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, 2

Initial Assessment and Diagnostic Workup

Before initiating treatment, obtain the following laboratory studies to determine the underlying cause 1, 3:

• Intact parathyroid hormone (iPTH) - distinguishes PTH-dependent (primary hyperparathyroidism) from PTH-independent causes 3, 4
• Parathyroid hormone-related protein (PTHrP) - elevated in malignancy-associated hypercalcemia 3
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D - evaluates vitamin D-mediated hypercalcemia 1, 3
• Serum calcium, albumin, phosphorus, magnesium - calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin] 1, 2
• Serum creatinine and BUN - assess renal function before bisphosphonate administration 1, 2
• Ionized calcium - preferred over corrected calcium to avoid pseudo-hypercalcemia 1

Assess for symptoms including polyuria, polydipsia, nausea, vomiting, confusion, dehydration, abdominal pain, and mental status changes 1, 4.

Treatment Algorithm

Step 1: Immediate Hydration

Administer IV normal saline aggressively to correct hypovolemia and promote calciuresis 1, 2, 4:

• Target urine output of 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg) 1
• Aim for total diuresis >2.5 L/day in adults 1
• Administer boluses of 250-500 mL every 15 minutes until rehydration is achieved 1
• Avoid overhydration in patients with cardiac or renal insufficiency 1, 2
• Use loop diuretics (furosemide) only after complete volume repletion and only in patients with renal or cardiac insufficiency to prevent fluid overload 1, 5
• Never use loop diuretics before volume repletion as this worsens hypercalcemia 1, 2

Step 2: Definitive Bisphosphonate Therapy

Zoledronic acid is the preferred bisphosphonate due to superior efficacy compared to pamidronate 1, 2, 4:

• Standard dose: 4 mg IV infused over no less than 15 minutes 1, 2
• Initiate early without waiting for complete rehydration 1
• Onset of action: 2-4 days, with peak effect at 4-7 days 1
• Duration of response: 30-40 days (vs. 17 days for pamidronate) 6

Dose adjustments for renal impairment (for chronic use in malignancy, not acute hypercalcemia) 2:

• CrCl >60 mL/min: 4 mg
• CrCl 50-60 mL/min: 3.5 mg
• CrCl 40-49 mL/min: 3.3 mg
• CrCl 30-39 mL/min: 3 mg
• Do not use in severe renal impairment (CrCl <30 mL/min) 2

Monitor serum creatinine before each dose and withhold if renal deterioration occurs (increase of 0.5 mg/dL if normal baseline, or 1.0 mg/dL if abnormal baseline) 2.

Retreatment: May repeat 4 mg dose if calcium does not normalize, but wait minimum 7 days between doses 2.

Step 3: Adjunctive Therapies for Rapid Control

Calcitonin provides rapid onset (within hours) but limited efficacy and duration 1, 7:

• Dose: 100 IU subcutaneously or intramuscularly every 12 hours (or 200 IU/day intranasal) 1
• Use as a bridge therapy until bisphosphonates take effect 1, 4
• Tachyphylaxis develops within 48-72 hours, limiting usefulness 1, 6
• Contraindicated if allergy to calcitonin-salmon 1

Combination therapy: Calcitonin plus bisphosphonates provides both rapid and sustained calcium reduction 1, 6, 7.

Cause-Specific Definitive Treatment

Malignancy-Associated Hypercalcemia

Treat the underlying cancer as this is essential for long-term control 1, 3:

• Hydration plus zoledronic acid is the cornerstone 1, 4
• Continue bisphosphonates for up to 2 years in multiple myeloma or bone metastases 1
• Plasmapheresis for symptomatic hyperviscosity in multiple myeloma 1
• Prognosis is poor with median survival approximately 1 month 1

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

Glucocorticoids are the primary treatment 1, 3, 4:

• Prednisone 1 mg/kg/day orally (or methylprednisolone IV equivalent) 1
• Taper over 2-4 months depending on response 1
• Effective for sarcoidosis, some lymphomas, and vitamin D toxicity 1, 3, 5
• Immediately discontinue all vitamin D and calcium supplements 1, 3

Monitoring during steroid therapy 1:

• Pneumocystis pneumonia prophylaxis if ≥20 mg methylprednisolone equivalent for ≥4 weeks
• GI prophylaxis with proton pump inhibitor
• Tuberculosis screening before initiation in granulomatous disease
• Paradoxically provide calcium/vitamin D supplementation for bone protection with prolonged use (carefully monitored)

Primary Hyperparathyroidism

Parathyroidectomy is the only curative treatment 3, 4:

• Indicated for symptomatic patients 3, 7
• Also indicated if: age <50 years, calcium >1 mg/dL above upper limit, osteoporosis, impaired kidney function, kidney stones, or hypercalciuria 3
• Observation is appropriate for patients >50 years with calcium <1 mg/dL above normal and no skeletal or renal disease 4, 7

Tertiary Hyperparathyroidism (CKD Patients)

Consider parathyroidectomy for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 1.

Immediate medication adjustments 1:

• Discontinue all calcium-based phosphate binders immediately 1
• Stop all vitamin D analogs (calcitriol, paricalcitol) and supplements 1
• Consider lower dialysate calcium concentration (1.5-2.0 mEq/L) 1

Refractory or Severe Hypercalcemia

Dialysis

Reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 1, 5, 7:

• Use calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) 1
• Hemodialysis effectively removes calcium through diffusive therapy 1
• Generally reserved for patients with CrCl <30 mL/min and severe hypercalcemia 5

Denosumab

Consider in patients with renal failure who cannot receive bisphosphonates 1, 4:

• Higher risk of severe hypocalcemia compared to bisphosphonates 1
• Requires aggressive calcium and vitamin D supplementation 1

Critical Monitoring and Prevention

During treatment, monitor 1, 3:

• Serum calcium, creatinine, and electrolytes (potassium, magnesium) every 6-12 hours during acute phase 1
• ECG for QT interval prolongation in severe hypercalcemia 1
• Fluid status to avoid hypervolemia 1

Prevent hypocalcemia after treatment 1, 2:

• Administer oral calcium 500 mg plus vitamin D 400 IU daily during bisphosphonate therapy 1, 2
• Correct pre-existing hypocalcemia before initiating bisphosphonates 1
• Asymptomatic hypocalcemia does not require treatment 1
• Treat only symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 1

Critical Pitfalls to Avoid

• Never use loop diuretics before complete volume repletion - worsens hypercalcemia 1, 2, 5
• Avoid NSAIDs and IV contrast in patients with renal impairment - further deteriorates kidney function 1
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia - temporary measures provide only 1-4 hours of benefit 1
• Never restrict calcium intake without medical supervision - can worsen bone disease 1
• Avoid overhydration in cardiac or renal failure patients - use loop diuretics cautiously after volume repletion 1, 2
• Do not use bisphosphonates in severe renal impairment (CrCl <30 mL/min) without considering dialysis 2
• Measure ionized calcium or calculate corrected calcium - avoid misdiagnosis from pseudo-hypercalcemia 1, 2
• Discontinue nephrotoxic medications during treatment 1