait training, balance exercises, and strengthening (particularly important post-operatively) 4
• Vision and hearing assessment to address sensory deficits contributing to falls 4
• Medication review to eliminate drugs increasing fall risk (sedatives, anticholinergics, antihypertensives causing orthostasis) 4
• Adequate nutrition: Ensure protein intake ≥1.0 g/kg/day and correct any vitamin D deficiency (target 25-OH vitamin D ≥30 ng/mL) 1, 4

Investigate Secondary Causes of Osteoporosis

Re-evaluate for secondary causes if not comprehensively assessed previously 4:

• Thyroid function (hyperthyroidism accelerates bone loss) 4
• Parathyroid hormone (primary hyperparathyroidism) 4
• Serum protein electrophoresis (multiple myeloma, especially given breast cancer history) 4
• Celiac serology (malabsorption) 4
• 24-hour urine calcium (idiopathic hypercalciuria) 4
• Vitamin D and calcium levels 1, 4

Monitoring During Transition

• Serum calcium should be checked 7–10 days after zoledronic acid infusion, then monthly for 3 months, given the patient's age and renal function 3
• Bone turnover markers (CTX, P1NP) at 3 and 6 months to confirm suppression of rebound and later anabolic response to teriparatide 2, 8
• DXA scan at 12–24 months to document response to anabolic therapy 1
• Clinical surveillance for new thigh, hip, or groin pain that could herald contralateral AFF 1, 6, 3
• Dental examination before any future denosumab use to minimize osteonecrosis of the jaw risk 1

Critical Pitfalls to Avoid

1. Never discontinue denosumab without immediate bisphosphonate transition—this is the single most dangerous error and can result in catastrophic multiple vertebral fractures 1, 6, 2, 3

2. Do not simply resume denosumab after the AFF heals—this patient has demonstrated treatment failure (fracture on therapy) and requires a different approach 4

3. Do not leave the patient without any osteoporosis treatment—her age (88), T-score (–2.5), fragility fracture, and breast cancer history place her at extremely high risk 1, 9, 4

4. Do not use oral bisphosphonates post-denosumab—intravenous zoledronic acid is strongly preferred for adequate rebound suppression 1, 2

5. Do not delay orthopedic consultation—AFFs require surgical evaluation and often prophylactic fixation 1

Special Considerations in This Cancer Survivor

This patient's breast cancer history adds complexity 1:

• If she previously received aromatase inhibitor therapy, this contributed to accelerated bone loss 1
• Ensure she is not currently on endocrine therapy that would continue to compromise bone health 1
• Her 9-year alendronate course may have been initiated for cancer treatment-induced bone loss rather than primary osteoporosis 1
• The ESMO guidelines support aggressive bone protection in cancer survivors with osteoporosis 1