What are the treatment options for hypercalcemia?

Treatment of Hypercalcemia

Initiate treatment with intravenous normal saline hydration followed by bisphosphonates (preferably zoledronic acid 4 mg IV) for moderate to severe hypercalcemia, while simultaneously treating the underlying cause. 1, 2

Severity Classification and Initial Management

Mild Hypercalcemia (Total Ca <12 mg/dL or ionized Ca 5.6-8.0 mg/dL)

• Conservative management with oral hydration, salt restriction, and ambulation is typically sufficient 3, 4
• Approximately 20% of patients experience constitutional symptoms like fatigue and constipation despite mild elevation 3
• Observation may be appropriate in patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease 3

Moderate to Severe Hypercalcemia (Total Ca ≥12 mg/dL or ionized Ca >8.0 mg/dL)

• Severe hypercalcemia (≥14 mg/dL or ionized ≥10 mg/dL) causes nausea, vomiting, dehydration, confusion, somnolence, and coma 3
• Requires immediate intervention with hydration and antiresorptive therapy 1, 2

Treatment Algorithm

Step 1: Hydration (First-Line for All Symptomatic Cases)

• Administer IV normal saline to correct hypovolemia and promote calciuresis 1, 2
• Target urine output of at least 100 mL/hour (3 mL/kg/hour in children <10 kg) 1, 2
• Avoid overhydration in patients with cardiac failure 5, 6
• Critical pitfall: Do not use diuretics before correcting hypovolemia 6
• Loop diuretics (furosemide) should only be added if renal or cardiac insufficiency exists to prevent fluid overload 1, 7

Step 2: Bisphosphonate Therapy (Definitive Treatment)

• Zoledronic acid is the preferred agent: 4 mg IV over no less than 15 minutes 1, 2
• Alternative: Pamidronate disodium (dose varies by severity) 6, 8
• Bisphosphonates take 2-4 days to achieve maximum effect but provide sustained calcium reduction 8, 4
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia 1, 2

Step 3: Calcitonin (For Rapid Effect When Needed)

• Use calcitonin-salmon 100 IU subcutaneously or intramuscularly for immediate short-term management 1, 9, 7
• Effects begin within 1-3 minutes but last only 30-60 minutes to hours 2, 9
• Tachyphylaxis develops rapidly, limiting sustained use 4
• Best strategy: Combine calcitonin with bisphosphonates when rapid calcium reduction is essential—calcitonin provides immediate effect while awaiting bisphosphonate action 1, 8

Step 4: Cause-Specific Therapies

For Malignancy-Associated Hypercalcemia

• Treat the underlying cancer when possible 1, 10
• Hydration plus bisphosphonates remain the mainstay 5, 1
• Plasmapheresis for symptomatic hyperviscosity in multiple myeloma 5, 1

For Vitamin D-Mediated Hypercalcemia (Sarcoidosis, Lymphoma, Vitamin D Intoxication)

• Glucocorticoids are the primary treatment 10, 3, 7
• Avoid vitamin D supplements in all hypercalcemic patients 1, 10, 2

For 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 10
• Observation with monitoring is acceptable for asymptomatic patients >50 years with minimal elevation and no complications 3

Step 5: Refractory or Special Situations

Renal Insufficiency

• Hemodialysis with low-calcium or calcium-free dialysate for severe hypercalcemia with renal failure 1, 2, 7
• Use denosumab cautiously in kidney failure patients when bisphosphonates are contraindicated 3
• Avoid NSAIDs and IV contrast media in patients with renal impairment 5, 1, 2

Persistent Hypercalcemia Despite Treatment

• Consider parathyroidectomy for tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism despite optimized medical therapy) 1

Monitoring Requirements

• Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 1, 10, 2
• Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates, though symptomatic hypocalcemia is rare 8
• Check for increases in serum creatinine: pamidronate (2%), ibandronate (1%), etidronate (8%), clodronate (5%) 8

Common Pitfalls to Avoid

• Never use diuretics before correcting hypovolemia—this worsens dehydration and hypercalcemia 6
• Do not restrict calcium intake without medical supervision in specific conditions like Williams syndrome with normocalcemia 1
• Avoid delaying bisphosphonates while waiting for diagnostic workup in severe symptomatic cases 1, 2
• Do not use plicamycin (mithramycin) as first-line therapy—reserve only for bisphosphonate-refractory cases due to significant toxicity 8, 4
• Bisphosphonates can cause transient fever, lymphocytopenia, malaise, and myalgias within 36 hours of first dose (usually self-limiting) 8