What is the treatment approach for a patient with hypercalcaemia?

Treatment 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

Immediate Assessment and Severity Classification

• Measure ionized calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling, which can lead to inaccurate diagnosis 1
• Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 1
• Classify severity:
  • Mild: <12 mg/dL (often asymptomatic) 3
  • Moderate: 12-14 mg/dL 3
  • Severe: ≥14 mg/dL (associated with nausea, vomiting, confusion, somnolence, coma) 3

Diagnostic Workup

Measure intact PTH immediately to distinguish PTH-dependent from PTH-independent causes 3:

• Elevated or normal PTH = primary hyperparathyroidism 3
• Suppressed PTH (<20 pg/mL) = malignancy or other causes 3

Additional essential labs 1:

• PTHrP (elevated in malignancy-associated hypercalcemia) 4
• 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D (measure BOTH together for diagnostic accuracy) 1
• Serum creatinine, BUN (assess renal function before bisphosphonate therapy) 1, 2
• Albumin, magnesium, phosphorus 1

Treatment Algorithm

Step 1: Aggressive Hydration (Initiate Immediately)

Administer IV normal saline aggressively targeting urine output of 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg) 1:

• Give boluses of 250-500 mL every 15 minutes until rehydration achieved 1
• Continue hydration to maintain diuresis >2.5 L/day in adults 1
• Avoid loop diuretics (furosemide) before complete volume repletion; only use in patients with renal or cardiac insufficiency to prevent fluid overload 1, 5

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

Zoledronic acid 4 mg IV is the preferred bisphosphonate due to superior efficacy compared to pamidronate 6, 1, 2:

• Infuse over no less than 15 minutes 2
• Normalizes calcium in 50% of patients by day 4 (vs. 33% with pamidronate) 6
• Do not delay bisphosphonate therapy—initiate early without waiting for completion of rehydration 1

Dose adjustments for renal impairment (for CrCl <60 mL/min) 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
• Do not use in severe renal impairment (CrCl <30 mL/min) 2

Monitor serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase ≥0.5 mg/dL from normal baseline or ≥1.0 mg/dL from abnormal baseline) 2

Alternative: Pamidronate 90 mg IV infused over 2 hours if zoledronic acid unavailable 6, 1, 5

Step 3: Adjunctive Rapid-Acting Agents (Bridge Therapy)

Calcitonin 100 IU subcutaneously or intramuscularly for immediate short-term management of severe symptomatic hypercalcemia 1, 7:

• Provides rapid onset within hours but limited efficacy (lasts only 1-4 hours) 1
• Use as bridge until bisphosphonates take effect (typically 2-4 days) 1
• Tachyphylaxis develops rapidly; not suitable for long-term control 1

Step 4: Cause-Specific Therapy

For vitamin D-mediated hypercalcemia (granulomatous diseases like sarcoidosis, lymphomas, vitamin D intoxication):

• Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 1, 3
• Reduces excessive intestinal calcium absorption 6, 1
• Allow 3-6 months to demonstrate responsiveness 1

For malignancy-associated hypercalcemia:

• Treat underlying cancer when possible (median survival ~1 month without cancer treatment) 1
• Continue bisphosphonates for up to 2 years in multiple myeloma or bone metastases 1

For primary hyperparathyroidism:

• Parathyroidectomy is definitive treatment for symptomatic patients or those with osteoporosis, impaired kidney function, kidney stones, age ≥50 years, or calcium >0.25 mmol/L above upper limit 4

Step 5: Refractory or Severe Cases with Renal Failure

Denosumab 120 mg subcutaneously for bisphosphonate-refractory hypercalcemia 6:

• Lowers calcium in 64% of patients within 10 days 6
• Monitor closely for hypocalcemia (higher risk than with zoledronic acid) 6
• Start calcium and vitamin D supplements if needed 6

Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 1, 7

Supportive Care and Monitoring

Coadminister oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 1, 2

Monitor closely 1:

• Serum calcium, creatinine, electrolytes (especially potassium, magnesium) every 6-12 hours during acute phase
• ECG for QT interval prolongation in severe hypercalcemia 1

Critical Pitfalls to Avoid

• Never use doses >4 mg zoledronic acid for initial treatment; reserve 8-mg dose only for relapsed/refractory cases 6
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney deterioration 1
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 1
• Verify pregnancy status before initiating bisphosphonates in females of reproductive potential; can cause fetal harm 2
• Retreatment with zoledronic acid requires minimum 7-day interval if calcium does not normalize 2
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 1

Special Populations

Chronic kidney disease patients 1:

• Immediately discontinue all calcium-based phosphate binders and vitamin D analogs (calcitriol, paricalcitol)
• Consider lower dialysate calcium concentration (1.5-2.0 mEq/L) if PTH suppressed
• Target corrected calcium 8.4-9.5 mg/dL (lower end of range preferred)

Multiple myeloma patients on lenalidomide/bortezomib 1:

• Temporarily discontinue myeloma therapy until calcium normalizes
• Initiate aggressive IV saline + zoledronic acid 4 mg immediately
• Reassess disease status as hypercalcemia indicates active disease