What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

The treatment of hypercalcemia begins with aggressive intravenous fluid resuscitation with normal saline, followed by bisphosphonates (preferably zoledronic acid 4 mg IV) for moderate to severe cases, with additional therapies such as denosumab, glucocorticoids, or calcitonin based on specific clinical scenarios. 1

Initial Assessment and Management

Severity Classification

• Mild hypercalcemia: Total calcium <12 mg/dL (<3 mmol/L)
• Moderate hypercalcemia: Total calcium 12.0-13.5 mg/dL (3.0-3.4 mmol/L)
• Severe hypercalcemia: Total calcium >13.5 mg/dL (>3.4 mmol/L) 1, 2

First-Line Treatment: Hydration

• Begin with intravenous normal saline to:
  • Correct hypercalcemia-associated hypovolemia
  • Promote calciuresis
  • Target urine output >2 L/day or >2 mL/kg/hour 1
• Important: Avoid overhydration in patients with cardiac failure 1
• Caution: Do not use diuretics before correcting hypovolemia 1

Pharmacological Management

Bisphosphonates (First-Line Pharmacological Therapy)

• Preferred agent: Zoledronic acid 4 mg IV infused over 15 minutes 1, 3
  • Superior efficacy and longer duration of action (30-40 days) compared to other bisphosphonates
  • Response rate of 50% by day 4 1
  • FDA-approved for hypercalcemia of malignancy with albumin-corrected calcium ≥12 mg/dL 3
• Alternative: Pamidronate 90 mg IV infused over 2 hours (less potent, duration ~17 days) 1
• Dose adjustment: Reduce dose in renal impairment (see table below) 1, 3

Baseline Creatinine Clearance (mL/min)	Zoledronic Acid Dose (mg)
>60	4
50-60	3.5
40-49	3.3
30-39	3

Second-Line Agents

• Denosumab: 120 mg SC with additional doses on days 8 and 15 of first month 1, 4

  • Indicated for hypercalcemia refractory to bisphosphonates
  • Preferred in patients with severe renal impairment
  • Response rate of 64% 1
  • Monitor for hypocalcemia after treatment 1, 4

• Calcitonin: For immediate short-term management of severe symptomatic hypercalcemia 1, 5

  • Rapid but short-lived effect
  • Tachyphylaxis limits prolonged use 6

• Glucocorticoids: For hypercalcemia due to:

  • Vitamin D toxicity
  • Granulomatous disorders (e.g., sarcoidosis, tuberculosis)
  • Some lymphomas 1, 7

• Loop diuretics (e.g., furosemide): To enhance calcium excretion

  • Only after adequate hydration 1, 5
  • May be needed for patients at risk of fluid overload 6

Special Considerations

Renal Impairment

• Avoid bisphosphonates in severe renal impairment
• Consider denosumab as an alternative 1, 4
• For patients with renal failure, dialysis with calcium-free or low-calcium solution may be necessary 6

Malignancy-Related Hypercalcemia

• Target underlying malignancy when possible 6
• Minimum of 7 days before retreatment with zoledronic acid 1, 3
• Consider retreatment if calcium does not normalize or rises again 1

Primary Hyperparathyroidism

• Definitive treatment is parathyroidectomy for appropriate surgical candidates 2
• For non-surgical candidates, medical management is required

Monitoring and Follow-up

• Regular monitoring of:
  • Serum calcium, phosphate, magnesium
  • Renal function
  • Urine output (target >2 L/day) 1
• Watch for hypocalcemia after treatment, especially with denosumab 1, 4
• Dental examination before starting bisphosphonate therapy due to risk of osteonecrosis of the jaw 1

Common Pitfalls to Avoid

1. Using diuretics before correcting hypovolemia
2. Inadequate hydration before bisphosphonate administration
3. Administering bisphosphonates too rapidly
4. Treating laboratory values without addressing the underlying cause
5. Delaying treatment of severe hypercalcemia
6. Failing to monitor for hypocalcemia after treatment 1