What is the management approach for hypercalcemia?

Management of Hypercalcemia

Initiate aggressive IV normal saline hydration immediately, 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

Initial Assessment and Diagnostic Workup

Before initiating treatment, obtain the following laboratory studies to determine the underlying etiology:

• Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, calcium, phosphorus, and magnesium 1
• Check ionized calcium rather than relying solely on corrected calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 1
• Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 [4.0 - patient albumin (g/dL)] 1
• Assess renal function with serum creatinine and calculate creatinine clearance using Cockcroft-Gault formula 1, 2

Key diagnostic distinction: Elevated or normal PTH indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) points to malignancy or other causes 3

Treatment Algorithm by Severity

Mild Hypercalcemia (Total calcium <12 mg/dL)

• Conservative management with hydration and observation is appropriate for asymptomatic patients 1, 3
• For primary hyperparathyroidism in patients >50 years with calcium <1 mg above upper normal limit and no skeletal/kidney disease, observation with monitoring is acceptable 3
• Consider parathyroidectomy for younger patients or those meeting surgical criteria 1

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

Step 1: Aggressive Hydration

• Administer IV normal saline to restore urine output to approximately 100-150 mL/hour (or 2 L/day) 1, 4
• In children <10 kg, target 3 mL/kg/hour 1
• Avoid overhydration in patients with cardiac or renal insufficiency; use loop diuretics (furosemide) after volume repletion to prevent fluid overload 1
• Do not use diuretics before correcting hypovolemia 1

Step 2: Bisphosphonate Therapy (First-Line Definitive Treatment)

Zoledronic acid is the preferred bisphosphonate due to superior efficacy compared to pamidronate 1, 2, 5

Standard dosing for normal renal function (CrCl >60 mL/min):

• 4 mg IV infused over no less than 15 minutes 1, 2
• Repeat every 3-4 weeks for malignancy-associated hypercalcemia 2

Dose adjustments for renal impairment (baseline CrCl ≤60 mL/min): 1, 2

• CrCl 50-60 mL/min: 3.5 mg
• CrCl 40-49 mL/min: 3.3 mg
• CrCl 30-39 mL/min: 3.0 mg

Critical monitoring requirements:

• Check serum creatinine before each dose 1, 2
• Withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in normal baseline creatinine or 1.0 mg/dL in abnormal baseline) 2
• Resume only when creatinine returns to within 10% of baseline 2

Step 3: Adjunctive Rapid-Acting Therapy

Calcitonin for immediate short-term control:

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly every 12 hours provides rapid onset within hours but limited efficacy 1
• Use as a bridge until bisphosphonates take effect (bisphosphonates have delayed action of 2-4 days) 1, 3
• Tachyphylaxis develops within 48 hours, limiting long-term utility 1

Etiology-Specific Considerations

Malignancy-Associated Hypercalcemia

• Hydration plus zoledronic acid 4 mg IV is the cornerstone of treatment 1
• For multiple myeloma: add corticosteroids (prednisone 1 mg/kg/day or methylprednisolone IV equivalent) 1
• Plasmapheresis for symptomatic hyperviscosity in multiple myeloma 1
• Temporarily discontinue myeloma therapy (lenalidomide, bortezomib) until calcium normalizes 1
• Consider denosumab in patients with renal insufficiency where bisphosphonates are contraindicated 4

Granulomatous Disease/Vitamin D Intoxication/Lymphoma

Corticosteroids are first-line therapy for hypercalcemia due to excessive intestinal calcium absorption: 1, 3

• Prednisone 1 mg/kg/day orally or methylprednisolone IV equivalent 1
• Taper over 2-4 months depending on response 1
• Add PPI for GI prophylaxis 1
• Provide pneumocystis prophylaxis if ≥20 mg methylprednisolone equivalent for ≥4 weeks 1

Primary Hyperparathyroidism

• Parathyroidectomy is definitive treatment for patients meeting surgical criteria 1
• Calcimimetics may be considered when surgery is not possible or patients don't meet surgical criteria 5

Refractory or Severe Hypercalcemia with Renal Failure

Indications for dialysis: 1, 4

• Severe hypercalcemia persisting despite standard medical therapy
• Acute oliguric renal failure or anuria due to calcium-induced nephropathy
• Severe electrolyte abnormalities accompanying hypercalcemia

Dialysis prescription:

• Intermittent hemodialysis (IHD) is highly effective for rapid calcium removal with clearance rates of 70-100 mL/min 4
• Use calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) 1, 4
• Continuous renal replacement therapy (CRRT) is preferred for hemodynamically unstable patients 4
• Daily hemodialysis may provide improved outcomes in severe cases 4
• High-flux dialyzers benefit patients with multiple myeloma 4

Supportive Care and Monitoring

Mandatory supplementation during bisphosphonate therapy:

• Oral calcium 500 mg plus vitamin D 400 IU daily to prevent treatment-induced hypocalcemia 1, 2
• Correct pre-existing hypocalcemia before initiating bisphosphonates 1
• Monitor serum calcium closely, especially with denosumab which carries higher hypocalcemia risk 1

Ongoing monitoring:

• Monitor serum calcium, renal function, and electrolytes regularly 1
• Assess for ECG changes, particularly QT interval prolongation in severe hypercalcemia 1
• Watch for rebound hypercalcemia after dialysis, requiring potentially repeated treatments 4

Critical Pitfalls to Avoid

• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia; temporary measures like insulin and beta-agonists provide only 1-4 hours of benefit 1
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney deterioration 1
• Do not restrict calcium intake excessively without supervision, as this can worsen bone disease 1
• Do not delay dialysis initiation in severe symptomatic hypercalcemia with renal failure 4
• Avoid calcium-containing phosphate binders in dialysis patients with hypercalcemia 4
• Do not rely on corrected calcium instead of ionized calcium, as it can lead to inaccurate diagnosis 1
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 1

Retreatment Considerations

For hypercalcemia of malignancy:

• Allow minimum of 7 days before retreatment to assess full response to initial dose 2
• Reassess renal function before each retreatment 2
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1