What is the treatment approach for a patient with hypercalcemia?

Treatment of Hypercalcemia

Initiate aggressive IV normal saline hydration immediately, targeting urine output of 100-150 mL/hour, followed by IV zoledronic acid 4 mg infused over at least 15 minutes as the definitive first-line treatment for moderate to severe hypercalcemia. 1

Initial Assessment and Diagnostic Workup

Before initiating treatment, obtain the following laboratory tests to determine the underlying cause:

• Measure intact PTH first to distinguish PTH-dependent (primary hyperparathyroidism) from PTH-independent causes (malignancy, vitamin D disorders, granulomatous disease) 2
• Check ionized calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 2
• If PTH is suppressed (<20 pg/mL), measure PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, and magnesium 1, 2
• Assess renal function with serum creatinine and BUN, as this affects bisphosphonate dosing 1
• Calculate corrected calcium if using total calcium: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin] 1

Severity Classification and Symptoms

• Mild hypercalcemia (total calcium <12 mg/dL): Usually asymptomatic but may cause fatigue and constipation in 20% of patients 3
• Moderate hypercalcemia (12-14 mg/dL): Presents with polyuria, polydipsia, nausea, vomiting, abdominal pain, and myalgia 4
• Severe hypercalcemia (≥14 mg/dL): Associated with mental status changes, confusion, somnolence, coma, bradycardia, hypotension, dehydration, and acute renal failure 4, 3

Treatment Algorithm

Step 1: Hydration (Immediate)

• Administer IV normal saline aggressively to correct hypovolemia and promote calciuresis, targeting urine output of 100-150 mL/hour 1
• Give boluses of 250-500 mL every 15 minutes until rehydration is achieved 1
• Aim for total diuresis >2.5 L/day in adults while waiting for bisphosphonates to take effect 1
• Use balanced crystalloids over 0.9% saline when possible to avoid hyperchloremic metabolic acidosis with large volumes 1
• Loop diuretics (furosemide) should only be used AFTER complete volume repletion and only in patients with renal or cardiac insufficiency to prevent fluid overload 1, 5

Critical pitfall: Never use loop diuretics before correcting hypovolemia, as this worsens hypercalcemia by reducing calcium excretion 5, 6

Step 2: Bisphosphonate Therapy (Definitive Treatment)

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate due to superior efficacy compared to pamidronate, normalizing calcium in 50% of patients by day 4 1, 3
• Pamidronate 60-90 mg IV is an acceptable alternative if zoledronic acid is unavailable 1, 5
• Initiate bisphosphonate therapy early without waiting for complete rehydration 1
• Adjust zoledronic acid dose for creatinine clearance <60 mL/min 1
• Monitor serum creatinine before each dose and withhold if renal deterioration occurs 1
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia, as temporary measures provide only 1-4 hours of benefit 1

Step 3: Adjunctive Therapies (When Indicated)

Calcitonin (for rapid but temporary effect):

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly every 12 hours provides rapid onset within hours but limited efficacy 1
• Use as a bridge until bisphosphonates take effect (3-5 days) 1
• Tachyphylaxis develops within 48 hours, limiting long-term use 1

Corticosteroids (for specific etiologies):

• Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent for hypercalcemia due to granulomatous diseases (sarcoidosis), vitamin D intoxication, some lymphomas, and multiple myeloma 1, 4
• Corticosteroids work by reducing excessive intestinal calcium absorption 4
• Allow 3-6 months to demonstrate responsiveness before escalation 1
• Target lowest effective dose ≤10 mg/day to minimize toxicity 1

Step 4: Refractory or Severe Cases

Denosumab:

• Denosumab 120 mg subcutaneously for bisphosphonate-refractory hypercalcemia, lowering calcium in 64% of patients within 10 days 1
• Higher risk of hypocalcemia with denosumab—correct hypocalcemia before initiating and monitor closely 1
• Administer oral calcium 500 mg plus vitamin D 400 IU daily during treatment 1

Dialysis:

• Reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 1
• Use calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) 1, 6
• Hemodialysis effectively removes calcium through diffusive therapy 1

Etiology-Specific Management

Primary Hyperparathyroidism

• Parathyroidectomy is indicated for symptomatic patients, those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal 4
• Observation may be appropriate for patients >50 years with calcium <1 mg/dL above normal and no skeletal or kidney disease 3

Malignancy-Associated Hypercalcemia

• Treat the underlying cancer when possible—hypercalcemia of malignancy carries poor prognosis with median survival approximately 1 month 1
• For multiple myeloma: hydration, zoledronic acid 4 mg IV, and corticosteroids 1
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1
• Plasmapheresis as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 1

Granulomatous Disease (Sarcoidosis)

• Corticosteroids are primary therapy due to excessive 1,25-dihydroxyvitamin D production by activated macrophages 4, 2
• If unable to wean below 10 mg/day prednisone after 3-6 months, add methotrexate as steroid-sparing agent 1

Vitamin D Intoxication

• Immediately discontinue all vitamin D supplements and calcium-based supplements 4
• Corticosteroids are effective for reducing intestinal calcium absorption 4
• Avoid vitamin D supplements in all patients with active hypercalcemia 2

Chronic Kidney Disease

• Immediately discontinue all calcium-based phosphate binders and vitamin D analogs (calcitriol, paricalcitol) 1
• Consider lower dialysate calcium concentration (1.5-2.0 mEq/L) if PTH is suppressed 1
• Target corrected calcium 8.4-9.5 mg/dL, preferably at lower end of range 1

Monitoring During Treatment

• Monitor serum calcium, creatinine, and electrolytes (especially potassium and magnesium) every 6-12 hours during acute phase 1
• Assess for ECG changes, particularly QT interval prolongation in severe hypercalcemia 1
• Reduce IV fluid rate once stable diuresis of 100-150 mL/hour is achieved 1

Critical Medications to Avoid

• Discontinue thiazide diuretics, lithium, and excessive calcium/vitamin D supplements 2
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney damage 1
• Stop any nephrotoxic medications 1

Special Populations

Pediatric patients (Williams syndrome):

• Low-calcium diet and increased water intake under medical supervision 4
• Avoid vitamin D supplements, particularly in early childhood 1

Patients on cancer therapy:

• For patients on lenalidomide and bortezomib with severe hypercalcemia, temporarily discontinue these agents until calcium normalizes 1