What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Initiate immediate IV normal saline hydration and administer zoledronic acid 4 mg IV as first-line definitive therapy for moderate to severe hypercalcemia, with calcitonin serving as a rapid bridge until bisphosphonates take effect. 1, 2, 3

Initial Stabilization: Hydration First

• Administer IV normal saline immediately 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). 1, 2, 3

• Vigorous saline hydration should be initiated promptly with an attempt to restore urine output to approximately 2 L/day throughout treatment. 3, 4, 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 patients and should never be employed prior to correction of hypovolemia. 1, 2, 3

• Avoid overhydration, especially in patients with cardiac failure. 3, 4, 3

Definitive Pharmacologic Treatment

Bisphosphonates: First-Line Therapy

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate due to superior efficacy compared to pamidronate. 1, 2, 3, 5

• 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; dose adjustments are not necessary for mild-to-moderate renal impairment (serum creatinine <4.5 mg/dL) when treating hypercalcemia of malignancy. 3

• For patients with creatinine clearance 50-60 mL/min, reduce zoledronic acid 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

• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not normalize after initial treatment, with a minimum of 7 days between doses. 3

• Pamidronate is an alternative bisphosphonate but is less effective than zoledronic acid. 4, 5

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, 6, 5, 7

• Calcitonin has a more rapid onset than bisphosphonates but less sustained effect, making it ideal for immediate short-term management of severe symptomatic hypercalcemia. 8, 7

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, 2, 5

• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases from solid tumors. 1, 6

• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients. 1, 2, 6

• The prognosis for hypercalcemia of malignancy is poor, with this condition associated with poor survival. 5

Vitamin D-Mediated and Granulomatous Disease

• Glucocorticoids are effective as primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), and some lymphomas. 1, 5, 8, 7

• Glucocorticoids work by reducing intestinal calcium absorption in conditions with elevated vitamin D levels. 8, 9

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

• For asymptomatic patients older than 50 years with serum calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring may be appropriate. 5

• The prognosis for asymptomatic primary hyperparathyroidism is excellent with either medical or surgical management. 5

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, 5, 7

• Hemodialysis achieves calcium clearance and can rapidly lower serum calcium levels in patients who cannot tolerate or have failed other therapies. 10

Diagnostic Workup to Guide Treatment

• Measure intact PTH as the most important initial test to distinguish PTH-dependent from PTH-independent causes. 1, 6, 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, 7

• Also measure PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, and phosphorus to determine underlying cause. 1, 6

• 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, 2, 6

• Measure serum creatinine before each zoledronic acid dose and withhold treatment for renal deterioration (increase of 0.5 mg/dL in patients with normal baseline creatinine, or 1.0 mg/dL in those with abnormal baseline). 3

• Resume zoledronic acid only when creatinine returns to within 10% of baseline value, at the same dose as prior to interruption. 3

Critical Pitfalls to Avoid

• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen outcomes. 1, 2

• Avoid all vitamin D supplements in patients with hypercalcemia regardless of etiology. 1, 2, 6

• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function. 1, 2, 6

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

• Do not use loop diuretics before correcting hypovolemia, as this can worsen renal function and hypercalcemia. 3, 4, 3

• Mild or asymptomatic hypercalcemia (total calcium <12 mg/dL) may be treated with conservative measures (saline hydration) alone without requiring bisphosphonates. 3, 4, 3, 5