What is the management of Paget's disease?

Management of Paget's Disease of Bone

Bisphosphonates are the mainstay of treatment for Paget's disease of bone, with zoledronic acid being the most effective agent for symptomatic patients. 1

Diagnosis and Clinical Presentation

• Paget's disease is a common bone condition affecting 1-2% of the population over age 55, characterized by focal increased bone remodeling activity resulting in sclerotic or lytic lesions 2
• Most cases are diagnosed incidentally on radiographs or as isolated elevation of serum alkaline phosphatase 2
• Symptomatic patients present with bone pain, fractures, arthritis, and features of compression neuropathy 2
• Diagnosis is made based on typical radiological features on plain films, while radionuclide bone scans are recommended to assess the extent of disease 1

Indications for Treatment

• Treatment is indicated in patients with:
  • Symptomatic disease (bone pain, joint pain, neurological complications) 3
  • Alkaline phosphatase at least twice the upper limit of normal 4
  • Disease at sites at risk for future complications 3
  • Planned elective surgery at an active pagetic site (to reduce intraoperative blood loss) 3
  • Management of rare instances of immobilization hypercalcemia with polyostotic disease 3

First-Line Treatment: Bisphosphonates

Zoledronic Acid (Preferred)

• A single 5 mg intravenous infusion is the current standard therapy 1
• Leads to normalization of serum alkaline phosphatase in 89% of patients 3
• Provides sustained reduction in bone pain and markers of bone turnover 2
• Results in extended suppression of bone turnover 1

Alendronate

• FDA-approved for Paget's disease at 40 mg once daily for six months 4
• Re-treatment may be considered after six months in patients who have relapsed, based on increases in serum alkaline phosphatase 4
• Response (defined as normalization of serum alkaline phosphatase or decrease from baseline ≥60%) occurs in approximately 85% of patients 4

Other Bisphosphonates

• Pamidronate: In Paget's disease, effects following a single injection are sustained for months 5
• Risedronate: Effective for Paget's disease but contraindicated if GFR <30 ml/min/1.73 m² 5
• Etidronate: Less potent than newer bisphosphonates and considered a second-line choice 3

Administration Considerations

• For alendronate:

  • Take at least 30 minutes before first food, beverage, or medication of the day with plain water only 4
  • Patients should not lie down for at least 30 minutes after taking 4
  • Should not be taken at bedtime or before arising for the day 4

• Calcium and vitamin D supplementation:

  • Patients should take supplemental calcium if dietary intake is inadequate 4
  • Vitamin D supplementation may be needed, especially for those at increased risk for insufficiency 4

Treatment Approach

1. For symptomatic patients:

   • First-line: Single 5 mg IV infusion of zoledronic acid 1
   • Alternative: Alendronate 40 mg daily for six months 4

2. For asymptomatic patients with elevated alkaline phosphatase:

   • Treatment is indicated if alkaline phosphatase is at least twice the upper limit of normal 4
   • Treatment is also indicated if patients are at risk for future complications from their disease 4

3. For patients with renal impairment:

   • Dose adjustments or alternative agents may be needed based on GFR 5
   • Alendronate is not recommended in patients with GFR <35 ml/min/1.73 m² 5

Monitoring and Follow-up

• Monitor serum alkaline phosphatase periodically to assess response to treatment 4
• Re-treatment may be considered after six months in patients who relapse (based on increases in serum alkaline phosphatase) 4
• Bone histology shows normal lamellar bone production during treatment with alendronate 4

Important Considerations and Caveats

• Symptomatic vs. Intensive Treatment: Evidence suggests that striving to maintain normal alkaline phosphatase levels with intensive bisphosphonate therapy confers no clinical advantage over symptom-driven management in established Paget's disease 6
• Treatment of Asymptomatic Patients: Bisphosphonates should be reserved for symptomatic patients, as treatment has been associated with increased fracture rates in asymptomatic patients 2
• Side Effects:
  • IV bisphosphonates may induce acute phase reactions with fever and flu-like symptoms with the first dose 3
  • Oral bisphosphonates can cause esophageal irritation 3
  • Calcium and vitamin D repletion are mandatory to avoid hypocalcemia 3
• Acquired Resistance: Some patients may develop resistance to certain bisphosphonates (particularly etidronate and pamidronate), requiring substitution with a different bisphosphonate 3