What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Initiate treatment with intravenous normal saline hydration to correct hypovolemia and promote calciuresis, followed immediately by bisphosphonate therapy (preferably zoledronic acid 4 mg IV over 15 minutes) for moderate to severe hypercalcemia. 1, 2, 3

Initial Assessment and Severity Classification

Before initiating treatment, classify hypercalcemia severity to guide management intensity 2:

• Mild: Corrected calcium >10 to <11 mg/dL (>5.0 to <5.5 mEq/L) 2
• Moderate: 11 to 12 mg/dL (5.5 to 6.0 mEq/L) 2
• Severe: >14 mg/dL (>6.0 mEq/L) 2, 4

Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 2

Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, magnesium, and renal function to determine the underlying cause 1, 5, 2

Treatment Algorithm by Severity

Mild Asymptomatic Hypercalcemia

• Conservative management with saline hydration may be sufficient 3, 6
• Avoid vitamin D supplements 1, 5, 2
• Address underlying cause (parathyroidectomy for primary hyperparathyroidism if indicated) 5, 4

Moderate to Severe Hypercalcemia

Step 1: Aggressive Hydration

• Administer IV normal saline to restore extracellular volume and promote calciuresis 1, 2, 6
• Target urine output of at least 100 mL/hour (3 mL/kg/hour in children <10 kg) 1, 2
• Loop diuretics (furosemide) should only be used in patients with renal or cardiac insufficiency to prevent fluid overload—not before correcting hypovolemia 1, 3, 6

Step 2: Bisphosphonate Therapy

• Zoledronic acid is the preferred bisphosphonate: 4 mg IV infused over no less than 15 minutes 1, 3, 4
• For patients with reduced renal function (CrCl 30-60 mL/min), dose-reduce zoledronic acid according to creatinine clearance 3:
  • CrCl 50-60 mL/min: 3.5 mg
  • CrCl 40-49 mL/min: 3.3 mg
  • CrCl 30-39 mL/min: 3.0 mg
• Alternative: Pamidronate, though zoledronic acid demonstrates superior efficacy and longer duration of response (30-40 days vs 17 days) 7
• Bisphosphonates take 2-4 days to achieve maximal effect 8, 7
• May continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1

Step 3: Calcitonin for Immediate Effect (if severe/symptomatic)

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid onset (within hours) but modest efficacy 1, 6, 7
• Use as a bridge therapy while waiting for bisphosphonates to take effect 1, 7
• Combination of calcitonin plus bisphosphonates enhances rate of calcium decline 8, 7

Cause-Specific Considerations

Vitamin D-Mediated Hypercalcemia

Glucocorticoids are the primary treatment for hypercalcemia due to sarcoidosis, lymphomas, granulomatous diseases, or vitamin D intoxication 5, 2, 6, 4, 8

Malignancy-Associated Hypercalcemia

• Treat the underlying cancer when possible 1, 5
• Bisphosphonates are first-line pharmacologic therapy 1, 5, 4
• For refractory cases or renal impairment, consider denosumab 120 mg subcutaneously 2, 4
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 1

Primary Hyperparathyroidism

• Parathyroidectomy is indicated for symptomatic patients or those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal 5
• Observation is appropriate for patients >50 years with calcium <1 mg/dL above normal and no skeletal or kidney disease 4

Renal Failure

• Hemodialysis is reserved for severe hypercalcemia complicated by renal insufficiency 1, 6
• Denosumab may be preferred over bisphosphonates in patients with significant renal impairment 2, 4

Retreatment and Monitoring

• If serum calcium does not normalize after initial bisphosphonate treatment, allow minimum 7 days before retreating with zoledronic acid 4 mg 3
• Monitor serum calcium, renal function (creatinine), and electrolytes regularly 1, 5, 2
• Withhold bisphosphonates if creatinine increases by 0.5 mg/dL (normal baseline) or 1.0 mg/dL (abnormal baseline); resume when creatinine returns to within 10% of baseline 3
• Supplement with oral calcium 500 mg and vitamin D 400 IU daily during bisphosphonate therapy to prevent hypocalcemia 3

Critical Pitfalls to Avoid

• Do not use loop diuretics before correcting hypovolemia—this worsens volume depletion 3, 6
• Avoid NSAIDs and IV contrast in patients with renal impairment to prevent further renal deterioration 1
• Do not delay bisphosphonate therapy in moderate to severe cases—temporary measures like calcitonin provide only 1-4 hour benefit 1
• Monitor for bisphosphonate complications: renal toxicity, osteonecrosis of jaw, and post-treatment hypocalcemia (especially with denosumab) 2, 7
• Always calculate corrected calcium—hyperalbuminemia can mask true hypercalcemia 2