How to manage a patient with elevated Parathyroid Hormone-related Protein (PTHrP) and hypercalcemia?

Management of Elevated PTHrP with Hypercalcemia

For patients with elevated Parathyroid Hormone-related Protein (PTHrP) and hypercalcemia, aggressive treatment with IV fluid rehydration followed by bisphosphonate therapy is the cornerstone of management.

Initial Assessment and Diagnosis

• PTHrP-mediated hypercalcemia is characterized by:

  • Suppressed intact parathyroid hormone (iPTH) level
  • Low or normal calcitriol level
  • Elevated serum calcium
  • Elevated PTHrP levels

• Diagnostic evaluation should include measuring:

  • Serum calcium, albumin (for corrected calcium)
  • iPTH
  • PTHrP
  • 1,25-dihydroxyvitamin D
  • 25-hydroxyvitamin D
  • Magnesium and phosphorus 1

Immediate Management of Hypercalcemia

Step 1: Rehydration

• Begin with IV crystalloid fluids not containing calcium
• Target rehydration with 2-3 liters of normal saline per day
• Aim for urine output of approximately 2 L/day
• Caution: Avoid overhydration in patients with cardiac failure 1, 2

Step 2: Bisphosphonate Therapy

• After adequate hydration, administer IV bisphosphonates:

  • First-line option: Zoledronic acid 4 mg IV infused over 15 minutes (preferred due to higher efficacy)
  • Alternative: Pamidronate 90 mg IV infused over 2-4 hours 3, 2

• Bisphosphonates work by:

  • Inhibiting osteoclastic bone resorption
  • Alleviating bone pain
  • Potentially preventing cancer cell expansion in bone metastatic lesions 4

Step 3: Additional Therapies

• Loop diuretics (e.g., furosemide) may be added only after correction of hypovolemia
• Note: Recent evidence suggests furosemide may not provide significant additional benefit over saline hydration alone 5
• For refractory cases, consider:
  • Glucocorticoids (especially if hypercalcemia is due to lymphomas or vitamin D excess)
  • Calcitonin (for short-term use)
  • Denosumab (particularly in patients with renal failure) 1, 2

Monitoring and Follow-up

• Monitor serum calcium levels daily until stabilized

• Check renal function regularly (serum creatinine)

• Watch for potential bisphosphonate side effects:

  • Renal dysfunction
  • Hypocalcemia
  • Fever/flu-like symptoms 1

• Discontinue bisphosphonates if:

  • Unexplained albuminuria (>500 mg/24 hours)
  • Increase in serum creatinine >0.5 mg/dL
  • Absolute creatinine value >1.4 mg/dL 1

Treatment of Underlying Cause

• PTHrP-mediated hypercalcemia is most commonly associated with malignancy
• Identify and treat the underlying malignancy (often squamous cell carcinomas, breast cancer, or multiple myeloma)
• Important note: Median survival after discovery of hypercalcemia of malignancy in lung cancer patients is approximately 1 month 1

Special Considerations

• For severe hypercalcemia (>14.0 mg/dL):

  • More aggressive hydration may be needed
  • Watch for mental status changes, bradycardia, and hypotension
  • Consider ICU monitoring 1

• For patients with renal dysfunction:

  • Adjust bisphosphonate dosing
  • Consider denosumab as an alternative
  • More careful monitoring of fluid status 1

Long-term Management

• For recurrent hypercalcemia, retreatment with the same bisphosphonate may be considered
• For refractory cases, zoledronic acid at higher doses (8 mg) may be considered 1
• Regular monitoring of calcium levels and renal function is essential

Remember that while treating the hypercalcemia is critical for immediate symptom relief and preventing complications, addressing the underlying cause (typically malignancy) is essential for long-term management.