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 (zoledronic acid 4 mg IV over 15 minutes) as the first-line pharmacological intervention, particularly for cancer-related hypercalcemia. 1

Initial Assessment and Classification

• Hypercalcemia severity classification:

  • Mild: Total calcium <12 mg/dL (<3 mmol/L)
  • Moderate: Total calcium 12-14 mg/dL (3-3.5 mmol/L)
  • Severe: Total calcium ≥14 mg/dL (≥3.5 mmol/L) 1, 2

• Calculate corrected calcium if albumin is abnormal:

  • Corrected calcium = Total calcium + 0.8 × (4.0 - serum albumin) 1

Treatment Algorithm

Step 1: Hydration and Volume Expansion

• Begin with aggressive IV normal saline to:
  • Correct hypercalcemia-associated hypovolemia
  • Promote calciuresis
  • Target urine output >2 L/day or >2 mL/kg/hour 1, 3
• Critical caution: Do not use diuretics before correcting hypovolemia 1, 3
• Avoid overhydration in patients with cardiac failure 1

Step 2: Pharmacological Interventions

For Moderate to Severe Hypercalcemia:

1. Bisphosphonates (first-line):

   • Zoledronic acid 4 mg IV over 15 minutes (preferred)
     • Superior efficacy with 50% response by day 4
     • Longer duration of action (30-40 days) 1, 3
   • Alternative: Pamidronate 90 mg IV over 2 hours
     • Less potent with shorter duration (17 days) 1
   • Dose adjustment for renal impairment (see table in guidelines) 3

2. Denosumab:

   • For hypercalcemia refractory to bisphosphonates
   • Particularly useful in patients with severe renal impairment
   • Response rate of 64% 1

3. Calcitonin:

   • For immediate short-term management of severe symptomatic hypercalcemia
   • Rapid but modest effect
   • Can be combined with bisphosphonates for faster response 1, 4

4. Glucocorticoids:

   • For hypercalcemia due to:
     • Vitamin D toxicity
     • Granulomatous disorders (sarcoidosis, tuberculosis)
     • Some lymphomas 1, 4

5. Loop diuretics (e.g., furosemide):

   • Only after adequate hydration
   • Enhances calcium excretion 1, 3

Step 3: Monitoring and Follow-up

• Monitor:

  • Serum calcium, phosphate, magnesium
  • Renal function
  • Urine output (target >2 L/day)
  • Watch for hypocalcemia after treatment, especially with denosumab 1

• Retreatment considerations:

  • Wait minimum 7 days before retreatment with zoledronic acid
  • Consider retreatment if calcium does not normalize or rises again 1, 3

Special Considerations

Cause-Specific Approaches

1. Primary Hyperparathyroidism:

   • Observation may be appropriate for patients >50 years with serum calcium <1 mg/dL above upper limit and no evidence of skeletal or kidney disease 1, 2
   • Parathyroidectomy for symptomatic cases or those with complications

2. Malignancy-Related Hypercalcemia:

   • Most aggressive treatment approach with IV fluids and bisphosphonates
   • Address underlying malignancy 2

3. Vitamin D Toxicity:

   • Discontinue vitamin D supplementation if calcium >10.2 mg/dL
   • Consider glucocorticoids 1

Renal Considerations

• Reduce bisphosphonate dose in patients with renal impairment
• Avoid bisphosphonates in severe renal impairment; consider denosumab instead 1, 3
• Consider dialysis for severe hypercalcemia with renal failure 4

Potential Complications and Pitfalls

Common Complications

• Cardiac arrhythmias (QT interval shortening, heart blocks)
• Neurological symptoms (confusion, somnolence, coma)
• Electrolyte imbalances (hypokalemia, hypomagnesemia) 1

Treatment-Related Adverse Effects

• Bisphosphonates: Acute-phase reaction (fever, myalgia), hypocalcemia, osteonecrosis of jaw
• Perform dental examination before starting bisphosphonate therapy 1, 3

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

By following this structured approach to hypercalcemia management, focusing on aggressive hydration followed by appropriate pharmacological interventions based on severity and cause, clinicians can effectively reduce mortality and morbidity associated with this potentially life-threatening condition.