What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Initiate immediate IV normal saline hydration targeting urine output ≥100 mL/hour, followed by IV zoledronic acid 4 mg infused over at least 15 minutes—this combination represents the cornerstone of treatment for moderate to severe hypercalcemia regardless of underlying cause. 1, 2, 3

Initial Stabilization and Hydration

• Aggressive IV normal saline is the first-line intervention to restore extracellular volume and enhance urinary calcium excretion, maintaining 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 patients and should never be given before correcting hypovolemia. 4, 1, 2

• Patients must be adequately rehydrated prior to bisphosphonate administration, but overhydration must be avoided, especially in those with cardiac failure. 4, 3

Definitive Pharmacologic Treatment

Bisphosphonates (First-Line Definitive Therapy)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate, demonstrating superior efficacy compared to pamidronate with longer duration of response (30-40 days vs 17 days). 1, 2, 3, 5

• Do not delay bisphosphonate administration in moderate to severe hypercalcemia while waiting for complete diagnostic workup—treat first, diagnose concurrently, as bisphosphonates have a 2-4 day delayed onset of action. 1, 2

• For patients with baseline creatinine clearance 50-60 mL/min, reduce 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. 3

• Monitor serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in patients with normal baseline, or 1.0 mg/dL in those with abnormal baseline). 1, 3

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

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, 5

• Calcitonin has limited efficacy and should be used primarily in patients who cannot tolerate other treatments or when rapid reduction is needed in combination with bisphosphonates. 1, 6

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. 4, 2, 5

• The combination of hydration, zoledronic acid, and calcitonin forms the acute management approach, with median survival after discovery being approximately 1 month in lung cancer patients. 4, 1

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

• Measure PTHrP levels, as parathyroid hormone-related protein production is the most common mechanism in malignancy-associated hypercalcemia, particularly with squamous cell carcinomas. 4, 2

Vitamin D-Mediated Hypercalcemia (Granulomatous Disease, Lymphoma)

• Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), and some lymphomas. 1, 2, 5

• Glucocorticoids address the unregulated 1-alpha-hydroxylase activity in activated macrophages that drives vitamin D-mediated hypercalcemia. 7

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

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. 2, 5

• For 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. 5

• Calcimimetic agents may be considered when surgery is not possible or patients do not meet surgical criteria, though they should be used with extreme caution due to risk of severe hypocalcemia and QT prolongation. 2, 8

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, 9

• Denosumab may be indicated in patients with kidney failure who cannot receive bisphosphonates. 5

Diagnostic Workup to Guide Treatment

• Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, phosphorus, creatinine, and BUN to determine underlying mechanism. 4, 7, 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, 5

• Calculate corrected calcium or preferably measure ionized calcium directly to assess true severity. 7, 5

Monitoring and Supportive Care

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

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia. 1, 2

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

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

Critical Pitfalls to Avoid

• Do not use loop diuretics before correcting hypovolemia—diuretic therapy should not be employed prior to correction of volume depletion. 4, 3

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

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

• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients. 2

• Temporarily discontinue nephrotoxic medications (including chemotherapy agents like lenalidomide and bortezomib) until calcium normalizes in patients with severe hypercalcemia. 1

• Allow a minimum of 7 days before retreatment with zoledronic acid to allow for full response to the initial dose. 3