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 zoledronic acid 4 mg IV infused over no less than 15 minutes as first-line definitive therapy. 1, 2

Initial Stabilization and Volume Repletion

• Aggressive IV normal saline is the cornerstone of initial management, correcting the hypovolemia that universally accompanies hypercalcemia and promoting calciuresis through enhanced renal calcium excretion. 1, 3

• Target urine output of 100-150 mL/hour in adults; maintain 3 mL/kg/hour in children weighing less than 10 kg. 1, 3

• 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

• Avoid overhydration, particularly in patients with heart failure or significant renal impairment, as this can precipitate pulmonary edema. 3

Definitive Pharmacologic Treatment

Bisphosphonates: First-Line Therapy

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate, demonstrating superior efficacy compared to pamidronate with longer duration of response (30-40 days versus 17 days). 1, 3, 2

• Do not delay bisphosphonate administration while awaiting complete diagnostic workup in moderate to severe hypercalcemia—treat first, diagnose concurrently, as the 2-4 day delayed onset of action means early initiation is critical. 1, 3

• Dose adjustments are required for renal impairment when creatinine clearance is less than 60 mL/min: CrCl 50-60 mL/min use 3.5 mg; CrCl 40-49 mL/min use 3.3 mg; CrCl 30-39 mL/min use 3.0 mg. 3, 2

• Monitor 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). 3, 2

• Pamidronate 60-90 mg IV is an acceptable alternative if zoledronic acid is unavailable, though it is less potent and has shorter duration of action. 3, 4

• Retreatment may be considered if serum calcium does not normalize after initial treatment, with a minimum 7-day interval to allow full response to the initial dose. 2

Calcitonin: Rapid Bridge Therapy

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid but modest calcium reduction within hours, making it ideal as bridge therapy until bisphosphonates take effect. 1, 3

• The hypocalcemic effect is transient and modest, typically lowering calcium by only 1-2 mg/dL, with tachyphylaxis developing within 48 hours. 1, 5

• Combining calcitonin with bisphosphonates enhances the rate of calcium decline, addressing the delayed onset of bisphosphonate action while providing sustained control. 1, 4

Cause-Specific Treatment Strategies

Malignancy-Associated Hypercalcemia

• Treatment of the underlying cancer is essential for long-term control and should be pursued alongside acute calcium-lowering measures, as hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month. 1, 3, 6

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

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

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

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 in sarcoidosis-specific treatment. 3

• 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, 6

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, 6, 5

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

• For persistent hypercalcemic hyperparathyroidism despite optimized medical therapy (tertiary hyperparathyroidism), parathyroid resection should be considered. 1, 3

Refractory or Severe Hypercalcemia

• Dialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for patients with severe hypercalcemia complicated by renal insufficiency or oliguria, as hemodialysis effectively removes calcium through diffusive therapy. 1, 3

• Denosumab may be considered in patients with kidney failure when bisphosphonates are contraindicated, though it carries higher risk of severe hypocalcemia requiring close monitoring. 3, 5

Diagnostic Workup to Guide Treatment

• Measure intact PTH as the most important initial test to distinguish PTH-dependent from PTH-independent causes: 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, 6, 7

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

• Calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)], though ionized calcium is more accurate and avoids pseudo-hypercalcemia from hemolysis or improper sampling. 3

• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma. 1, 6

Monitoring and Supportive Care

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

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia, particularly with denosumab which carries higher risk. 3, 2

• Correct hypocalcemia before initiating bisphosphonate therapy and monitor serum calcium closely. 3

• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg. 3

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

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

• Immediately discontinue all calcium-based phosphate binders, vitamin D analogs (calcitriol, paricalcitol), and vitamin D supplements in patients presenting with hypercalcemia. 3, 6

• Do not rely on corrected calcium instead of ionized calcium, as it can lead to inaccurate diagnosis. 3

• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy, as measuring only one can miss vitamin D-mediated hypercalcemia. 3

• Assess for medication history including thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A intake. 3