What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Immediate IV normal saline hydration followed by zoledronic acid 4 mg IV over 15 minutes is the first-line treatment for moderate to severe hypercalcemia, with calcitonin added only when rapid calcium reduction is needed within hours. 1, 2, 3

Initial Stabilization and Hydration

• 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, 4, 3

• Vigorous saline hydration should be initiated promptly with an attempt to restore urine output to approximately 2 L/day throughout treatment. 3, 5, 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 used before correcting hypovolemia. 2, 4, 3, 5, 3

• Overhydration must be avoided, especially in patients with cardiac failure. 3, 5, 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 for hypercalcemia treatment, with superior efficacy compared to pamidronate. 6, 1, 2, 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, 4

• Pamidronate disodium is an alternative bisphosphonate when zoledronic acid is unavailable, though it has a shorter duration of response (17 days vs. 30-40 days with zoledronic acid). 5, 7

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

• Serum creatinine must be assessed before each bisphosphonate dose, and treatment should be withheld 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

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

• In patients with multiple myeloma or bone metastases, bisphosphonate therapy should be continued for up to 2 years. 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. 1, 2, 8

• Calcitonin should be used primarily in patients who cannot tolerate other treatments or when rapid calcium reduction is essential, as tachyphylaxis limits its long-term effectiveness. 1, 9, 10

• Combining calcitonin with bisphosphonates enhances the rate of serum calcium decline when rapid reduction is warranted. 10, 7

Severity-Based Treatment Algorithm

Mild Hypercalcemia (Total Calcium <12 mg/dL)

• Mild or asymptomatic hypercalcemia may be treated with conservative measures including saline hydration with or without loop diuretics. 3, 5, 3, 8

• In primary hyperparathyroidism 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. 8

Moderate to Severe Hypercalcemia (Total Calcium ≥12 mg/dL)

• Hydration plus bisphosphonates (zoledronic acid preferred) form the cornerstone of treatment. 6, 1, 2, 4, 8

• Add calcitonin if rapid calcium reduction is needed due to severe symptoms (confusion, somnolence, coma). 1, 2, 8

Refractory or Severe Hypercalcemia with Renal Failure

• 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. 6, 1, 2, 4, 9, 11

• Denosumab may be indicated in patients with kidney failure who cannot receive bisphosphonates. 8

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. 1, 2, 4, 8, 9

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

• Hydration, bisphosphonates (zoledronic acid preferred), and steroids form the treatment approach for hypercalcemia due to multiple myeloma. 6, 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. 2, 8, 10, 11

• Avoid all vitamin D supplements in patients with hypercalcemia regardless of etiology. 1, 2, 4

Primary Hyperparathyroidism

• Parathyroidectomy is the definitive curative 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, 2, 8

• For persistent hypercalcemic hyperparathyroidism despite optimized medical therapy (tertiary hyperparathyroidism), parathyroid resection should be considered. 1, 2

Diagnostic Workup to Guide Treatment

• Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, and phosphorus to determine the underlying cause. 1, 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. 8, 11

• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma. 2

Monitoring and Follow-Up

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

• Serum creatinine should be measured before each zoledronic acid dose, and treatment withheld for renal deterioration. 3

• Patients receiving bisphosphonates should also be administered oral calcium supplement 500 mg and vitamin D 400 IU daily to prevent hypocalcemia. 3

Critical Pitfalls to Avoid

• Do not use loop diuretics before correcting hypovolemia—diuretic therapy should not be employed prior to correction of volume depletion. 3, 5, 3

• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function. 6, 1, 2, 4

• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently. 2, 4

• Do not restrict calcium intake without medical supervision in normocalcemic patients. 2, 4

• Avoid vitamin D supplements in all patients with active hypercalcemia. 1, 2, 4

• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg. 6