What is the management approach for a patient with hypercalcemia?

Management of Hypercalcemia

Immediately initiate aggressive IV normal saline hydration targeting urine output of 100-150 mL/hour, followed by IV zoledronic acid 4 mg infused over at least 15 minutes as the cornerstone of treatment for moderate to severe hypercalcemia. 1, 2

Initial Assessment and Diagnostic Workup

Before initiating treatment, obtain the following laboratory tests to determine the underlying cause and guide therapy 1, 2:

• Measure intact parathyroid hormone (iPTH) - this is the single most important test to differentiate causes: elevated or normal PTH indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) points to other etiologies 2, 3
• Obtain PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, calcium, albumin, magnesium, phosphorus, creatinine, and BUN 1, 2
• Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin], or preferably measure ionized calcium directly to avoid pseudo-hypercalcemia 1, 2
• Assess severity to guide treatment urgency: Mild (10-11 mg/dL), Moderate (11-13.5 mg/dL), Severe (>14 mg/dL) 2, 3

Treatment Algorithm

Step 1: Aggressive Hydration (Initiate Immediately)

• Administer IV normal saline aggressively to correct hypovolemia and promote calciuresis, targeting urine output of 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg) 1, 2, 4
• Infuse 2-3 liters of saline per day initially; balanced crystalloids are preferred over 0.9% saline when possible to avoid hyperchloremic metabolic acidosis 1, 5
• Critical pitfall: Do NOT use loop diuretics (furosemide) before complete volume repletion, as this worsens dehydration and hypercalcemia 1, 2, 6
• Loop diuretics should only be used AFTER volume repletion in patients with renal or cardiac insufficiency to prevent fluid overload 1, 7
• Continue hydration to maintain diuresis >2.5 L/day in adults while waiting for bisphosphonates to take effect 1

Step 2: Bisphosphonate Therapy (First-Line 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 approximately 50% of patients by day 4 1, 2, 4, 3
• Do NOT exceed 4 mg dose or infuse faster than 15 minutes - both increase risk of renal toxicity without added benefit 4
• Pamidronate IV may be used as an alternative if zoledronic acid is unavailable 1
• Check serum creatinine before each dose and withhold treatment if renal deterioration occurs 1, 4
• Dose adjustments required for creatinine clearance <60 mL/min 1
• Correct hypocalcemia before initiating bisphosphonates to prevent severe post-treatment hypocalcemia 1

Step 3: Adjunctive Therapies (Based on Etiology and Severity)

For Rapid Calcium Reduction (Bridge Therapy):

• Calcitonin-salmon 100 IU subcutaneously or intramuscularly provides rapid onset within hours but has limited efficacy and tachyphylaxis develops quickly 1, 3, 7
• Use calcitonin as a bridge until bisphosphonates take effect, not as monotherapy 1

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

• Glucocorticoids are the primary treatment for hypercalcemia due to excessive intestinal calcium absorption 1, 8, 3, 7
• Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 1
• Particularly effective in sarcoidosis, some lymphomas, and multiple myeloma 1, 8

For Bisphosphonate-Refractory Hypercalcemia:

• Denosumab 120 mg subcutaneously lowers calcium in 64% of patients within 10 days 1, 2
• Preferred in patients with impaired renal function due to lower rates of renal toxicity, but carries higher risk of hypocalcemia 1

For Severe Hypercalcemia with Renal Failure:

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) is reserved for severe hypercalcemia complicated by renal insufficiency or oliguria 1, 7

Etiology-Specific Considerations

Primary Hyperparathyroidism:

• Parathyroidectomy is indicated for symptomatic patients or those with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium >0.25 mmol/L above upper limit of normal 8, 3
• Observation may be appropriate in patients >50 years with calcium <1 mg above upper normal limit 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, 3
• Combination therapy: hydration + zoledronic acid + steroids (for multiple myeloma) 1
• Plasmapheresis for symptomatic hyperviscosity in multiple myeloma 1

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) 1

Critical Pitfalls to Avoid

• Never delay bisphosphonate therapy in moderate-severe hypercalcemia while relying solely on temporary measures like calcitonin (provides only 1-4 hours benefit) 1, 2
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney damage 1, 2
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 1
• Furosemide has no additional benefit beyond saline hydration alone and may worsen hypercalcemia if given before volume repletion 6
• Asymptomatic hypocalcemia post-treatment does not require intervention - only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 1

Monitoring and Follow-Up

• Monitor serum calcium, creatinine, phosphorus, magnesium, and electrolytes every 6-12 hours during acute phase 1, 2
• Perform baseline dental examination before chronic bisphosphonate use due to osteonecrosis of jaw risk 1, 2, 4
• Assess ECG for QT interval prolongation in severe hypercalcemia 1
• Continue bisphosphonate therapy for up to 2 years in patients with multiple myeloma or bone metastases 1