What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Immediately initiate IV normal saline to restore extracellular volume and enhance urinary calcium excretion, targeting urine output of at least 100 mL/hour, followed by zoledronic acid 4 mg IV as first-line definitive therapy for moderate to severe hypercalcemia. 1, 2

Initial Stabilization and Hydration

Vigorous saline hydration is the cornerstone of acute hypercalcemia management and should be started immediately upon diagnosis. 1, 3

• Administer IV normal saline to correct hypovolemia and promote calciuresis, maintaining urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg) 1, 4
• Patients must be adequately rehydrated prior to bisphosphonate administration 3
• 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
• Diuretic therapy should not be employed prior to correction of hypovolemia 3

This represents a critical shift from older practices that routinely used loop diuretics; current evidence shows they are unnecessary and potentially harmful in euvolemic patients. 1

Definitive Pharmacologic Treatment

Bisphosphonates (First-Line Therapy)

Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate, with superior efficacy compared to pamidronate. 1, 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
• Assess serum creatinine prior to each treatment 3
• No dose adjustment is necessary for mild-to-moderate renal impairment (serum creatinine <4.5 mg/dL) in hypercalcemia of malignancy 3
• For patients with creatinine clearance 50-60 mL/min, reduce dose to 3.5 mg; for 40-49 mL/min, use 3.3 mg; for 30-39 mL/min, use 3 mg 3
• Bisphosphonates are particularly effective for malignancy-associated hypercalcemia and should be continued for up to 2 years in patients with multiple myeloma or bone metastases 1, 4

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

• Use calcitonin when immediate calcium lowering is needed while awaiting bisphosphonate effect 4, 5
• The hypocalcemic effect is modest compared to bisphosphonates but onset is within hours rather than days 1

Cause-Specific Treatment Algorithms

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

• Hydration, bisphosphonates, and calcitonin form the cornerstone of acute management 1, 4
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients 1, 4
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 4, 3

Vitamin D-Mediated Hypercalcemia

Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption. 1, 5

• Use glucocorticoids for vitamin D intoxication, granulomatous disorders (sarcoidosis), and some lymphomas 1, 6
• Avoid all vitamin D supplements in patients with hypercalcemia regardless of etiology 1, 4, 2

Primary Hyperparathyroidism

Parathyroidectomy is the definitive treatment for symptomatic primary hyperparathyroidism. 1, 4

• Consider surgery 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
• For patients older than 50 years with serum calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation may be appropriate 5
• For persistent hypercalcemic hyperparathyroidism despite optimized medical therapy (tertiary hyperparathyroidism), parathyroid resection should be considered 4

Refractory or Severe Hypercalcemia

Dialysis is reserved for patients with severe hypercalcemia complicated by renal insufficiency. 1, 2, 6

• Hemodialysis effectively removes calcium through diffusive therapy 1, 4
• Consider dialysis when serum calcium is ≥14 mg/dL (≥3.5 mmol/L) with renal failure 5, 6

Retreatment Protocol

If serum calcium does not return to normal or remain normal after initial treatment, retreatment with zoledronic acid 4 mg may be considered. 3

• Allow a minimum of 7 days to 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
• Withhold treatment for renal deterioration (increase of 0.5 mg/dL in normal baseline creatinine or 1.0 mg/dL in abnormal baseline) 3
• Resume treatment only when creatinine returns to within 10% of baseline value 3

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, 4

• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism 1, 5
• Suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes 1, 5
• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma 1

Monitoring Requirements

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

• Patients should receive an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily when being treated for multiple myeloma or bone metastases 3

Critical Pitfalls to Avoid

Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently. 1, 2

• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen outcomes 1, 2
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function 1, 4, 2
• Avoid vitamin D supplements in all patients with active hypercalcemia 1, 4, 2
• Do not routinely use loop diuretics in all hypercalcemic patients—reserve for those with renal or cardiac insufficiency 1, 2