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 treatment approach tailored to the underlying cause identified by intact PTH measurement. 1, 2

Initial Stabilization and Hydration

• 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
• Ensure adequate rehydration before administering any bisphosphonate therapy to prevent renal toxicity. 3
• Loop diuretics (furosemide) should only be added in patients with renal or cardiac insufficiency to prevent fluid overload—they are not routinely indicated for all hypercalcemic patients and should never be given before correcting hypovolemia. 1, 2, 4

Diagnostic Workup to Guide Treatment

• Measure intact PTH immediately to distinguish PTH-dependent from PTH-independent causes—this is the single most important test. 1, 2, 5
• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes. 6, 5
• Obtain PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, magnesium, phosphorus, and renal function to determine the specific etiology. 1, 6
• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma. 6, 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, 3, 7, 4
• Do not delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action. 1, 2
• 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
• Assess serum creatinine before each dose and adjust dosing for renal impairment: reduce to 3.5 mg for CrCl 50-60 mL/min, 3.3 mg for CrCl 40-49 mL/min, and 3 mg for CrCl 30-39 mL/min. 1, 3
• Do not use in patients with severe renal impairment (CrCl <30 mL/min) as treatment is not recommended in this population. 3
• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not normalize, with a minimum of 7 days between doses. 3

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, 8
• Calcitonin has limited long-term efficacy due to tachyphylaxis but is useful for immediate short-term management of severe symptomatic hypercalcemia. 1, 8, 4
• Standard dosing is 200 IU per day as nasal spray or 100 IU subcutaneously/intramuscularly every other day. 1

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. 6, 2, 5
• Hydration plus bisphosphonates (zoledronic acid preferred) form the cornerstone of acute management. 1, 2
• Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients. 1, 2
• Zoledronic acid is superior to both clodronate and pamidronate in treating malignancy-associated hypercalcemia. 7

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

• Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), and some lymphomas. 1, 6, 2, 5, 4
• Avoid all vitamin D supplements in patients with active hypercalcemia regardless of etiology. 1, 6, 2

Primary Hyperparathyroidism

• Parathyroidectomy is the definitive treatment for symptomatic primary hyperparathyroidism and should be considered for patients with: osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal. 6, 2, 5
• 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, as hemodialysis effectively removes calcium through diffusive therapy. 1, 2, 5, 4
• Denosumab may be indicated in patients with kidney failure who cannot receive bisphosphonates. 5

Supportive Care and Monitoring

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent hypocalcemia. 1, 3
• Correct hypocalcemia before initiating bisphosphonate therapy and monitor serum calcium closely, especially with denosumab which carries higher risk of hypocalcemia. 1
• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 1, 2
• Withhold treatment for renal deterioration (increase of 0.5 mg/dL in normal baseline creatinine or 1.0 mg/dL in abnormal baseline creatinine) and resume only when creatinine returns to within 10% of baseline. 3

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 use bisphosphonate doses greater than 4 mg as renal toxicity may be greater with higher doses. 3
• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen outcomes. 1, 2
• Avoid sedatives and narcotic analgesics in mild hypercalcemia, as they can reduce activity and oral intake, raising serum calcium levels. 9
• Asymptomatic hypocalcemia following treatment does not require intervention—only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg. 1

Special Populations

• In Williams syndrome with hypercalcemia, recommend a low-calcium diet and increased water intake under medical supervision. 6
• In pediatric patients, maintain urine output of 3 mL/kg/hour in children <10 kg during hydration therapy. 1, 2
• In geriatric patients, exercise special care to monitor renal function closely. 3