What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Immediately initiate IV normal saline hydration targeting urine output ≥100 mL/hour, followed by IV zoledronic acid 4 mg as the preferred bisphosphonate for definitive treatment. 1, 2

Initial Stabilization and Hydration

• Administer IV normal saline immediately to restore extracellular volume and enhance urinary calcium excretion, maintaining urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg). 1, 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 patients. 1, 2
• Hydration alone can promote calciuresis and is the foundation of acute management before definitive pharmacologic therapy takes effect. 3

Definitive Pharmacologic Treatment

Bisphosphonates (First-Line)

• Zoledronic acid 4 mg IV is the preferred bisphosphonate for hypercalcemia treatment, with superior efficacy compared to pamidronate. 1, 2
• Do not delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action. 2
• Pamidronate is an alternative bisphosphonate if zoledronic acid is unavailable, though it has shorter duration of response (17 days vs 30-40 days with zoledronic acid). 4
• 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

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. 2, 5
• For hypercalcemic emergencies, the FDA-approved dosing is 4 International Units/kg every 12 hours subcutaneously or intramuscularly, escalating to 8 International Units/kg every 12 hours if inadequate response after 1-2 days, with maximum dosing of 8 International Units/kg every 6 hours. 5
• Calcitonin has good tolerability but limited long-term efficacy due to tachyphylaxis; it should be combined with bisphosphonates when rapid calcium reduction is needed. 4

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. 2, 6
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients. 1, 2
• Hydration, bisphosphonates, and calcitonin form the cornerstone of acute management in malignancy-related hypercalcemia. 1

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), and some lymphomas. 6, 7
• Avoid all vitamin D supplements in patients with hypercalcemia regardless of etiology. 2, 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. 6
• For persistent hypercalcemic hyperparathyroidism despite optimized medical therapy (tertiary hyperparathyroidism), parathyroid resection should be considered. 1
• Asymptomatic patients over 50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease may be observed without immediate intervention. 7

Refractory or Severe Hypercalcemia

• Dialysis is reserved for patients with severe hypercalcemia complicated by renal insufficiency, as hemodialysis effectively removes calcium through diffusive therapy. 1, 2
• Denosumab may be indicated in patients with kidney failure who cannot receive bisphosphonates. 7
• 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. 8

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
• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes. 6, 7
• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma. 6

Monitoring and Follow-Up

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 1, 2
• Monitor for bisphosphonate-related renal toxicity, particularly with zoledronic acid, though nitrogen-containing bisphosphonates have lower rates of creatinine elevation (1-2%) compared to older agents. 4
• Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates, though symptomatic hypocalcemia is rare. 4

Critical Pitfalls to Avoid

• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen outcomes. 2
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function. 1, 2
• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently. 2
• Avoid vitamin D supplements in all patients with active hypercalcemia. 2, 6

Severity-Based Treatment Algorithm

• Mild hypercalcemia (total calcium <12 mg/dL): Usually asymptomatic; treat underlying cause, ensure adequate hydration, and observe if due to primary hyperparathyroidism in appropriate candidates. 7
• Moderate hypercalcemia (total calcium 12-14 mg/dL): Initiate IV hydration and bisphosphonates; symptoms may include fatigue, constipation, polyuria, polydipsia. 3, 7
• Severe hypercalcemia (total calcium ≥14 mg/dL or ionized calcium ≥10 mg/dL): Aggressive IV hydration, immediate calcitonin for rapid effect, followed by bisphosphonates; associated with nausea, vomiting, confusion, somnolence, and potential coma. 5, 7