What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Initiate immediate IV normal saline hydration 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, 3

Initial Stabilization and Hydration

• Administer IV normal saline immediately as the cornerstone of acute management, maintaining urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg) 1, 4, 2
• 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 hypercalcemic patients 1, 4, 5
• Assess serum creatinine before initiating definitive therapy, as renal function determines bisphosphonate dosing 3

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, 4, 2, 3
• Do not delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action 1, 2
• For patients with creatinine clearance 50-60 mL/min, reduce dose to 3.5 mg; for CrCl 40-49 mL/min use 3.3 mg; for CrCl 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
• Monitor serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in patients with normal baseline or 1.0 mg/dL in those with abnormal baseline) 3

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, 4, 2, 5
• Calcitonin has limited long-term efficacy due to tachyphylaxis but is valuable for immediate short-term management of severe symptomatic hypercalcemia 4, 6

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, 4, 2
• Hydration, bisphosphonates (zoledronic acid preferred), 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, 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 1, 5

Vitamin D-Mediated Hypercalcemia

• Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), and some lymphomas 1, 4, 5, 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 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, 5
• In patients older than 50 years with serum calcium levels 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 7, 1

Refractory or Severe Hypercalcemia

• Dialysis with calcium-free or low-calcium solution is reserved for patients with severe hypercalcemia complicated by renal insufficiency, as hemodialysis effectively removes calcium through diffusive therapy 1, 4, 2, 5
• Denosumab 120 mg subcutaneously may be considered in patients with renal failure who cannot receive bisphosphonates, though it carries higher risk of severe hypocalcemia 4, 8
• Calcimimetics may be considered for severe hyperparathyroidism despite normocalcemia or hypercalcemic hyperparathyroidism failing other treatments, though cinacalcet should be used with extreme caution due to risk of severe hypocalcemia and QT prolongation 7, 1

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

Monitoring During Treatment

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness 1, 4, 2
• Patients receiving bisphosphonates should be administered oral calcium supplement 500 mg plus vitamin D 400 IU daily to prevent treatment-induced hypocalcemia 4, 3
• Correct hypocalcemia before initiating bisphosphonate or denosumab therapy and monitor serum calcium closely, especially with denosumab which carries higher risk 4, 8

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
• Do not use loop diuretics routinely before correcting hypovolemia—diuretic therapy should not be employed prior to correction of volume depletion 3, 6
• Avoid vitamin D supplements in all patients with active hypercalcemia 1, 4, 2
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) 4