What is the treatment approach for a patient with hypercalcemia?

Treatment of Hypercalcemia

Immediate Management: Hydration First

Initiate aggressive IV normal saline hydration immediately to correct hypovolemia and promote calciuresis, targeting urine output of 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg). 1, 2 This is the cornerstone of initial treatment regardless of underlying cause and should be started promptly before definitive pharmacologic therapy. 1, 3

• Administer boluses of 250-500 mL crystalloids every 15 minutes until rehydration is achieved, then maintain diuresis >2.5 L/day in adults. 1
• Avoid overhydration in patients with cardiac or renal insufficiency—use loop diuretics (furosemide) only after complete volume repletion to prevent fluid overload. 1, 2
• Do not use loop diuretics before correcting hypovolemia, as this worsens the hypercalcemia. 2, 4

Definitive Pharmacologic Treatment: Bisphosphonates

Administer zoledronic acid 4 mg IV infused over no less than 15 minutes as the preferred first-line agent for moderate to severe hypercalcemia. 1, 2 Zoledronic acid is superior to pamidronate, normalizing calcium in 50% of patients by day 4 with longer duration of response (30-40 days vs 17 days). 1, 5

Dosing Algorithm by Renal Function

For patients with creatinine clearance >60 mL/min: Give full dose of 4 mg IV over 15 minutes. 2

For patients with reduced renal function at baseline (CrCl 30-60 mL/min), use dose-adjusted regimen: 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 zoledronic acid in severe renal impairment (CrCl <30 mL/min)—consider denosumab 120 mg subcutaneously or dialysis instead. 1, 3

Critical Monitoring Requirements

• Measure serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL from normal baseline or 1.0 mg/dL from abnormal baseline). 2
• Resume treatment only when creatinine returns to within 10% of baseline value, using the same dose as before interruption. 2
• Monitor serum calcium, electrolytes (especially potassium and magnesium), and renal function every 6-12 hours during acute phase. 1

Adjunctive Rapid-Acting Therapy: Calcitonin

For severe symptomatic hypercalcemia requiring immediate reduction, add calcitonin-salmon 100 IU subcutaneously or intramuscularly as a bridge until bisphosphonates take effect. 1, 3 Calcitonin provides rapid onset within hours but limited efficacy and duration (only 1-4 hours of benefit with tachyphylaxis developing). 1, 5

• Calcitonin should never be used as monotherapy but only in combination with bisphosphonates when rapid calcium reduction is essential. 5

Cause-Specific Definitive Treatment

For Malignancy-Associated Hypercalcemia

Treat the underlying cancer with appropriate chemotherapy, as this is essential for long-term control. 1, 6 Hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month. 1

• In multiple myeloma specifically: Use hydration + zoledronic acid + corticosteroids (prednisone 1 mg/kg/day or methylprednisolone IV equivalent). 1, 6
• Consider plasmapheresis as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma. 1
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases. 1

For Granulomatous Disease (Sarcoidosis, Some Lymphomas)

Use corticosteroids as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption from unregulated 1,25-dihydroxyvitamin D production. 1, 6, 3

• Start prednisone 20-40 mg/day orally (or methylprednisolone IV equivalent) and allow 3-6 months to demonstrate responsiveness. 1
• Target the lowest effective dose ≤10 mg/day to minimize toxicity; if unable to wean below 10 mg/day after 3-6 months, add methotrexate as steroid-sparing agent. 1

For Primary Hyperparathyroidism

Parathyroidectomy is the only curative intervention and 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. 6, 3

• In patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring is appropriate. 3

For Tertiary Hyperparathyroidism in CKD

Consider parathyroidectomy for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy. 1

Refractory or Severe Hypercalcemia with Renal Failure

Use hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) for severe hypercalcemia complicated by renal insufficiency or oliguria. 1, 3, 4

• Denosumab 120 mg subcutaneously is effective for bisphosphonate-refractory hypercalcemia, lowering calcium in 64% of patients within 10 days. 1

Essential Supportive Measures

Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia. 1, 2 This paradoxical supplementation is necessary despite treating hypercalcemia, as bisphosphonates carry high risk of subsequent hypocalcemia (up to 50% of patients, though symptomatic hypocalcemia is rare). 5

• Correct pre-existing hypocalcemia before initiating bisphosphonate therapy. 1
• Only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg; asymptomatic hypocalcemia does not require intervention. 1

Retreatment Protocol

If serum calcium does not normalize or remain normal after initial treatment, retreatment with zoledronic acid 4 mg may be considered after a minimum of 7 days to allow for full response to the initial dose. 2

Critical Pitfalls to Avoid

• Never use doses >4 mg zoledronic acid for initial treatment—reserve 8 mg dose only for relapsed/refractory cases, as higher doses increase renal toxicity risk. 1
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney function deterioration. 1
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease. 1
• Avoid vitamin D supplements in patients with active hypercalcemia, particularly in early childhood. 1, 6
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia—temporary measures like calcitonin provide only 1-4 hours of benefit with rebound. 1

Diagnostic Workup to Guide Treatment

Measure the following to determine underlying cause: 1, 6

• Intact PTH (elevated/normal = primary hyperparathyroidism; suppressed <20 pg/mL = other causes)
• PTHrP (elevated in humoral hypercalcemia of malignancy)
• 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together (not just one)
• Ionized calcium (more accurate than corrected calcium, which can be misleading)
• Albumin, phosphorus, magnesium, creatinine, BUN