What is the approach to managing hypercalcemia?

Approach to Hypercalcemia

Initial Diagnostic Workup

Measure ionized calcium rather than relying solely on corrected calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 1. If ionized calcium is unavailable, calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 [4 - Serum albumin (g/dL)] 1, 2.

The single most important initial test is intact parathyroid hormone (PTH), which distinguishes PTH-dependent from PTH-independent causes 1, 3:

• Elevated or normal PTH = Primary hyperparathyroidism
• Suppressed PTH (<20 pg/mL) = Malignancy or other causes

Additional essential labs include 1:

• PTH-related protein (PTHrP) if PTH is suppressed
• 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D (measure both together for diagnostic accuracy)
• Albumin, phosphorus, magnesium
• Serum creatinine and BUN to assess renal function
• Malignancy markers if PTH suppressed

Obtain medication history specifically for thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D (>400 IU/day), and vitamin A 1.

Severity Classification and Symptom Assessment

Mild hypercalcemia: Total calcium <12 mg/dL (<3 mmol/L) or ionized calcium 5.6-8.0 mg/dL (1.4-2 mmol/L) 3

• Usually asymptomatic but may cause fatigue and constipation in ~20% 3

Severe hypercalcemia: Total calcium ≥14 mg/dL (≥3.5 mmol/L) or ionized calcium ≥10 mg/dL (≥2.5 mmol/L) 3

• Causes nausea, vomiting, dehydration, confusion, somnolence, coma 3
• Check ECG for QT interval prolongation 1

Treatment Algorithm

Step 1: Immediate Hydration (All Symptomatic Cases)

Administer IV normal saline aggressively targeting urine output of 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg) 1. This is the cornerstone of initial therapy and should be started immediately 1, 3, 4.

• Restore extracellular volume with 2-3 liters of saline per day initially 5
• Avoid overhydration in patients with cardiac or renal insufficiency; use loop diuretics (furosemide) after volume repletion to prevent fluid overload 1, 4
• Do not use diuretics before correcting hypovolemia 2

Step 2: Bisphosphonate Therapy (Moderate to Severe Hypercalcemia)

Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred first-line bisphosphonate 1, 2, 3. This is superior to pamidronate and should not be delayed in moderate to severe cases 1, 6.

Critical dosing considerations 2:

• Never infuse over less than 15 minutes (5-minute infusions increase renal toxicity risk)
• Never use 8 mg doses (associated with increased renal toxicity without added benefit)
• Check serum creatinine before each dose
• Adjust dose for renal impairment (CrCl <60 mL/min):
  • CrCl 50-60: 3.5 mg
  • CrCl 40-49: 3.3 mg
  • CrCl 30-39: 3.0 mg
  • Contraindicated if CrCl <30 mL/min

Pamidronate is an alternative if zoledronic acid unavailable 1.

Correct hypocalcemia before initiating bisphosphonates and supplement with oral calcium 500 mg plus vitamin D 400 IU daily during treatment 1, 2.

Bisphosphonates take 2-4 days to achieve full effect 1. Retreatment may be considered if calcium does not normalize, with minimum 7 days between doses 2.

Step 3: Calcitonin (For Rapid Short-Term Control)

Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid onset within hours but limited efficacy 1, 3. Use as a bridge until bisphosphonates take effect 1.

• Acts within 1-3 hours but effect lasts only 1-4 hours 1
• Tachyphylaxis develops rapidly
• Contraindicated if allergy to calcitonin-salmon 1

Step 4: Etiology-Specific Therapy

For hypercalcemia due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous diseases like sarcoidosis, some lymphomas, multiple myeloma):

Prednisone 1 mg/kg/day orally or methylprednisolone IV equivalent 1, 3, 4:

• Taper over 2-4 months depending on response 1
• Provide PPI prophylaxis for all patients 1
• Provide pneumocystis prophylaxis if ≥20 mg methylprednisolone equivalent for ≥4 weeks 1
• Screen for tuberculosis before initiating in granulomatous disease 1

For malignancy-associated hypercalcemia:

• Treat underlying cancer when possible (median survival ~1 month if untreated) 1
• In multiple myeloma: hydration + zoledronic acid + steroids ± calcitonin 1
• Plasmapheresis for symptomatic hyperviscosity in multiple myeloma 1

For primary hyperparathyroidism:

• Parathyroidectomy is definitive treatment 1, 3
• Observation appropriate if: age >50 years, calcium <1 mg above upper normal limit, no skeletal or kidney disease 3

Step 5: Refractory Cases

Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 1, 4.

Denosumab may be considered in patients with kidney failure who cannot receive bisphosphonates 3.

For CKD patients with hypercalcemia and low PTH: Consider lower dialysate calcium (1.5-2.0 mEq/L) to stimulate PTH and increase bone turnover, allowing PTH to rise to at least 100 pg/mL 1.

Critical Pitfalls to Avoid

• Never rely on corrected calcium instead of ionized calcium when available 1
• Never infuse zoledronic acid over less than 15 minutes 2
• Never use NSAIDs or IV contrast in patients with renal impairment 1
• Never restrict calcium intake excessively without supervision (can worsen bone disease) 1
• Do not delay bisphosphonate therapy in moderate to severe cases 1
• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 1
• Discontinue nephrotoxic medications to prevent worsening renal function 1

Monitoring

• Check serum creatinine before each bisphosphonate dose and withhold if renal deterioration occurs (increase ≥0.5 mg/dL if normal baseline, or ≥1.0 mg/dL if abnormal baseline) 2
• Resume bisphosphonates only when creatinine returns to within 10% of baseline 2
• Monitor serum calcium, renal function, and electrolytes regularly 1