What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

The treatment of hypercalcemia should begin with aggressive IV fluid resuscitation with normal saline, followed by bisphosphonates (preferably zoledronic acid 4 mg IV over 15 minutes) as the first-line pharmacological intervention. 1

Initial Assessment and Management

Severity Classification

• Mild hypercalcemia: Total calcium <12 mg/dL (<3 mmol/L)
• Severe hypercalcemia: Total calcium ≥14 mg/dL (≥3.5 mmol/L) or rapid onset
• Calculate corrected calcium: Total calcium + 0.8 × (4.0 - serum albumin) 1

Step 1: Fluid Resuscitation

• Begin with intravenous normal saline to:
  • Correct hypercalcemia-associated hypovolemia
  • Promote calciuresis
  • Target urine output >2 L/day or >2 mL/kg/hour 1
• Avoid overhydration in patients with cardiac failure 1

Step 2: Pharmacological Intervention

Bisphosphonates (First-line)

• Zoledronic acid 4 mg IV over 15 minutes (preferred)
  • Superior efficacy with 50% response rate by day 4
  • Longer duration of action (30-40 days) 1
• Pamidronate 90 mg IV over 2 hours (alternative)
  • Less potent with shorter duration (17 days) 1
• Reserve 8 mg dose of zoledronic acid for refractory cases 1

Denosumab

• Consider for hypercalcemia refractory to bisphosphonates
• Particularly useful in patients with renal impairment
• Effective response rate of 64% 1
• Monitor closely for hypocalcemia after treatment 1

Calcitonin

• For immediate short-term management of severe symptomatic hypercalcemia 1, 2
• Starting dose: 4 International Units/kg body weight every 12 hours SC/IM
• May increase to 8 International Units/kg every 12 hours if response unsatisfactory
• Maximum dose: 8 International Units/kg every 6 hours 2

Glucocorticoids

• For hypercalcemia due to:
  • Vitamin D toxicity
  • Granulomatous disorders (sarcoidosis, tuberculosis)
  • Some lymphomas 1, 3

Loop Diuretics

• Use only after adequate hydration
• Enhances calcium excretion 1
• Never use diuretics before correcting hypovolemia 1

Cause-Specific Considerations

Primary Hyperparathyroidism (PHPT)

• Accounts for approximately 90% of hypercalcemia cases along with malignancy 1
• Parathyroidectomy may be considered based on:
  • Age
  • Serum calcium level
  • Kidney or skeletal involvement 3
• For patients >50 years with serum calcium <1 mg above upper limit and no evidence of skeletal or kidney disease, observation may be appropriate 3
• Calcimimetic agents may be used when surgery is not possible 4

Malignancy-Associated Hypercalcemia

• Divided into:
  • Humoral MAH (paraneoplastic release of PTHrP)
  • Osteolytic MAH (direct bone invasion) 4
• Zoledronate is superior to clodronate or pamidronate 4
• Consider denosumab in refractory cases 1, 5

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

Common Pitfalls to Avoid

• Using diuretics before correcting hypovolemia
• Failing to correct calcium for albumin
• Inadequate hydration before bisphosphonate administration
• Treating laboratory values without addressing the underlying cause
• Delaying treatment of severe hypercalcemia
• Administering bisphosphonates too rapidly
• Failing to monitor for hypocalcemia after treatment 1

Special Considerations

• Reduce bisphosphonate dose in patients with renal impairment
• Avoid bisphosphonates in severe renal impairment; consider denosumab instead 1
• Perform dental examination before starting bisphosphonate therapy due to risk of osteonecrosis of the jaw 1
• Common adverse effects of bisphosphonates:
  • Acute-phase reaction (fever, myalgia) within 36 hours of first dose
  • Hypocalcemia (occurs in up to 50% of treated patients)
  • Electrolyte imbalances (hypokalemia, hypomagnesemia) 1