What are alternative treatments to bisphosphonates (BPs) for osteoporosis?

Alternative Treatments to Bisphosphonates for Osteoporosis

Denosumab is the recommended second-line treatment for patients with osteoporosis who have contraindications to or experience adverse effects from bisphosphonates. 1

First-Line Treatment: Bisphosphonates

Before discussing alternatives, it's important to understand that bisphosphonates remain the first-line therapy for osteoporosis due to:

• Strong evidence showing reduction in hip fractures (6 fewer events per 1000 patients), clinical vertebral fractures (18 fewer events per 1000 patients), and radiographic vertebral fractures (56 fewer events per 1000 patients) compared to placebo 1
• Cost-effectiveness and availability in generic formulations 1
• Long-established safety profile despite rare adverse events 1

Second-Line Treatment Options

1. Denosumab (RANK Ligand Inhibitor)

Denosumab is the most strongly recommended alternative when bisphosphonates cannot be used:

• Recommended by the American College of Physicians as second-line therapy for both postmenopausal women (moderate-certainty evidence) and men (low-certainty evidence) with primary osteoporosis 1
• Mechanism: Binds to RANKL (like osteoprotegerin) to reduce binding between RANK and RANKL, inhibiting osteoclastogenesis and reducing bone resorption 2
• Advantages:
  • Achieves greater suppression of bone turnover markers and greater increases in BMD compared to bisphosphonates 3, 4
  • Convenient biannual subcutaneous administration (60mg every 6 months) 5, 2
  • Can be used in patients with impaired renal function 2, 3
• Important considerations:
  • Discontinuation causes rapid reversal of effects and increased fracture risk, requiring immediate follow-up treatment 3
  • Limited safety data in patients treated with immunosuppressive agents 1

2. Teriparatide (Parathyroid Hormone Analog)

• Recommended as third-line therapy after bisphosphonates and denosumab 1
• Only FDA-approved anabolic (bone-forming) agent for osteoporosis 6
• Advantages:
  • Increases new bone formation rather than just preventing resorption 6
  • Particularly useful in severe osteoporosis or patients with fractures 1
• Limitations:
  • Higher cost and burden of therapy with daily injections 1
  • Limited to 2 years of treatment 6

3. Raloxifene (Selective Estrogen Receptor Modulator)

• Recommended only for postmenopausal women when other options are not appropriate 1
• Limitations:
  • Lack of adequate data on benefits for vertebral and hip fractures in specific populations 1
  • Potential harms including clotting risks 1
  • Not recommended for men 1

4. Intravenous Bisphosphonates

When oral bisphosphonates cannot be tolerated:

• IV zoledronic acid or pamidronate can be considered 1
• Particularly useful when:
  • Gastrointestinal issues prevent oral administration 3
  • Adherence to oral regimens is poor 1
• Limitations:
  • Higher risk profile for IV infusion compared to oral therapy 1

Special Considerations

Renal Impairment

• Denosumab is preferred over bisphosphonates in patients with impaired renal function 2, 3

Glucocorticoid-Induced Osteoporosis

• Treatment hierarchy remains similar: oral bisphosphonates first, followed by IV bisphosphonates, teriparatide, and denosumab 1
• Denosumab has shown efficacy in glucocorticoid-induced osteoporosis with 60mg subcutaneous injections every 6 months 5

Combination Therapy

• Combination of teriparatide with denosumab or zoledronic acid (but not alendronate) provides increased BMD gains at all sites 3

Important Caveats

• Regardless of treatment choice, adequate calcium (1,000-1,200 mg/day) and vitamin D (600-800 IU/day) intake should be maintained 1
• Lifestyle modifications including weight-bearing exercise, smoking cessation, and limiting alcohol intake are recommended alongside pharmacological therapy 1
• When switching from bisphosphonates to denosumab, be aware that discontinuation of denosumab without follow-up treatment can lead to rapid bone loss and increased fracture risk 3

Treatment Algorithm

1. First-line: Oral bisphosphonates (alendronate, risedronate) 1
2. If contraindicated, not tolerated, or ineffective:
   • Second-line: Denosumab 1
   • Third-line: Teriparatide 1
   • Fourth-line: IV bisphosphonates 1
   • For postmenopausal women only (if above options not suitable): Raloxifene 1