What are the treatment options for hypercalcemia?

Treatment of Hypercalcemia

Initiate immediate IV normal saline hydration followed by 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 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, 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 hypercalcemia patients and should never be given before correcting hypovolemia. 1, 2, 3

• Vigorous saline hydration is an integral part of therapy, with attempts to restore urine output to approximately 2 L/day, but avoid overhydration in patients with cardiac failure. 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, with superior efficacy compared to pamidronate and longer duration of response (30-40 days vs 17 days). 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, as temporary measures provide only short-term benefit. 1, 2

• For patients with creatinine clearance (CrCl) 50-60 mL/min, reduce dose to 3.5 mg; CrCl 40-49 mL/min use 3.3 mg; CrCl 30-39 mL/min use 3 mg. 3

• Monitor serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in normal baseline or 1.0 mg/dL in abnormal baseline). 3

• Continue bisphosphonate therapy 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 (onset 2-4 days). 1, 2, 4

• Calcitonin has limited efficacy for long-term control but offers the advantage of acute onset, making combination therapy with bisphosphonates valuable when rapid reduction is warranted. 1, 4

Cause-Specific Treatment Strategies

Malignancy-Associated Hypercalcemia

• Treatment of the underlying cancer is essential for long-term control and should be pursued alongside acute calcium-lowering measures. 5, 2

• Hydration plus bisphosphonates (zoledronic acid preferred) form the cornerstone of acute management. 1, 2

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

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, 5, 2, 6

• Avoid all vitamin D supplements in patients with active hypercalcemia regardless of etiology. 1, 5, 2

Primary Hyperparathyroidism

• Parathyroidectomy is the definitive treatment for symptomatic primary hyperparathyroidism and should be considered for patients with: 5, 2

  • Osteoporosis
  • Impaired kidney function
  • Kidney stones or hypercalciuria
  • Age ≥50 years
  • Calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal

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

• In patients >50 years with serum calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring may be appropriate. 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, 7

• Denosumab may be indicated in patients with kidney failure when bisphosphonates are contraindicated, though it carries higher risk of hypocalcemia. 1, 8, 6

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, 5, 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. 5, 7, 6

• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma. 5, 2

Supplementation During Treatment

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent treatment-induced hypocalcemia. 1, 3

• Correct pre-existing hypocalcemia before initiating bisphosphonate therapy, especially with denosumab which carries higher hypocalcemia risk. 1, 8

Monitoring and Follow-Up

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 1, 5, 2

• Monitor serum creatinine before each zoledronic acid dose and withhold treatment if renal deterioration occurs. 1, 3

Critical Pitfalls to Avoid

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

• Do not employ diuretic therapy prior to correction of hypovolemia. 3

• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate. 1