What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Immediately initiate IV normal saline hydration 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), followed by IV zoledronic acid 4 mg infused over no less than 15 minutes as first-line definitive therapy. 1, 2

Initial Stabilization and Hydration

• Aggressive IV normal saline is the cornerstone of initial management, correcting hypovolemia and promoting calciuresis in all patients with symptomatic or severe hypercalcemia. 1, 3, 4

• Loop diuretics (furosemide) should ONLY be added in patients with renal or cardiac insufficiency to prevent fluid overload—they are NOT routinely indicated for all hypercalcemic patients and should never be given before volume repletion. 1, 3, 4

• Maintain adequate hydration throughout treatment while carefully avoiding overhydration, particularly in patients with heart failure or renal impairment. 1, 3

Definitive Pharmacologic Treatment

Bisphosphonates (First-Line Therapy)

• Zoledronic acid 4 mg IV is the preferred bisphosphonate, with superior efficacy compared to pamidronate, and should be infused over no less than 15 minutes. 1, 3, 2

• Do NOT delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action, even while diagnostic workup is ongoing. 1, 3, 4

• For patients with baseline creatinine clearance (CrCl) ≤60 mL/min, dose reduction is required: CrCl 50-60 mL/min use 3.5 mg; CrCl 40-49 mL/min use 3.3 mg; CrCl 30-39 mL/min use 3 mg. 2

• Assess serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in patients with normal baseline creatinine, or 1.0 mg/dL in those with abnormal baseline). 2

• Patients should receive oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia. 3, 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, 3, 4

• Calcitonin has limited efficacy and tachyphylaxis develops quickly, but its rapid onset makes it valuable for immediate short-term management of severe symptomatic hypercalcemia. 3, 5

Cause-Specific Treatment Approaches

Malignancy-Associated Hypercalcemia

• Treatment of the underlying cancer is essential for long-term control and should be pursued alongside acute calcium-lowering measures. 1, 3, 4

• Hydration, bisphosphonates (zoledronic acid preferred), and calcitonin form the cornerstone of acute management. 1, 3

• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases. 1, 3

• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients. 1, 3, 4

Vitamin D-Mediated Hypercalcemia

• Glucocorticoids (prednisone 1 mg/kg/day orally or methylprednisolone IV equivalent) are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), and some lymphomas. 1, 3, 5

• Taper corticosteroids over 2-4 months depending on response, and provide pneumocystis pneumonia prophylaxis for patients receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks. 3

• Avoid ALL vitamin D supplements in patients with hypercalcemia regardless of etiology. 1, 3, 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. 1

• In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation with monitoring may be appropriate. 5

Refractory or Severe Hypercalcemia

• Dialysis with calcium-free or low-calcium dialysate is reserved for patients with severe hypercalcemia complicated by renal insufficiency, as hemodialysis effectively removes calcium through diffusive therapy. 1, 3, 4

• Denosumab may be considered in patients with kidney failure who cannot receive bisphosphonates, though it carries higher risk of hypocalcemia requiring close monitoring. 3, 5

Diagnostic Workup to Guide Treatment

• Measure intact PTH first—this is the most important initial test to distinguish PTH-dependent from PTH-independent causes. 1, 3, 5

• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes. 1, 5, 6

• Also measure PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, magnesium, and phosphorus to determine underlying cause. 1, 3

• Measure ionized calcium to avoid pseudo-hypercalcemia, which can occur due to hemolysis or improper sampling. 3

Monitoring and Follow-Up

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 1, 3, 4

• Assess ECG for QT interval prolongation in patients with severe hypercalcemia. 3

• If retreatment with zoledronic acid is needed, allow a minimum of 7 days to elapse before retreatment to allow for full response to the initial dose. 2

Critical Pitfalls to Avoid

• Do NOT restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen bone disease and outcomes. 1, 3, 4

• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function. 1, 3, 4

• Do NOT delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently. 1, 4

• Do not use loop diuretics before correcting hypovolemia, as this worsens volume depletion and hypercalcemia. 1

• Avoid relying on corrected calcium instead of ionized calcium, as it can lead to inaccurate diagnosis. 3

• Obtain medication history for thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A, as these can contribute to hypercalcemia. 3