What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Initiate immediate IV normal saline hydration targeting urine output ≥100 mL/hour, followed by IV zoledronic acid 4 mg infused over at least 15 minutes as the cornerstone of treatment for moderate to severe hypercalcemia. 1, 2

Initial Assessment

Before initiating treatment, measure the following to determine the underlying cause 1, 3:

• Intact parathyroid hormone (iPTH) - distinguishes PTH-dependent (elevated/normal in primary hyperparathyroidism) from PTH-independent causes (suppressed <20 pg/mL) 4
• PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D 1, 3
• Calcium (corrected for albumin or ionized calcium), albumin, phosphorus, magnesium 1, 3
• Renal function (serum creatinine, BUN) 1
• Malignancy markers if PTH is suppressed 3

Assess for symptoms: polyuria, polydipsia, nausea, vomiting, confusion, dehydration, mental status changes, bradycardia, hypotension 1, 3

Treatment Algorithm by Severity

Mild Hypercalcemia (Total calcium <12 mg/dL)

• Asymptomatic patients may not require acute intervention 4
• If due to primary hyperparathyroidism in patients >50 years with calcium <1 mg above upper normal limit and no skeletal/kidney disease, observation with monitoring is appropriate 4
• Consider parathyroidectomy for symptomatic patients or those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, or age ≥50 years 3

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

Step 1: Aggressive Hydration 1, 2, 4

• Administer IV normal saline to correct hypovolemia and promote calciuresis
• Target urine output ≥100 mL/hour (3 mL/kg/hour in children <10 kg) 1
• Add loop diuretics (furosemide) only after volume repletion in patients with renal or cardiac insufficiency to prevent fluid overload 1, 5

Step 2: Bisphosphonate Therapy 1, 4, 6

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred agent - superior efficacy compared to pamidronate with longer duration of response (30-40 days vs 17 days) 1, 6, 7
• Alternative: Pamidronate IV if zoledronic acid unavailable 1
• Monitor serum creatinine before each dose and withhold if renal deterioration occurs 1
• Adjust dosing for renal impairment 1
• Do not delay bisphosphonate therapy - temporary measures provide only 1-4 hours of benefit 1

Step 3: Adjunctive Rapid-Acting Agents (if needed)

Calcitonin 1, 8, 6, 5

• Provides rapid onset within hours but limited efficacy
• Use as bridge until bisphosphonates take effect (which have delayed action of 2-4 days) 1, 6
• Dosing for hypercalcemia: Start with 4 IU/kg every 12 hours subcutaneously or intramuscularly 8
• May increase to 8 IU/kg every 12 hours if inadequate response after 1-2 days, maximum 8 IU/kg every 6 hours 8
• Combining calcitonin with bisphosphonates enhances rate of calcium decline 9, 6

Cause-Specific Definitive Treatment

Malignancy-Associated Hypercalcemia 1, 3, 4

• Treat underlying cancer when possible - essential for long-term control
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• Consider plasmapheresis as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 1
• Prognosis is poor with median survival approximately 1 month 1

Vitamin D-Mediated Hypercalcemia 1, 3, 4

• Glucocorticoids are the primary treatment for excessive intestinal calcium absorption from:
  • Vitamin D intoxication
  • Granulomatous diseases (sarcoidosis)
  • Some lymphomas
  • Multiple myeloma 1, 4, 5
• Addresses unregulated 1-alpha-hydroxylase activity in activated macrophages 2

Primary Hyperparathyroidism 3, 4

• Parathyroidectomy is the only curative intervention 6
• Indicated for symptomatic patients, osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit 3

Tertiary Hyperparathyroidism (CKD patients) 1

• Consider parathyroidectomy for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy

Severe Hypercalcemia with Renal Failure

Hemodialysis with calcium-free or low-calcium dialysate is reserved for patients with severe hypercalcemia complicated by renal insufficiency or oliguria 1, 5

Critical Pitfalls to Avoid

• Avoid overhydration in patients with cardiac or renal insufficiency - use loop diuretics after volume repletion 1
• 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 - can worsen bone disease 1
• Avoid vitamin D supplements in patients with hypercalcemia 1, 3
• Temporarily discontinue nephrotoxic medications including myeloma therapies (lenalidomide, bortezomib) until calcium normalizes 1
• Restrict calcium-based phosphate binders in CKD patients to avoid hypercalcemia 1

Monitoring and Prevention

• Monitor serum calcium, renal function, and electrolytes regularly 1, 2, 3
• Provide calcium supplementation 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 1
• Correct hypocalcemia before initiating bisphosphonate therapy 1
• Monitor closely with denosumab which carries higher hypocalcemia risk 1
• Assess ECG for QT interval prolongation in severe hypercalcemia 1
• Only treat symptomatic hypocalcemia (tetany, seizures) following treatment with calcium gluconate 50-100 mg/kg 1