What are the treatment options for hypercalcemia?

Treatment of Hypercalcemia

Immediate Management: Hydration First

Intravenous normal saline is the cornerstone of initial treatment for all hypercalcemia, targeting urine output of at least 100 mL/hour to correct hypovolemia and promote calciuresis. 1, 2

• Vigorous saline hydration should be initiated promptly, aiming to restore urine output to approximately 2 L/day throughout treatment 3
• Loop diuretics (furosemide) should only be added if renal or cardiac insufficiency is present to prevent fluid overload—never use diuretics before correcting hypovolemia 1, 3
• Adequate hydration must be maintained throughout treatment, but overhydration must be avoided in patients with heart failure 3

Definitive Pharmacologic Treatment

Bisphosphonates: First-Line for Moderate to Severe Hypercalcemia

Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate, superior to pamidronate, and should be administered after initiating hydration. 1, 2, 3, 4

• Bisphosphonates are the first-line treatment for moderate to severe hypercalcemia (calcium ≥12 mg/dL), especially malignancy-associated hypercalcemia 1, 5, 4
• The maximum recommended dose for hypercalcemia of malignancy is 4 mg as a single infusion over at least 15 minutes 3
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia—temporary measures provide only 1-4 hours of benefit 1
• Onset of action takes 2-4 days, with peak effect at 4-7 days 4

Dose adjustments for renal impairment (for multiple myeloma/bone metastases, NOT acute hypercalcemia of malignancy): 3

• CrCl >60 mL/min: 4 mg

• CrCl 50-60 mL/min: 3.5 mg

• CrCl 40-49 mL/min: 3.3 mg

• CrCl 30-39 mL/min: 3 mg

• Assess serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in normal baseline or 1.0 mg/dL in abnormal baseline) 3

• Monitor serum creatinine before each zoledronic acid dose 1, 3

Calcitonin: Rapid but Short-Term Bridge Therapy

Calcitonin provides rapid onset within hours but limited efficacy and duration, making it useful only as a bridge until bisphosphonates take effect. 1, 4

• Standard dosing: 200 IU/day as nasal spray or 100 IU subcutaneously/intramuscularly every other day 1
• Use primarily in patients who cannot tolerate other treatments or need immediate short-term management of severe symptomatic hypercalcemia 1, 6
• Tachyphylaxis develops, limiting usefulness beyond 48 hours 7

Glucocorticoids: For Vitamin D-Mediated Hypercalcemia

Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption from vitamin D intoxication, granulomatous diseases (sarcoidosis), some lymphomas, and multiple myeloma. 1, 2, 5, 4

• Effective by addressing unregulated 1-alpha-hydroxylase activity in activated macrophages 2
• Should be used as primary treatment when hypercalcemia is vitamin D-mediated 4, 6

Cause-Specific Definitive Treatment

Primary Hyperparathyroidism

Parathyroidectomy is indicated for symptomatic patients and those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal. 5

• For patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring is appropriate 4
• Parathyroidectomy is also considered for tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism) despite optimized medical therapy 1

Malignancy-Associated Hypercalcemia

Treating the underlying cancer with chemotherapy is essential for long-term control of hypercalcemia in patients with malignancy. 2, 5

• For multiple myeloma: hydration, zoledronic acid (preferred), steroids, and/or calcitonin 1
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 1

Granulomatous Disease with Lymphadenopathy

The combination of hypercalcemia and lymphadenopathy strongly suggests lymphoma or granulomatous disease—treat with glucocorticoids for vitamin D-mediated mechanisms and chemotherapy for underlying lymphoma. 2

Refractory or Severe Hypercalcemia with Renal Failure

Dialysis with calcium-free or low-calcium solution is reserved for patients with severe hypercalcemia complicated by renal insufficiency. 1, 6

• Hemodialysis effectively removes calcium through diffusive therapy 1
• Denosumab may be indicated in patients with kidney failure 4

Monitoring and Supportive Care

• Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 1, 2, 5
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 1, 3
• Correct hypocalcemia before initiating bisphosphonate therapy, especially with denosumab which carries higher risk 1
• Assess ECG for QT interval prolongation in severe hypercalcemia 1

Critical Pitfalls to Avoid

• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further kidney function deterioration 1
• Avoid vitamin D supplements in patients with hypercalcemia, particularly in early childhood 1, 5
• Do not use diuretics before correcting hypovolemia 3
• Discontinue any nephrotoxic medications to avoid worsening renal function 1
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 1

Retreatment Considerations

• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not normalize after initial treatment 3
• A minimum of 7 days should elapse before retreatment to allow for full response to the initial dose 3
• Renal function must be carefully monitored, and serum creatinine assessed prior to retreatment 3