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 calcitonin added only when rapid calcium reduction is needed within hours. 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

• 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 used before correcting hypovolemia. 1, 2

• Vigorous saline hydration is an integral part of therapy and should be initiated promptly, but overhydration must be avoided in patients with cardiac failure. 3

Definitive Pharmacologic Treatment

Bisphosphonates (First-Line Therapy)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate for moderate to severe hypercalcemia, with superior efficacy and longer duration of response (30-40 days) compared to pamidronate (17 days). 1, 2, 4

• Do not delay bisphosphonate administration in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action. 1, 2

• Pamidronate disodium is an alternative bisphosphonate indicated for moderate or severe hypercalcemia associated with malignancy, though it is less potent than zoledronic acid. 3, 5

• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases. 1

• Monitor serum creatinine before each dose and withhold treatment if renal deterioration occurs; dose adjustments are required for renal impairment. 1

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, 6

• Calcitonin is indicated for early treatment of hypercalcemic emergencies when rapid decrease in serum calcium is required, but tachyphylaxis limits its sustained use. 6, 7

• Standard dosing is 200 IU per day as nasal spray or 100 IU subcutaneously/intramuscularly every other day. 1

• Use calcitonin primarily in patients who cannot tolerate other treatments or when immediate calcium reduction is necessary. 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. 8, 2, 4

• For multiple myeloma patients: use hydration, zoledronic acid (preferred), furosemide, steroids, and/or calcitonin. 1

• Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients. 1, 2

• Hypercalcemia of malignancy is associated with poor survival and typically presents with rapid onset, higher calcium levels (>12 mg/dL), severe symptoms, and marked anemia. 4, 7

Vitamin D-Mediated Hypercalcemia

• Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, granulomatous disorders (sarcoidosis), some lymphomas, and multiple myeloma. 1, 8, 2, 4

• Avoid all vitamin D supplements in patients with active hypercalcemia regardless of etiology. 1, 8, 2

Primary Hyperparathyroidism

• Parathyroidectomy is the definitive treatment and should be considered for symptomatic patients, those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal. 8, 2, 4

• In patients older than 50 years with serum calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring may be appropriate. 4

• For tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism despite optimized medical therapy), parathyroid resection should be considered. 1, 2

• The prognosis for asymptomatic primary hyperparathyroidism is excellent with either medical or surgical management. 4

Refractory or Severe Hypercalcemia

• 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, 7

• Denosumab may be indicated in patients with kidney failure who cannot receive bisphosphonates. 4

Diagnostic Workup to Guide Treatment

• Measure intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, and phosphorus to determine underlying cause. 1, 2

• Serum intact PTH is the most important initial 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. 8, 2, 4

• PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma. 8, 2

• Evaluate for symptoms: polyuria, polydipsia, nausea, vomiting, confusion, abdominal pain, myalgia, dehydration, and mental status changes. 1, 8

Monitoring and Follow-Up

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 1, 8, 2

• Correct hypocalcemia before initiating bisphosphonate therapy and monitor serum calcium closely, especially with denosumab which carries higher risk of hypocalcemia. 1

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent 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 (e.g., Williams syndrome with normocalcemia). 1, 2

• Do not use loop diuretics prior to correction of hypovolemia. 3

• Asymptomatic hypocalcemia following treatment does not require intervention; only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg. 1

• The safety and efficacy of pamidronate in hypercalcemia associated with hyperparathyroidism or non-tumor-related conditions has not been established. 3