How do I treat hypercalcemia?

Treatment of Critically High Calcium (Hypercalcemia)

For critically high calcium (severe hypercalcemia ≥14 mg/dL or ionized calcium ≥10 mg/dL), immediately initiate aggressive IV normal saline hydration followed by IV zoledronic acid 4 mg infused over at least 15 minutes, while calcitonin can be added for rapid onset within hours as a bridge until bisphosphonates take effect. 1, 2, 3

Immediate Assessment

• Verify the diagnosis: Measure albumin-corrected calcium using the formula: corrected calcium (mg/dL) = total calcium (mg/dL) + 0.8 × (4.0 - serum albumin g/dL) 4, 2
• Assess severity: Severe hypercalcemia is defined as total calcium ≥14 mg/dL (≥3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L), which causes nausea, vomiting, dehydration, confusion, somnolence, and coma 3
• Check renal function: Assess serum creatinine before treatment, as hypercalcemia causes renal impairment through nephrocalcinosis and volume contraction 2, 5
• Obtain ECG: Look for QT interval changes, though these are variable 4
• Measure intact PTH: This distinguishes PTH-dependent (primary hyperparathyroidism with elevated/normal PTH) from PTH-independent causes (malignancy with suppressed PTH <20 pg/mL) 3

Treatment Algorithm

Step 1: Aggressive Hydration (Start Immediately)

• Administer IV normal saline to correct hypovolemia and promote calciuresis, targeting urine output of 100-150 mL/hour 1
• Vigorous saline hydration should restore urine output to approximately 2 L/day 4
• Monitor fluid status carefully to avoid overhydration, especially in patients with cardiac or renal failure 4, 1
• Loop diuretics (furosemide 40-80 mg IV) may be necessary in patients with renal or cardiac insufficiency to prevent fluid overload, but should NOT be used before correcting hypovolemia 1, 6

Step 2: Bisphosphonate Therapy (First-Line Definitive Treatment)

• Zoledronic acid 4 mg IV is the preferred bisphosphonate, infused over no less than 15 minutes 1, 2, 3
• Zoledronic acid is superior to pamidronate in efficacy 1, 6
• Onset of action: 2-4 days, with peak effect at 4-7 days 3, 5
• Duration of effect: Can maintain normocalcemia for weeks 6
• Dose adjustments for renal impairment: If baseline creatinine clearance (CrCl) is 30-60 mL/min, reduce dose (CrCl 50-60: use 3.5 mg; CrCl 40-49: use 3.3 mg; CrCl 30-39: use 3.0 mg) 2
• Monitor renal function before each dose and withhold if creatinine increases by 0.5 mg/dL (normal baseline) or 1.0 mg/dL (abnormal baseline) 2

Step 3: Calcitonin (Bridge Therapy for Rapid Effect)

• Calcitonin-salmon 4 IU/kg subcutaneously or intramuscularly every 12 hours provides rapid onset within hours but has limited efficacy 1, 7, 3
• If response is unsatisfactory after 1-2 days, increase to 8 IU/kg every 12 hours 7
• Maximum dose: 8 IU/kg every 6 hours 7
• Use calcitonin as a bridge until bisphosphonates take effect, as its action is short-lived (effects last only hours to 1-2 days) 1, 6
• Calcitonin is particularly useful when rapid calcium reduction is needed in symptomatic patients 7, 3

Step 4: Additional Therapies Based on Etiology

For hypercalcemia due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous diseases like sarcoidosis, some lymphomas, multiple myeloma):

• Glucocorticoids are the primary treatment 1, 3, 8
• Prednisone or equivalent corticosteroid therapy is effective in these specific conditions 1, 6

For hypercalcemia with severe renal failure:

• Hemodialysis with calcium-free or low-calcium dialysate (1.5-2.0 mEq/L) is reserved for severe hypercalcemia complicated by renal insufficiency 4, 1, 6
• Dialysis effectively removes calcium through diffusive therapy 1
• Do not prolong low-calcium dialysis as it leads to marked bone demineralization 4

For malignancy-associated hypercalcemia with hyperviscosity (multiple myeloma):

• Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity 1

Step 5: Supportive Measures

• Discontinue contributing medications: Stop thiazide diuretics, calcium supplements, vitamin D supplements, and vitamin A 1, 3
• Correct electrolyte deficiencies: Replace potassium and magnesium as needed 5
• Mobilize the patient: Get patients out of bed to stand or walk, as immobilization increases bone resorption 5
• Avoid sedatives and narcotic analgesics that reduce activity and oral intake, which can raise calcium levels 5

Step 6: Calcium and Vitamin D Supplementation Post-Treatment

• After bisphosphonate treatment, provide oral calcium supplement 500 mg plus vitamin D 400 IU daily to prevent hypocalcemia 1, 2
• Monitor serum calcium closely, especially with denosumab which carries higher risk of hypocalcemia 1
• Only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg; asymptomatic hypocalcemia does not require intervention 1

Monitoring Protocol

• Check serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 1
• Monitor serum creatinine before each bisphosphonate dose 1, 2
• Retreatment with zoledronic acid 4 mg may be considered if calcium does not normalize after initial treatment, with a minimum of 7 days between doses 2
• For patients with multiple myeloma or bone metastases, continue bisphosphonate therapy for up to 2 years 1

Critical Pitfalls to Avoid

• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia, as temporary measures like calcitonin provide only short-term benefit 1
• Do not use loop diuretics before correcting hypovolemia, as this worsens volume contraction 4, 5
• Do not use low-calcium dialysate for prolonged periods without treating the primary cause, as it causes severe bone demineralization 4
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney damage 1
• Do not restrict calcium intake without medical supervision in patients with normocalcemia 1
• Remember that calcium, insulin, and beta-agonists do not remove calcium from the body—they only temporize 1

Treatment of Underlying Cause

• For primary hyperparathyroidism: Parathyroidectomy is definitive treatment for patients meeting surgical criteria (age <50 years, calcium >1 mg/dL above upper limit, or evidence of skeletal/kidney disease) 1, 3
• For malignancy-associated hypercalcemia: Treat the underlying cancer when possible; prognosis is poor with median survival often measured in weeks to months 1, 3
• For tertiary hyperparathyroidism: Consider parathyroidectomy for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 1