What is the treatment approach for hypercalcemia?

Treatment of Hypercalcemia

Initiate aggressive IV normal saline hydration immediately, targeting urine output of 100-150 mL/hour, followed by IV zoledronic acid 4 mg infused over at least 15 minutes as first-line definitive therapy for moderate to severe hypercalcemia. 1, 2

Immediate Management Algorithm

1. Hydration (First-Line Initial Therapy)

• Begin IV normal saline promptly to correct hypovolemia and promote calciuresis, aiming for urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg) 1, 3
• Volume expansion is an integral part of hypercalcemia therapy and should be initiated before any other intervention 3, 4
• Monitor fluid status carefully to avoid hypervolemia, particularly in patients with cardiac failure, renal insufficiency, or oliguria 1, 2
• Loop diuretics (furosemide) should only be used after volume repletion to prevent fluid overload in patients with cardiac or renal insufficiency—never employ diuretics before correcting hypovolemia 1, 3

2. Bisphosphonate Therapy (First-Line Definitive Treatment)

Zoledronic acid is the preferred bisphosphonate due to superior efficacy compared to pamidronate 1, 2, 4

Dosing:

• Zoledronic acid: 4 mg IV infused over no less than 15 minutes 1, 2
• Do not exceed 4 mg as renal toxicity increases with higher doses 2
• Adjust dose for renal impairment: CrCl >60 mL/min: 4 mg; CrCl 50-60: 3.5 mg; CrCl 40-49: 3.3 mg; CrCl 30-39: 3.0 mg 2
• Pamidronate alternative: 60-90 mg IV if zoledronic acid unavailable 1, 3

Timing and Efficacy:

• Bisphosphonates normalize calcium in approximately 50% of patients by day 4, but require 48-72 hours before hypocalcemic action manifests 2, 5
• Do not delay bisphosphonate administration—administer the first dose early, even before waiting for full effects of volume expansion 1, 6
• Duration of response: zoledronic acid 30-40 days vs pamidronate 17 days 5

Critical Monitoring:

• Measure serum creatinine before each dose and withhold if renal deterioration occurs 1
• Perform baseline dental examination before starting therapy to assess osteonecrosis of jaw (ONJ) risk; avoid invasive dental procedures during treatment 2
• Correct pre-existing hypocalcemia before initiating bisphosphonates 1

3. Calcitonin (Bridge Therapy for Rapid Effect)

• Calcitonin-salmon 4 International Units/kg subcutaneously or intramuscularly every 12 hours provides rapid onset within hours but limited efficacy 1, 7, 5
• Use as bridge therapy until bisphosphonates take effect, particularly when rapid calcium reduction is required 1, 5
• If response inadequate after 1-2 days, increase to 8 IU/kg every 12 hours; maximum 8 IU/kg every 6 hours 7
• Combining calcitonin with bisphosphonates enhances the rate of serum calcium decline 8, 5

Etiology-Specific Considerations

Malignancy-Associated Hypercalcemia:

• Hydration plus zoledronic acid is the cornerstone of treatment 1, 4
• Add corticosteroids for hypercalcemia due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous diseases, some lymphomas, multiple myeloma) 1, 4
• Plasmapheresis as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 1, 2
• Treat underlying malignancy when possible—hypercalcemia of malignancy carries poor prognosis with median survival approximately 1 month 1, 4

Primary Hyperparathyroidism:

• Mild asymptomatic hypercalcemia in patients >50 years with calcium <1 mg above upper normal limit and no skeletal/kidney disease may be observed 4
• Parathyroidectomy is curative and should be considered based on age, calcium level, and organ involvement 1, 4
• Parathyroidectomy is indicated for tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism) despite optimized medical therapy 1

Refractory or Severe Hypercalcemia

Denosumab:

• Preferred over bisphosphonates in patients with renal disease 2, 4
• Higher risk of hypocalcemia compared to bisphosphonates—monitor calcium closely and administer oral calcium 500 mg plus vitamin D 400 IU daily 1, 2

Dialysis:

• Reserved for severe hypercalcemia (≥14 mg/dL or ≥3.5 mmol/L) complicated by renal insufficiency or oliguria 1, 4
• Use calcium-free or low-calcium dialysate 1
• Hemodialysis effectively removes calcium through diffusive therapy 1

Critical Pitfalls to Avoid

• Never use loop diuretics before correcting hypovolemia—this worsens volume depletion 1, 3
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney deterioration 1, 2
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 1
• Avoid overhydration in patients with cardiac or renal insufficiency 1
• Discontinue nephrotoxic medications to prevent worsening renal function 1
• Assess for ECG changes, particularly QT interval prolongation, in severe hypercalcemia 1

Supportive Measures

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment 1, 2
• Encourage weight-bearing, standing, or walking to reduce bone resorption 8, 6
• Avoid sedatives and narcotic analgesics, which reduce activity and oral intake, potentially raising calcium levels 8
• Treat only symptomatic hypocalcemia post-treatment (tetany, seizures) with calcium gluconate 50-100 mg/kg—asymptomatic hypocalcemia does not require intervention 1, 2

Severity Classification

• Mild: Total calcium <12 mg/dL (<3 mmol/L)—usually asymptomatic, may be managed conservatively with hydration 3, 4
• Moderate: Total calcium 12-14 mg/dL—requires hydration plus bisphosphonates 1, 4
• Severe: Total calcium ≥14 mg/dL (≥3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L)—medical emergency requiring aggressive IV hydration, bisphosphonates, and consideration of calcitonin for rapid effect 1, 4