Is bone loss associated with darolutamide (Nubeqa) or abiraterone (Zytiga) hormone therapy in a male patient with prostate cancer recurrence?

Bone Loss with Darolutamide vs. Abiraterone in Prostate Cancer

Bone loss is primarily associated with the underlying androgen deprivation therapy (ADT) used in prostate cancer treatment, not specifically with darolutamide or abiraterone themselves—however, abiraterone requires concurrent prednisone which may compound bone loss risk, while darolutamide does not require corticosteroids. 1

Understanding the Primary Mechanism of Bone Loss

The bone loss concern in prostate cancer recurrence stems predominantly from ADT itself, which both darolutamide and abiraterone are administered alongside:

• ADT causes progressive loss of bone mineral density leading to measurable osteopenia or frank osteoporosis, increasing fracture risk even in patients with non-metastatic disease 1
• After 12 months of ADT, significant decreases occur in bone mineral density of the total hip and ultra-distal radius compared to age-matched controls 1
• ADT increases fracture risk for any clinical fracture, hip/femur fractures, and vertebral fractures, with risk increasing proportionally to the dose of GnRH agonist received 1

Abiraterone-Specific Bone Considerations

Abiraterone carries additional bone loss risk because it requires concurrent prednisone 5 mg daily, which independently contributes to bone loss:

• Abiraterone is administered with prednisone to manage mineralocorticoid excess side effects (hypertension, hypokalemia, edema) 1
• The combination showed adverse events related to mineralocorticoid excess and hormonal effects, though generally mild 1
• Older men (≥70 years) experienced increased toxicities with abiraterone, suggesting heterogeneity in clinical benefits by age and comorbidity 1

Darolutamide-Specific Bone Considerations

Darolutamide does not require concurrent corticosteroids, which theoretically reduces compounded bone loss risk:

• Adverse events with darolutamide were similar to placebo in the ARAMIS trial, with fatigue (12.1% vs 8.7%), pain in extremity (5.8% vs 3.2%), and rash (2.9% vs 0.9%) being most common 2
• No specific bone loss or fracture data is highlighted in the darolutamide evidence, suggesting it does not add significant bone-specific toxicity beyond baseline ADT effects 2

Essential Bone Protection Strategies

All men on ADT (regardless of whether receiving darolutamide or abiraterone) require proactive bone health management:

Baseline Assessment and Monitoring

• Calculate fracture risk using FRAX® tool, with BMD assessment included where feasible 3
• BMD should always be assessed where fracture risk calculated using FRAX® alone is close to intervention threshold 3
• Repeat FRAX® (including BMD) after 12-18 months for those near intervention threshold or starting additional systemic therapies 3

Universal Interventions

• Calcium and vitamin D supplementation for all patients on ADT 1
• Vitamin D at higher doses (700-800 IU/day) reduces hip fracture risk by 26% and non-vertebral fractures by 23%; 400 IU/day shows no benefit 1
• Lifestyle modifications including smoking cessation, moderation of alcohol consumption, and regular weight-bearing exercise 4, 5

Pharmacologic Bone Protection

• Zoledronic acid (4 mg annually or every 3 months) prevents ADT-induced bone loss and increases BMD by 5.6% in the lumbar spine 1
• Alendronate (70 mg orally weekly) increases BMD by 3.7% over 1 year in men on ADT 1
• Denosumab (120 mg subcutaneously every 4 weeks) for castration-resistant disease with bone metastases, though requires calcium supplementation and monitoring for hypocalcemia 1, 6
• Bisphosphonate therapy should be considered for men receiving ADT who are at substantial risk for fracture based on standard risk assessment tools 1

Clinical Decision Algorithm

For patients starting abiraterone:

• Recognize dual bone loss risk from both ADT and prednisone 1
• Implement bone protection measures at treatment initiation, particularly in older patients (≥70 years) 1
• Monitor for mineralocorticoid excess effects that may complicate bone health management 1

For patients starting darolutamide:

• Recognize bone loss risk from ADT alone 2
• Implement standard bone protection measures as with any ADT regimen 3
• No additional corticosteroid-related bone concerns 2

Critical Caveats

• Calcium supplementation alone (500-1,000 mg/day) cannot prevent bone mineral density loss from ADT and may be associated with cardiovascular disease risk 1
• Ensure dental evaluation before initiating bone-targeted therapy to reduce osteonecrosis of jaw risk 6
• Hypocalcemia is a not-uncommon side effect requiring dose modification when using zoledronic acid or denosumab 1
• Antiresorptive bone therapy has not shown benefit in the setting of noncastrate bone metastases for skeletal-related event risk reduction 1