How to treat hypercalcemia?

Treatment of Hypercalcemia

Immediate Initial Management

Administer IV normal saline immediately to restore extracellular volume and enhance urinary calcium excretion, targeting a urine output of at least 100 mL/hour (or 100-150 mL/hour in adults). 1, 2

• Vigorous saline hydration is an integral part of hypercalcemia therapy and should be initiated promptly, with an attempt to restore urine output to about 2 L/day throughout treatment. 3
• Balanced crystalloids are preferred over 0.9% saline when possible, as large volumes of saline can cause hyperchloremic metabolic acidosis. 2
• Patients must be adequately rehydrated prior to any other pharmacologic intervention. 3
• Loop diuretics (furosemide) should only be used AFTER complete volume repletion and only in patients with renal or cardiac insufficiency to prevent fluid overload—never before adequate hydration is achieved. 1, 2, 3

Definitive Pharmacologic Treatment

Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate and should be administered early without waiting for diagnostic workup completion in symptomatic patients. 1, 2, 3

• Zoledronic acid normalizes calcium in approximately 50% of patients by day 4 and is superior to pamidronate. 2, 4
• The FDA-approved dose for hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL) is 4 mg as a single-dose IV infusion over no less than 15 minutes. 3
• Do not delay bisphosphonate administration while waiting for diagnostic workup in moderate to severe hypercalcemia—they should be given early despite their delayed onset of action (3-6 days). 1, 2
• Dose adjustments are not necessary for mild-to-moderate renal impairment (serum creatinine <4.5 mg/dL) when treating hypercalcemia of malignancy. 3
• For patients with creatinine clearance 30-60 mL/min receiving chronic bisphosphonate therapy, dose reduction is required (see Table 1 in FDA label). 3

Bridging Therapy for Rapid Effect

Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid but modest calcium reduction within hours and should be used as a bridge until bisphosphonates take effect. 1, 2, 5

• Calcitonin has a more rapid onset than bisphosphonates but limited efficacy and duration of action. 2, 6, 7
• Standard dosing is 100 IU subcutaneously or intramuscularly every other day, or 200 IU per day as nasal spray. 2
• Combining calcitonin with bisphosphonates enhances the rate of decline of serum calcium. 6

Severity-Based Approach

Mild Hypercalcemia (Total calcium <12 mg/dL)

• May be treated conservatively with saline hydration alone, with or without loop diuretics after adequate rehydration. 3, 7
• Asymptomatic patients may not require acute intervention. 4

Moderate to Severe Hypercalcemia (Total calcium ≥12 mg/dL)

• Requires immediate IV saline plus bisphosphonate therapy. 1, 2, 4
• Consider adding calcitonin for more rapid initial calcium reduction. 1, 2

Severe Hypercalcemia with Renal Failure

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is indicated for severe hypercalcemia complicated by renal insufficiency or oliguria. 1, 2
• Denosumab 120 mg subcutaneously is preferred over bisphosphonates in patients with impaired renal function due to lower renal toxicity, though it carries higher risk of hypocalcemia. 2

Etiology-Specific Treatment

Vitamin D-Mediated Hypercalcemia

Corticosteroids (prednisone 20-40 mg/day orally or methylprednisolone IV equivalent) are the primary therapy for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous diseases (sarcoidosis), some lymphomas, and multiple myeloma. 2, 8, 4

• Glucocorticoids work by reducing intestinal calcium absorption in conditions with elevated 1,25-dihydroxyvitamin D. 2, 7
• Allow 3-6 months to demonstrate responsiveness before considering escalation. 2

Malignancy-Associated Hypercalcemia

• Treatment of the underlying cancer is essential for long-term control. 1, 8
• For bisphosphonate-refractory hypercalcemia, denosumab 120 mg subcutaneously lowers calcium in 64% of patients within 10 days. 2
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma. 1, 2

Primary Hyperparathyroidism

• Parathyroidectomy is indicated for symptomatic patients and those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal. 8
• Observation may be appropriate in patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease. 4

Critical Monitoring Requirements

• Assess serum creatinine before each bisphosphonate 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
• Monitor serum calcium, renal function, and electrolytes (especially potassium and magnesium) every 6-12 hours during acute phase. 2, 8
• Monitor ionized calcium concentration to prevent hypercalcemia when using calcium infusions for other indications. 1

Critical Pitfalls to Avoid

• Never restrict calcium intake without medical supervision in normocalcemic patients. 1
• Avoid all vitamin D supplements in patients with hypercalcemia. 1, 2, 8
• Do not use loop diuretics before adequate volume repletion—this worsens dehydration and hypercalcemia. 2, 3
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment. 1, 2
• Do not delay bisphosphonate therapy while awaiting full diagnostic evaluation in symptomatic patients. 1, 2
• Immediately discontinue all calcium-based phosphate binders, vitamin D analogs (calcitriol, paricalcitol), and calcium/vitamin D supplements. 2

Retreatment Considerations

• If serum calcium does not normalize after initial zoledronic acid dose, retreatment with 4 mg may be considered after a minimum of 7 days to allow full response to initial dose. 3
• Renal function must be carefully monitored before retreatment. 3

Supplementation During Treatment

• Patients receiving bisphosphonates for chronic conditions (not acute hypercalcemia) should receive oral calcium supplement 500 mg plus vitamin D 400 IU daily to prevent treatment-induced hypocalcemia. 2, 3
• This does NOT apply during acute hypercalcemia treatment—all calcium and vitamin D must be discontinued immediately. 2