What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Immediately initiate IV normal saline hydration 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), followed by early administration of zoledronic acid 4 mg IV as the preferred bisphosphonate for definitive treatment. 1, 2

Initial Stabilization and Hydration

• Administer IV normal saline as the first-line intervention to correct hypovolemia and promote calciuresis—this is an integral part of hypercalcemia therapy and should be initiated promptly. 1, 2, 3

• Maintain urine output at 100-150 mL/hour throughout treatment to maximize renal calcium excretion. 1, 4

• 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 used before correcting hypovolemia. 1, 2, 5

• Avoid overhydration, particularly in patients with heart failure or renal impairment, as this can cause life-threatening complications. 4, 5

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 and longer duration of response (30-40 days vs. 17 days). 1, 2, 3, 6

• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in moderate to severe hypercalcemia—initiate treatment early despite the 2-4 day delayed onset of action. 1, 2, 4

• Pamidronate is an acceptable alternative if zoledronic acid is unavailable, though it is less potent. 4, 5, 6

• Assess serum creatinine before each bisphosphonate dose and adjust dosing for renal impairment: reduce to 3.5 mg for CrCl 50-60 mL/min, 3.3 mg for CrCl 40-49 mL/min, and 3.0 mg for CrCl 30-39 mL/min. 3

• Withhold bisphosphonates if renal deterioration occurs (creatinine increase ≥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 calcium reduction within hours but has modest efficacy and should be used as a bridge until bisphosphonates take effect. 1, 2, 4

• Combining calcitonin with bisphosphonates enhances the rate of serum calcium decline when rapid reduction is needed. 7, 6

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, as hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month. 1, 2, 4, 8

• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases. 1, 4

• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients. 1, 2, 4

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, 8

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

Primary Hyperparathyroidism

• Parathyroidectomy is the definitive treatment and should be considered for patients with: symptomatic disease, osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal. 1, 8

• For patients >50 years with calcium <1 mg/dL above normal and no skeletal or kidney disease, observation with monitoring may be appropriate. 8

• Consider parathyroidectomy for tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism despite optimized medical therapy). 1, 4

Refractory or Severe Hypercalcemia

• Dialysis with calcium-free or low-calcium dialysate is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria, as hemodialysis effectively removes calcium through diffusive therapy. 1, 2, 4, 9

• Calcimimetics may be considered for severe hyperparathyroidism, though cinacalcet should be used with extreme caution due to risk of severe hypocalcemia and QT prolongation. 1

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

Diagnostic Workup to Guide Treatment

• Measure intact PTH as the most important initial test to distinguish PTH-dependent from PTH-independent causes: elevated or inappropriately normal PTH indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) suggests malignancy or other causes. 1, 4, 8

• Obtain PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, phosphorus, and magnesium to determine the underlying etiology. 1, 4

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

Monitoring and Supportive Care

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

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia. 4

• Correct hypocalcemia before initiating bisphosphonate therapy, especially with denosumab which carries higher risk. 4

• Assess ECG for QT interval prolongation in patients with severe hypercalcemia. 4

Critical Pitfalls to Avoid

• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen bone disease and outcomes. 1, 2, 4

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

• Do not use loop diuretics before correcting hypovolemia, as this worsens volume depletion and hypercalcemia. 5

• Retreatment with zoledronic acid may be considered if calcium does not normalize, but allow a minimum of 7 days between doses to assess full response. 3

• Asymptomatic hypocalcemia following treatment does not require intervention—only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg. 4