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, followed by IV zoledronic acid 4 mg infused over no less than 15 minutes as the preferred first-line definitive treatment for moderate to severe hypercalcemia. 1, 2, 3, 4

Initial Stabilization and Hydration

• Administer IV normal saline immediately as the cornerstone of acute management to correct hypovolemia and promote calciuresis, maintaining urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg). 1, 2, 3

• 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 and should never be used before correcting hypovolemia. 1, 2, 4, 5

• Vigorous saline hydration should aim to restore urine output to approximately 2 L/day throughout treatment, but overhydration must be avoided, especially in patients with cardiac failure. 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 for hypercalcemia treatment, with superior efficacy compared to pamidronate. 1, 2, 3, 4

• Do not delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action, and do not wait for complete diagnostic workup in symptomatic patients. 1, 2, 3

• For patients with creatinine clearance (CrCl) 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 3.0 mg. 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 creatinine, or 1.0 mg/dL in those with abnormal baseline). 1, 4

• Bisphosphonates should be continued for up to 2 years in patients with multiple myeloma or bone metastases. 1

• Pamidronate is an alternative bisphosphonate but is less effective than zoledronic acid. 5, 6

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, 3

• Calcitonin has limited efficacy and short duration of action due to tachyphylaxis, but its rapid onset makes it useful for severe symptomatic hypercalcemia requiring immediate intervention. 1, 6, 7

• Standard dosing is 200 IU per day as nasal spray or 100 IU subcutaneously/intramuscularly every other day, primarily for patients who cannot tolerate other treatments. 1

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, 3

• For multiple myeloma patients: use hydration, zoledronic acid (preferred), furosemide, steroids, and/or calcitonin; temporarily discontinue lenalidomide and bortezomib until calcium normalizes. 1

• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients. 1, 2, 3

• The prognosis for hypercalcemia of malignancy is poor, with survival closely tied to the underlying cancer. 6

Vitamin D-Mediated and Granulomatous Disease

• Glucocorticoids (corticosteroids) are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), and some lymphomas. 1, 2, 6, 8

• Avoid all vitamin D supplements in patients with active hypercalcemia regardless of etiology. 1, 2, 3

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 (>1 mg/dL) above upper limit of normal. 2, 6

• 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. 2, 6

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

• The prognosis for asymptomatic primary hyperparathyroidism is excellent with either medical or surgical management. 6

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, 2, 3

• In patients with kidney failure, denosumab may be indicated as an alternative to bisphosphonates. 6

• Assess ECG for changes, particularly QT interval prolongation, in patients with severe hypercalcemia. 1

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. 2, 6

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

• Approximately 90% of hypercalcemia cases are due to primary hyperparathyroidism or malignancy. 6

Supportive Care and Monitoring

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent treatment-induced hypocalcemia. 1

• Correct pre-existing hypocalcemia before initiating bisphosphonate therapy, and monitor serum calcium closely, especially with denosumab which carries higher risk of hypocalcemia. 1

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 1, 2, 3

• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment, with a minimum of 7 days between doses. 4

Critical Pitfalls to Avoid

• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen outcomes. 1, 2, 3

• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function. 1, 2, 3

• Discontinue any nephrotoxic medications to avoid worsening renal function in hypercalcemic patients. 1

• Do not use diuretic therapy prior to correction of hypovolemia. 4, 5

• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg. 1

• Sedatives and narcotic analgesics can raise serum calcium levels by reducing activity and oral intake—use cautiously. 8