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 zoledronic acid 4 mg IV infused over no less than 15 minutes as first-line definitive therapy. 1, 2

Initial Stabilization and Hydration

• Aggressive IV normal saline is the cornerstone of initial management, correcting the volume depletion that universally accompanies hypercalcemia and promoting calciuresis through enhanced renal calcium excretion 1, 3, 4
• Target urine output of 100-150 mL/hour to maximize calcium clearance 1, 5
• 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 given before adequate volume repletion 1, 5, 3
• Avoid overhydration, particularly in patients with heart failure or renal impairment, as this can precipitate pulmonary edema 5, 3

Definitive Pharmacologic Treatment

Bisphosphonates (First-Line)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate, demonstrating superior efficacy compared to pamidronate 1, 5, 3, 2
• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in moderate to severe hypercalcemia—treat first, diagnose concurrently, as bisphosphonates take 2-4 days to achieve maximal effect 1, 5, 3
• Dose adjustments are required for renal impairment (CrCl <60 mL/min): CrCl 50-60 mL/min use 3.5 mg; CrCl 40-49 mL/min use 3.3 mg; CrCl 30-39 mL/min use 3.0 mg 5, 2
• 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) 5, 2
• Pamidronate IV is an acceptable alternative if zoledronic acid is unavailable 5, 6

Calcitonin (Rapid Bridge Therapy)

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid calcium reduction within hours but has modest and transient efficacy, making it ideal as a bridge until bisphosphonates take effect 1, 5, 3, 4
• Standard dosing is 100 IU subcutaneously or intramuscularly every 12 hours, or 200 IU daily as nasal spray 5
• Tachyphylaxis develops within 48-72 hours, limiting its utility for prolonged management 5, 4

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, 5, 3, 4
• Hydration, bisphosphonates (zoledronic acid preferred), and calcitonin form the cornerstone of acute management 1, 5
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1, 5
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients 1, 5, 3
• Prognosis is poor, with median survival of approximately 1 month, underscoring the importance of treating the underlying malignancy 5, 4

Vitamin D-Mediated Hypercalcemia and Granulomatous Disease

• Glucocorticoids (prednisone 1 mg/kg/day orally or methylprednisolone IV equivalent) are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, sarcoidosis, granulomatous disorders, and some lymphomas 1, 5, 4, 7
• Taper corticosteroids over 2-4 months depending on response 5
• Provide pneumocystis pneumonia prophylaxis for patients receiving ≥20 mg methylprednisolone equivalent for ≥4 weeks 5
• Initiate GI prophylaxis with proton pump inhibitor therapy for all patients on corticosteroids 5
• Screen for tuberculosis with T-spot testing before initiating corticosteroids in granulomatous disease 5

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 1, 4
• In patients >50 years with serum calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring is appropriate 4
• For persistent hypercalcemic hyperparathyroidism despite optimized medical therapy (tertiary hyperparathyroidism), parathyroid resection should be considered 1, 5

Refractory or Severe Hypercalcemia

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria, as it effectively removes calcium through diffusive therapy 1, 5, 3, 8
• Denosumab may be considered in patients with kidney failure who cannot receive bisphosphonates, though it carries higher risk of severe rebound hypocalcemia 5
• Calcimimetics may be considered for severe hyperparathyroidism, but cinacalcet should be used with extreme caution due to risk of severe hypocalcemia and QT prolongation 1

Diagnostic Workup to Guide Treatment

• Measure intact PTH first—this is the single most important test to distinguish PTH-dependent from PTH-independent causes 1, 5, 4
• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism 1, 4, 8
• Suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes 1, 4, 8
• Additional workup: PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, phosphorus, magnesium, and ionized calcium 1, 5, 3
• Measure ionized calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 5
• Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 [4 - Serum albumin (g/dL)] 5

Monitoring and Follow-Up

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness 1, 5, 3
• Assess ECG for QT interval prolongation in patients with severe hypercalcemia 5
• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not normalize after initial treatment, with a minimum of 7 days between doses 2
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 5, 2

Critical Pitfalls to Avoid

• Do not use loop diuretics before adequate volume repletion—this worsens volume depletion and hypercalcemia 1, 5, 3
• Avoid vitamin D supplements in all patients with active hypercalcemia, regardless of etiology 1, 5, 3
• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen bone disease 1, 3
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further kidney deterioration 1, 5, 3
• Do not delay bisphosphonate administration while waiting for diagnostic workup in symptomatic patients—treat first, diagnose concurrently 1, 3
• Do not rely on corrected calcium instead of ionized calcium, as it can lead to inaccurate diagnosis 5
• Discontinue nephrotoxic medications to avoid worsening renal function 5
• Review medication history for thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A, as these can contribute to hypercalcemia 5