What is the treatment for hypercalcemia?

Treatment of Hypercalcemia

Immediately initiate IV normal saline hydration targeting urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg), followed by IV zoledronic acid 4 mg infused over no less than 15 minutes—do not delay bisphosphonate administration while awaiting complete diagnostic workup in symptomatic patients. 1, 2, 3

Initial Stabilization and Hydration

• Aggressive IV normal saline is the cornerstone of initial management, restoring extracellular volume and enhancing urinary calcium excretion through dilution and increased glomerular filtration 1, 4, 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 given before volume repletion 1, 4, 2

• Avoid overhydration, particularly in patients with heart failure or compromised renal function, as this can precipitate pulmonary edema 4

Definitive Pharmacologic Treatment

First-Line: Bisphosphonates

• Zoledronic acid 4 mg IV is the preferred bisphosphonate, demonstrating superior efficacy compared to pamidronate with longer duration of response (30-40 days vs 17 days) 1, 4, 2, 3, 5

• Infuse zoledronic acid over no less than 15 minutes to minimize renal toxicity 1, 4, 3

• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia—initiate early despite the 2-4 day delayed onset of action, as temporary measures provide only short-term benefit 1, 4, 2

• For patients with baseline creatinine clearance (CrCl) 50-60 mL/min, reduce dose to 3.5 mg; CrCl 40-49 mL/min use 3.3 mg; CrCl 30-39 mL/min use 3.0 mg 4, 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) 4, 3

Rapid Bridge Therapy: Calcitonin

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid but modest calcium reduction within hours, serving as a bridge until bisphosphonates take effect 1, 4, 2

• Calcitonin has limited long-term efficacy due to tachyphylaxis but offers the advantage of immediate onset, making combination therapy with bisphosphonates valuable when rapid reduction is needed 4, 6, 5

Cause-Specific Treatment Approaches

Malignancy-Associated Hypercalcemia

• Treatment of the underlying cancer is essential for long-term control and should be pursued alongside acute calcium-lowering measures 1, 4, 2

• Hydration plus bisphosphonates (zoledronic acid preferred) form the cornerstone of acute management 1, 4

• Consider continuing bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1, 4

• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma patients 1, 4, 2

• Denosumab 120 mg subcutaneously is an alternative for hypercalcemia of malignancy refractory to bisphosphonate therapy, though it carries higher risk of severe hypocalcemia 7, 8

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, 6

• 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 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 1

• In patients older than 50 years with serum calcium less than 1 mg/dL above upper normal limit and no skeletal or kidney disease, observation with monitoring may be appropriate 6

Refractory or Severe Hypercalcemia

• Dialysis with calcium-free or low-calcium dialysate is reserved for patients with severe hypercalcemia complicated by renal insufficiency or oliguria, as hemodialysis effectively removes calcium through diffusive therapy 1, 4, 2, 9

• For persistent hypercalcemic hyperparathyroidism despite optimized medical therapy (tertiary hyperparathyroidism), parathyroid resection should be considered 4

Essential Supportive Measures

• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during bisphosphonate treatment to prevent treatment-induced hypocalcemia 4

• Correct hypocalcemia before initiating bisphosphonate or denosumab therapy, as both agents can cause severe symptomatic hypocalcemia 4, 7

• Encourage mobilization—getting patients out of bed to stand or walk reduces bone resorption 10

Diagnostic Workup to Guide Treatment

• Measure intact PTH first to distinguish PTH-dependent from PTH-independent causes 1, 4, 6

• Elevated or inappropriately normal PTH with hypercalcemia indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) suggests malignancy or other non-PTH-mediated causes 1, 6

• Additional workup includes PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, phosphorus, and magnesium 1, 4

• 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 to assess treatment effectiveness 1, 4, 2

• Perform oral examination prior to starting bisphosphonates or denosumab to assess for risk of osteonecrosis of the jaw (ONJ), and avoid invasive dental procedures during treatment 7

• Monitor for ECG changes, particularly QT interval prolongation, in patients with severe hypercalcemia 4

Retreatment Considerations

• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment 3

• Allow a minimum of 7 days to elapse before retreatment to allow for full response to the initial dose 3

• Renal function must be carefully monitored and serum creatinine assessed prior to retreatment 3

Critical Pitfalls to Avoid

• Do not restrict calcium intake without medical supervision in normocalcemic patients, as this can worsen bone disease and outcomes 1, 4, 2

• Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further deterioration of kidney function 1, 4, 2

• Do not use loop diuretics before volume repletion—diuretic therapy should not be employed prior to correction of hypovolemia 3

• Avoid vitamin D supplements in all patients with active hypercalcemia, regardless of underlying cause 1, 4, 2

• Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently 1, 2

• Discontinue any nephrotoxic medications to avoid worsening renal function in hypercalcemic patients 4