Hypercalcemia Management
Immediate intravenous normal saline hydration combined with bisphosphonates (preferably zoledronic acid 4 mg IV) is the cornerstone of treatment for moderate to severe hypercalcemia, with calcitonin serving as a rapid bridge therapy while awaiting bisphosphonate effect.
Initial Stabilization and Hydration
Administer IV normal saline immediately to restore extracellular volume and enhance urinary calcium excretion, maintaining urine output of at least 100 mL/hour (or 3 mL/kg/hour in children <10 kg). 1, 2, 3 This corrects the hypercalcemia-associated hypovolemia and promotes calciuresis. 1
- 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 patients. 1, 2, 3 Recent evidence demonstrates furosemide provides no additional calcium-lowering benefit beyond saline hydration alone in severe hypercalcemia secondary to primary hyperparathyroidism. 4
Definitive Pharmacologic Treatment
Bisphosphonates (First-Line for Moderate to Severe Hypercalcemia)
Zoledronic acid 4 mg IV infused over 15 minutes is the preferred bisphosphonate, demonstrating superior efficacy with calcium normalization in 50% of patients by day 4 compared to 33% with 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. 3, 5 The 8 mg dose should be reserved for relapsed or refractory cases. 1
Critical safety consideration: Zoledronic acid 4 mg must be infused over at least 15 minutes (not 5 minutes) to reduce renal toxicity risk. 6 The 8 mg dose increases renal toxicity without added benefit. 6
Alternative bisphosphonates include pamidronate 90 mg IV over 2 hours or oral clodronate 1600 mg/day. 1
Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases, with frequency (monthly vs every 3 months) based on individual response. 1, 2
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. 2, 3, 7 It should be used primarily in patients who cannot tolerate other treatments or as temporary therapy. 2
- Standard dosing: 200 IU per day as nasal spray or 100 IU subcutaneously/intramuscularly every other day. 2
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, 3, 5
Hydration, bisphosphonates (preferably zoledronic acid), and calcitonin form the cornerstone of acute management. 1, 2, 3
Denosumab 120 mg subcutaneously is FDA-approved for bisphosphonate-refractory hypercalcemia of malignancy, lowering calcium in 64% of refractory patients within 10 days. 1 However, it lacks European approval for this indication and carries higher hypocalcemia risk requiring calcium monitoring and supplementation. 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, 8, 3, 5, 9
Primary Hyperparathyroidism
Parathyroidectomy is the definitive treatment for symptomatic primary hyperparathyroidism and should be considered for patients with: 8, 3
Osteoporosis
Impaired kidney function
Kidney stones or hypercalciuria
Age ≥50 years
Calcium >0.25 mmol/L (>1 mg/dL) above upper limit of normal
In patients older than 50 years with serum calcium less than 1 mg/dL above the 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. 2, 3
Refractory or Severe Hypercalcemia
Dialysis is reserved for patients with severe hypercalcemia (>14 mg/dL or >3.5 mmol/L) complicated by renal insufficiency, as hemodialysis effectively removes calcium through diffusive therapy. 2, 3, 5, 9
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, 8, 2, 3
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, 3, 9
PTHrP is elevated in many cases of malignancy-associated hypercalcemia, particularly squamous cell carcinomas and renal cell carcinoma. 1, 8, 3
Monitoring Requirements
Monitor serum calcium, ionized calcium, renal function (creatinine), and electrolytes (potassium, magnesium) regularly to assess treatment effectiveness. 8, 2, 3
Any unexplained albuminuria (>500 mg/24 hours) or serum creatinine increase >0.5 mg/dL or absolute value >1.4 mg/dL requires bisphosphonate discontinuation. 1
Calcium levels should be monitored post-denosumab treatment with calcium and vitamin D supplements started if necessary to prevent hypocalcemia. 1
Critical Pitfalls to Avoid
Do not use loop diuretics routinely—only add furosemide in patients with renal or cardiac insufficiency. 2, 3, 4 Evidence shows no additional benefit beyond saline alone in most patients.
Avoid NSAIDs and intravenous contrast media in patients with renal impairment to prevent further kidney function deterioration. 2, 3
Do not delay bisphosphonate administration while waiting for complete diagnostic workup in symptomatic patients—treat first, diagnose concurrently. 3
Never infuse zoledronic acid 4 mg over less than 15 minutes due to increased renal toxicity risk. 6
Do not restrict calcium intake without medical supervision in normocalcemic patients. 3