What are the treatment options for hypercalcemia?

Treatment of Hypercalcemia

Initiate immediate IV normal saline hydration followed by zoledronic acid 4 mg IV as first-line definitive therapy for moderate to severe hypercalcemia, with the specific treatment algorithm determined by the underlying cause identified through PTH measurement. 1, 2, 3

Immediate Stabilization

Hydration (First Step for All Patients)

• Administer IV normal saline immediately to restore extracellular volume and enhance urinary calcium excretion, targeting urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg) 1, 2
• Do not routinely use loop diuretics—furosemide should only be added in patients with renal or cardiac insufficiency to prevent fluid overload, not as standard therapy 1, 2
• Avoid overhydration, particularly in patients with cardiac failure 3

Rapid Bridge Therapy (When Immediate Effect Needed)

• 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
• Calcitonin has limited efficacy but rapid onset; use it to "buy time" while awaiting the 2-4 day delayed action of bisphosphonates 1

Definitive Pharmacologic Treatment

Bisphosphonates (First-Line for Most Cases)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate, with superior efficacy compared to pamidronate 1, 2, 3
• Do not delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the delayed onset of action 1, 2
• For hypercalcemia of malignancy, the maximum recommended dose is 4 mg as a single infusion over no less than 15 minutes 3
• Bisphosphonates are particularly effective for malignancy-associated hypercalcemia and should be continued for up to 2 years in patients with multiple myeloma or bone metastases 1, 2

Critical Dosing Adjustments for Renal Impairment:

• For CrCl 50-60 mL/min: reduce dose to 3.5 mg 3
• For CrCl 40-49 mL/min: reduce dose to 3.3 mg 3
• For CrCl 30-39 mL/min: reduce dose to 3.0 mg 3
• Measure serum creatinine before each dose and withhold treatment for renal deterioration (increase of 0.5 mg/dL if normal baseline, or 1.0 mg/dL if abnormal baseline) 3

Retreatment Considerations

• Allow a minimum of 7 days before retreatment to permit full response to the initial dose 3
• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not normalize or remain normal after initial treatment 3

Diagnostic Workup to Guide Cause-Specific Treatment

Essential Laboratory Tests

• Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, and phosphorus 1, 2
• PTH is the single most important test: elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes 4, 2, 5
• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma 4, 2

Cause-Specific Treatment Algorithms

Malignancy-Associated Hypercalcemia

• Treatment of the underlying cancer is essential for long-term control and should be pursued alongside acute calcium-lowering measures 4, 2
• Use hydration plus bisphosphonates (zoledronic acid preferred) as the cornerstone of acute management 1, 2
• For multiple myeloma specifically: add corticosteroids to the regimen of hydration, bisphosphonates, and calcitonin 1
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients 1, 2

Vitamin D-Mediated Hypercalcemia

• Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), and some lymphomas 1, 4, 2, 5
• Avoid all vitamin D supplements in patients with hypercalcemia regardless of etiology 1, 4, 2

Primary Hyperparathyroidism

• Parathyroidectomy is the definitive treatment for symptomatic primary hyperparathyroidism 4, 2
• Surgical indications include: osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal 4, 2
• For patients >50 years with serum calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring may be appropriate 5
• For persistent hypercalcemic hyperparathyroidism despite optimized medical therapy (tertiary hyperparathyroidism), parathyroid resection should be considered 1, 2

Refractory or Severe Hypercalcemia with Renal Failure

• Dialysis with calcium-free or low-calcium solution is reserved for patients with severe hypercalcemia complicated by renal insufficiency 1, 2
• Hemodialysis effectively removes calcium through diffusive therapy 1, 2
• Denosumab may be considered in patients with kidney failure when bisphosphonates are contraindicated, but carries higher risk of severe hypocalcemia 1, 5

Monitoring and Supplementation

Mandatory Supplementation During Bisphosphonate Therapy

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia 1, 3
• Correct pre-existing hypocalcemia before initiating bisphosphonates, as bisphosphonates can cause severe symptomatic hypocalcemia 1, 6

Ongoing Monitoring

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness 1, 2
• Monitor calcium levels closely during the first weeks of initiating therapy, especially with denosumab which carries higher risk of hypocalcemia 1

Critical Pitfalls to Avoid

• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently 2
• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function 1, 2
• Do not restrict calcium intake without medical supervision in normocalcemic patients 1, 2
• Avoid vitamin D supplements in all patients with active hypercalcemia 1, 4, 2
• Do not use loop diuretics before correcting hypovolemia—diuretic therapy should not be employed prior to correction of volume depletion 3
• Patients receiving denosumab (Xgeva) should not take Prolia, as they contain the same active ingredient 6

Severity-Based Approach

Mild Hypercalcemia (Total Calcium <12 mg/dL)

• Often asymptomatic or associated with constitutional symptoms like fatigue and constipation in approximately 20% of patients 5
• May be treated with conservative measures including saline hydration with or without loop diuretics 3
• If due to primary hyperparathyroidism, consider observation versus parathyroidectomy based on age and presence of complications 5

Severe Hypercalcemia (Total Calcium ≥14 mg/dL or Ionized Calcium ≥10 mg/dL)

• Can cause nausea, vomiting, dehydration, confusion, somnolence, and coma 5
• Requires aggressive treatment with IV hydration plus bisphosphonates 5
• Consider adding calcitonin for rapid initial effect while awaiting bisphosphonate action 2