What is the management for hypercalcemia?

Management of Hypercalcemia

Immediately initiate IV normal saline to restore extracellular volume and enhance urinary calcium excretion, targeting urine output of at least 100 mL/hour, followed by zoledronic acid 4 mg IV as first-line definitive therapy—do not delay bisphosphonate administration while waiting for diagnostic workup in symptomatic patients. 1, 2

Initial Stabilization and Hydration

• Administer IV normal saline immediately as the cornerstone of acute management to correct hypovolemia and promote calciuresis 1, 2, 3
• Maintain urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg) 1, 4
• Add loop diuretics (furosemide) ONLY in patients with renal or cardiac insufficiency to prevent fluid overload—they are not routinely indicated for all hypercalcemic patients 1, 2

Definitive Pharmacologic Treatment

Bisphosphonates (First-Line for Moderate to Severe Hypercalcemia)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate, with superior efficacy compared to pamidronate 1, 2, 4, 3
• Do not delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action 1, 2
• Adjust dosing for renal impairment when creatinine clearance is <60 mL/min 4
• Pamidronate (30-90 mg IV over 4 hours) is an alternative if zoledronic acid is unavailable, though less effective 4, 5
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1, 4

Calcitonin (Rapid Bridge Therapy)

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid but modest calcium reduction within hours, serving as a bridge until bisphosphonates take effect 1, 2, 4, 6
• Expect tachyphylaxis after 48-72 hours, limiting its use to short-term management 4, 7
• Particularly useful in severe symptomatic hypercalcemia requiring immediate intervention 6

Cause-Specific Treatment Strategies

Malignancy-Associated Hypercalcemia

• Treatment of the underlying cancer is essential for long-term control and should be pursued alongside acute calcium-lowering measures 1, 2, 3
• Hydration plus bisphosphonates (zoledronic acid preferred) form the cornerstone of acute management 1, 4
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients 1, 2, 4
• Prognosis is poor with median survival of approximately 1 month, making aggressive treatment decisions context-dependent 4, 3

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

• Glucocorticoids (prednisone 1 mg/kg/day orally or methylprednisolone IV equivalent) are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption 1, 4, 3, 6
• Effective in sarcoidosis, vitamin D intoxication, granulomatous disorders, and some lymphomas 1, 4, 7
• Taper over 2-4 months depending on response 4
• Avoid all vitamin D supplements in patients with hypercalcemia regardless of etiology 1, 2, 4

Primary Hyperparathyroidism

• Parathyroidectomy is the definitive treatment for symptomatic primary hyperparathyroidism 1, 3
• Surgical indications include: osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal 1, 3
• For patients >50 years with calcium <1 mg/dL above normal and no skeletal or kidney disease, observation with monitoring is appropriate 3
• Calcimimetics may be considered for severe hyperparathyroidism when surgery is not possible, though use with extreme caution due to risk of severe hypocalcemia and QT prolongation 1

Refractory or Severe Hypercalcemia

• Dialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for patients with severe hypercalcemia complicated by renal insufficiency or oliguria 1, 2, 4, 6
• Hemodialysis effectively removes calcium through diffusive therapy 1, 2, 4
• Denosumab may be considered in patients with kidney failure when bisphosphonates are contraindicated 3

Diagnostic Workup to Guide Treatment

• Measure intact PTH first—this is the most important initial test to distinguish PTH-dependent from PTH-independent causes 1, 4, 3
• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism 1, 3
• Suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes 1, 3
• Additional tests: PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, magnesium, phosphorus 1, 4
• Measure ionized calcium when possible to avoid pseudo-hypercalcemia from hemolysis or improper sampling 4, 3
• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma 1

Monitoring During Treatment

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly 1, 2
• Check serum creatinine before each dose of zoledronic acid and withhold if renal deterioration occurs 4
• Correct hypocalcemia before initiating bisphosphonate therapy 4
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 4
• Phosphate therapy may be needed in 30% of patients as levels decrease after pamidronate administration 5

Critical Pitfalls to Avoid

• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently 1, 2
• Do not use loop diuretics routinely in all hypercalcemic patients—reserve for those with renal or cardiac insufficiency 1, 2
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further kidney deterioration 1, 2, 4
• Do not restrict calcium intake without medical supervision in normocalcemic patients 1, 2
• Avoid all vitamin D supplements in patients with active hypercalcemia 1, 2, 4
• Do not rely on corrected calcium instead of ionized calcium, as it can lead to inaccurate diagnosis 4
• Temporarily discontinue nephrotoxic medications including lenalidomide and bortezomib in myeloma patients until calcium normalizes 4