What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Immediate IV normal saline hydration followed by zoledronic acid 4 mg IV over 15 minutes is the first-line treatment for moderate to severe hypercalcemia, with calcitonin added only when rapid calcium reduction is needed within hours. 1, 2, 3

Initial Stabilization and Hydration

• Administer IV normal saline immediately to restore extracellular volume and enhance urinary calcium excretion, targeting urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg). 1, 2, 4, 3

• Vigorous saline hydration should be initiated promptly with an attempt to restore urine output to approximately 2 L/day throughout treatment. 3, 5

• Loop diuretics such as furosemide should only be added in patients with renal or cardiac insufficiency to prevent fluid overload—they are NOT routinely indicated for all patients. 1, 2, 4

• Diuretic therapy must not be employed prior to correction of hypovolemia. 3, 5

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, with superior efficacy compared to pamidronate. 1, 2, 4, 3

• Do not delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action. 1, 2, 4

• For hypercalcemia of malignancy with albumin-corrected calcium ≥12 mg/dL (≥3.0 mmol/L), the maximum recommended dose is 4 mg as a single IV infusion. 3

• Assess serum creatinine prior to each treatment; dose adjustments are required for creatinine clearance ≤60 mL/min using the Cockcroft-Gault formula. 3

• Dose reductions for renal impairment: CrCl 50-60 mL/min = 3.5 mg; CrCl 40-49 mL/min = 3.3 mg; CrCl 30-39 mL/min = 3.0 mg. 3

• Withhold treatment for renal deterioration (increase of 0.5 mg/dL in normal baseline creatinine or 1.0 mg/dL in abnormal baseline); resume only when creatinine returns to within 10% of baseline. 3

• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not normalize, with a minimum of 7 days between doses. 3

• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases. 1, 2

Calcitonin (Rapid Bridge Therapy)

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid but modest calcium reduction within hours, serving as a bridge until bisphosphonates take effect. 1, 2, 4

• Calcitonin has limited efficacy and tachyphylaxis develops, restricting its use to patients requiring immediate calcium reduction or those who cannot tolerate other treatments. 1

• Standard dosing is 200 IU per day as nasal spray or 100 IU subcutaneously/intramuscularly every other day. 1

Severity-Based Treatment Algorithm

Mild Hypercalcemia (Corrected Calcium <12 mg/dL)

• Mild or asymptomatic hypercalcemia may be treated with conservative measures: saline hydration with or without loop diuretics. 3, 5

• For primary hyperparathyroidism in patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring may be appropriate. 6

Moderate to Severe Hypercalcemia (Corrected Calcium ≥12 mg/dL)

• Hydration plus bisphosphonates (zoledronic acid preferred) form the cornerstone of treatment. 1, 2, 4

• Add calcitonin for rapid onset when severe symptoms (nausea, vomiting, confusion, somnolence) are present. 1, 2, 4

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, 2, 4

• Hemodialysis effectively removes calcium through diffusive therapy, with uric acid clearance approximately 70-100 mL/min. 7, 1, 4

• Denosumab may be considered in patients with kidney failure who cannot receive bisphosphonates. 6

Cause-Specific Treatment Considerations

Malignancy-Associated Hypercalcemia

• Treatment of the underlying cancer is essential for long-term control and should be pursued alongside acute calcium-lowering measures. 1, 2, 4

• For multiple myeloma: hydration, zoledronic acid (preferred), and corticosteroids form the treatment approach. 1, 2

• Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients. 1, 2, 4

Vitamin D-Mediated Hypercalcemia

• Glucocorticoids are effective as primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), some lymphomas, and multiple myeloma. 1, 2, 4

• Avoid all vitamin D supplements in patients with hypercalcemia regardless of etiology. 1, 2, 4

Primary Hyperparathyroidism

• Parathyroidectomy is the definitive treatment for symptomatic primary hyperparathyroidism and should be considered for patients with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal. 2

• For persistent hypercalcemic hyperparathyroidism despite optimized medical therapy (tertiary hyperparathyroidism), parathyroid resection should be considered. 1, 2

Diagnostic Workup to Guide Treatment

• Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, and phosphorus to determine underlying cause. 1, 2

• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes. 2, 6

• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma. 2

Monitoring and Follow-Up

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 1, 2, 4

• Monitor serum creatinine before each dose of zoledronic acid and withhold treatment if renal deterioration occurs. 1, 3

• Patients receiving bisphosphonates should be administered oral calcium supplement 500 mg plus vitamin D 400 IU daily to prevent hypocalcemia. 1, 3

• Correct hypocalcemia before initiating bisphosphonate therapy and monitor serum calcium closely, especially with denosumab which carries higher risk of hypocalcemia. 1

Critical Pitfalls to Avoid

• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently. 2, 4

• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function. 1, 2, 4

• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen outcomes. 1, 2, 4

• Avoid vitamin D supplements in all patients with active hypercalcemia. 1, 2, 4

• Do not use loop diuretics routinely in all hypercalcemia patients—reserve for those with cardiac or renal insufficiency at risk of fluid overload. 1, 2, 4

• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg. 7