What are the differences between bisphosphonates, PTH (parathyroid hormone) analogues, and calcitonin for treating osteoporosis?

Bisphosphonates vs PTH Analogues vs Calcitonin for Osteoporosis Treatment

Bisphosphonates should be used as first-line treatment for osteoporosis due to their superior efficacy in reducing fracture risk, extensive safety data, and cost-effectiveness compared to PTH analogues and calcitonin. 1

Comparison of Efficacy

Bisphosphonates

• Reduce risk of hip fractures (6 fewer events per 1000 patients), clinical vertebral fractures (18 fewer events per 1000 patients), any clinical fracture (24 fewer events per 1000 patients), and radiographic vertebral fractures (56 fewer events per 1000 patients) compared to placebo 1
• Have the most favorable balance among benefits, harms, patient values and preferences, and cost among all drug classes evaluated for osteoporosis treatment 1
• Available in multiple formulations (oral daily, weekly, monthly, and intravenous) to improve adherence 2, 3
• Alendronate, risedronate, and zoledronic acid have demonstrated efficacy in reducing both vertebral and non-vertebral fractures 1, 4

PTH Analogues (Teriparatide)

• Indicated for patients at high risk for fracture or who have failed or are intolerant to other available osteoporosis therapy 5
• Reduces risk of any clinical fractures (27 fewer events per 1000 patients), radiographic vertebral fractures (69 fewer events per 1000 patients), and clinical vertebral fractures (45 fewer events per 1000 patients) 6
• Compared to bisphosphonates, teriparatide reduces radiographic vertebral fractures (66 fewer events per 1000 patients) and may reduce any clinical fracture (46 fewer events per 1000 patients) 6
• Should be reserved for patients with severe osteoporosis, very high fracture risk, or who have failed other therapies 1, 6

Calcitonin

• Less effective than bisphosphonates and PTH analogues 7
• Some randomized controlled trials have shown a decrease in vertebral fracture rate, but evidence is weaker 1
• Calcitonin given with calcium for six months in women with PBC with a z score of −2 did not affect the rate of bone loss compared with calcium alone 1
• Only recommended for women more than five years past menopause and as a third-line option 7

Safety Profile Comparison

Bisphosphonates

• High-certainty evidence shows no differences between bisphosphonates and placebo in serious adverse events and withdrawals due to adverse events at least 3 years after treatment initiation 1
• Associated with higher risk for atypical femoral fractures and osteonecrosis of the jaw (low certainty evidence), although observed events were uncommon (0.01% to 0.3% of users) 1
• Oral formulations may cause esophageal irritation and should be avoided in patients with esophageal varices 1
• Longer treatment duration may be associated with higher risk for osteonecrosis of the jaw and atypical femoral fractures 1

PTH Analogues (Teriparatide)

• Common side effects include arthralgia, pain, and nausea 5
• May cause transient orthostatic hypotension with initial doses 5
• Previously had a boxed warning about osteosarcoma risk (now removed), but still contraindicated in patients with increased risk of osteosarcoma 5
• Limited to 24 months of treatment during a patient's lifetime 5

Calcitonin

• Generally well-tolerated with rhinitis being the most common side effect for nasal spray formulation 1
• Weaker efficacy data compared to other options 7

Treatment Algorithm

1. First-line therapy: Bisphosphonates (alendronate, risedronate, or zoledronic acid) 1

   • Most cost-effective option with generic formulations available 1
   • Strong recommendation for postmenopausal women (high-certainty evidence) 1
   • Conditional recommendation for men (low-certainty evidence) 1

2. Second-line therapy: RANK ligand inhibitor (denosumab) 1

   • For patients with contraindications to or adverse effects from bisphosphonates 1
   • Comparable efficacy to bisphosphonates in fracture risk reduction 1

3. Third-line therapy for very high fracture risk: PTH analogue (teriparatide) or sclerostin inhibitor (romosozumab), followed by a bisphosphonate 1, 6

   • Reserved for patients with severe osteoporosis, multiple fractures, or failure of other therapies 6
   • Limited to 24 months of treatment 5
   • Should be followed by bisphosphonate therapy to maintain bone density gains 6

4. Alternative therapy: Calcitonin 1, 7

   • Generally not recommended as first-line due to weaker efficacy 7
   • May be considered in specific situations where other options are contraindicated 7

Key Clinical Considerations

• Bisphosphonates are significantly less expensive than other osteoporosis medications 1
• Oral bisphosphonates should be taken on an empty stomach, 0.5–2 hours before food and other drugs, and at a different time than calcium supplements 1
• Typical bisphosphonate therapy duration is 5 years, with consideration for interrupting therapy after 5-10 years 7
• After completing teriparatide treatment, patients should transition to a bisphosphonate to maintain bone density gains 6
• All patients should receive adequate calcium (1,000-1,200 mg daily) and vitamin D (600-800 IU daily) supplementation 7

Common Pitfalls to Avoid

• Using calcitonin as first-line therapy due to its weaker efficacy profile 7
• Administering alendronate to patients with significant renal impairment (GFR <35 mL/min/1.73m²) 7
• Discontinuing denosumab without follow-up bisphosphonate therapy, which can result in rebound bone loss 7
• Failing to ensure patients can remain upright for at least 30 minutes after taking oral bisphosphonates 7
• Not addressing modifiable risk factors (smoking, alcohol intake, inactivity) alongside pharmacological treatment 7