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

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. 1, 2

• Avoid overhydration, particularly in patients with cardiac failure. 1

Diagnostic Workup to Guide Treatment Selection

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

• 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 elevation indicates malignancy-associated hypercalcemia, particularly in squamous cell carcinomas and renal cell carcinoma. 4, 2

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 2-4 day delayed onset of action. 1, 2

• For patients with baseline creatinine clearance 50-60 mL/min, reduce zoledronic acid dose to 3.5 mg; for CrCl 40-49 mL/min use 3.3 mg; for CrCl 30-39 mL/min use 3.0 mg. 3

• Monitor serum creatinine before each dose and withhold treatment if renal deterioration occurs (increase of 0.5 mg/dL in patients with normal baseline or 1.0 mg/dL in those with abnormal baseline). 3

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

• 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

• 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 rapid calcium reduction is needed before bisphosphonates become effective. 1

Denosumab (Alternative for Renal Failure)

• Denosumab 120 mg subcutaneously every 4 weeks (with additional doses on Days 8 and 15 of first month) may be indicated in patients with kidney failure who cannot receive bisphosphonates. 6, 5

• Denosumab carries higher risk of severe hypocalcemia compared to bisphosphonates—correct hypocalcemia prior to initiating therapy and monitor calcium levels closely, especially in the first weeks. 1, 6

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during denosumab treatment. 1, 6

Cause-Specific Treatment Algorithms

Malignancy-Associated Hypercalcemia

• Hydration plus bisphosphonates (zoledronic acid preferred) form the cornerstone of acute management. 1, 2

• Treatment of the underlying cancer is essential for long-term control and should be pursued alongside acute calcium-lowering measures. 4, 2, 5

• For multiple myeloma patients with symptomatic hyperviscosity, add plasmapheresis as adjunctive therapy. 1, 2

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent treatment-induced hypocalcemia. 1

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

• Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption, including vitamin D intoxication, sarcoidosis, and some lymphomas. 1, 4, 2, 5

• Avoid all vitamin D supplements in patients with active hypercalcemia regardless of etiology. 1, 4, 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. 4, 2, 5

• For patients older than 50 years with serum calcium levels less than 1 mg/dL above the upper normal limit and no evidence of 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, 7, 5

Monitoring and Follow-Up

• Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 1, 4, 2

• Assess serum creatinine before each bisphosphonate dose and withhold treatment if renal deterioration occurs. 1, 3

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

Critical Pitfalls to Avoid

• Do not use loop diuretics routinely in all hypercalcemic patients—reserve them only for those with renal or cardiac insufficiency to prevent fluid overload. 1, 2

• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function. 1, 2

• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently. 2

• Avoid vitamin D supplements in all patients with active hypercalcemia. 1, 4, 2

• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen outcomes. 1, 2

• Correct hypocalcemia before initiating bisphosphonate or denosumab therapy to prevent severe symptomatic hypocalcemia. 1, 6

• Perform oral examination prior to starting bisphosphonates or denosumab and avoid invasive dental procedures during treatment to prevent osteonecrosis of the jaw. 6