What is the treatment approach for hypercalcemia?

Treatment of Hypercalcemia

Immediate Management: Hydration First

Intravenous normal saline is the cornerstone of initial hypercalcemia treatment, aiming to correct hypovolemia and promote calciuresis with a target urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg). 1, 2, 3

• Vigorous saline hydration should be initiated promptly as an integral part of therapy 2
• Loop diuretics (such as furosemide) should only be added if needed to prevent fluid overload in patients with renal or cardiac insufficiency—do not use diuretics before correcting hypovolemia 4, 1, 2
• Overhydration must be avoided, especially in patients with heart failure 2

Severity-Based Treatment Algorithm

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

• Conservative management with saline hydration alone may be sufficient 2, 3
• These patients are usually asymptomatic but may have constitutional symptoms like fatigue and constipation in approximately 20% of cases 3
• If due to primary hyperparathyroidism in patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation may be appropriate 3

Moderate to Severe Hypercalcemia (Total calcium ≥12 mg/dL)

Intravenous bisphosphonates are first-line pharmacologic treatment after hydration, with zoledronic acid preferred over pamidronate. 4, 1, 3

• Zoledronic acid 4 mg IV is the preferred bisphosphonate for hypercalcemia treatment 4, 1
• Pamidronate is an alternative bisphosphonate option 1, 2, 3
• Bisphosphonates typically take 2-4 days to achieve maximum effect, so they should be administered early 3, 5
• Duration of response: zoledronic acid provides 30-40 days of normocalcemia versus 17 days with pamidronate 5

Severe/Emergency Hypercalcemia (Total calcium ≥14 mg/dL or ionized calcium ≥10 mg/dL)

For rapid calcium reduction, add calcitonin 4-8 International Units/kg subcutaneously or intramuscularly every 6-12 hours as a bridge until bisphosphonates take effect. 1, 6, 3

• Calcitonin provides rapid onset (within hours) but modest and temporary effect 6, 3, 5
• Standard dosing: Start with 4 IU/kg every 12 hours; if inadequate response after 1-2 days, increase to 8 IU/kg every 12 hours; maximum 8 IU/kg every 6 hours 6
• Combining calcitonin with bisphosphonates enhances the rate of calcium decline by providing immediate effect while awaiting bisphosphonate action 7, 5
• Symptoms at this level include nausea, vomiting, dehydration, confusion, somnolence, and coma 3

Cause-Specific Considerations

Malignancy-Associated Hypercalcemia

• Treat the underlying cancer when possible 1, 8
• Bisphosphonates (zoledronic acid or pamidronate) are the mainstay 4, 1, 3
• Consider continuing bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 4, 1

Vitamin D-Mediated Hypercalcemia (Granulomatous Disease, Lymphoma, Vitamin D Intoxication)

• Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption 8, 3, 9
• This includes sarcoidosis, some lymphomas, and vitamin D toxicity 8, 3
• Avoid vitamin D supplements in all patients with hypercalcemia 1, 8

Primary Hyperparathyroidism

• Parathyroidectomy is the only curative treatment 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 normal limit 8, 3
• For patients not meeting surgical criteria, observation with monitoring is appropriate 3

Special Populations and Situations

Renal Insufficiency

• Avoid NSAIDs and intravenous contrast media to prevent worsening renal function 4, 1
• Dialysis is reserved for severe hypercalcemia complicated by renal failure 1, 9
• Denosumab may be considered in patients with kidney failure when bisphosphonates are contraindicated 3
• Use caution with bisphosphonates and monitor renal function carefully 8

Tertiary Hyperparathyroidism

• Parathyroidectomy is considered for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 1

Critical Pitfalls to Avoid

• Never use loop diuretics before correcting hypovolemia—this worsens dehydration and hypercalcemia 4, 2
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia, as temporary measures provide only 1-4 hours of benefit 1
• Avoid NSAIDs in patients with any degree of renal impairment 4, 1
• Do not restrict calcium intake without medical supervision, particularly in specific conditions like Williams syndrome with normocalcemia 1

Monitoring and Follow-up

• Monitor serum calcium, renal function, and electrolytes regularly to assess treatment effectiveness 1, 8
• Correct electrolyte deficiencies, particularly potassium and magnesium 7
• Re-evaluate the need for continued therapy periodically, especially with calcitonin-salmon due to possible malignancy association 6