What is the initial workup and treatment for a patient presenting with hypercalcemia?

Hypercalcemia Workup and Management

The initial workup for hypercalcemia should include measurement of serum calcium (corrected for albumin), intact parathyroid hormone (iPTH), phosphorus, magnesium, renal function tests, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D, followed by aggressive IV fluid resuscitation with normal saline for treatment. 1

Diagnostic Evaluation

Initial Laboratory Assessment

• Serum calcium (corrected for albumin using formula: Corrected calcium = Total calcium + 0.8 × (4.0 - serum albumin)) 1
• Intact parathyroid hormone (iPTH) - critical for determining if hypercalcemia is PTH-dependent or independent 1, 2
• Phosphorus - typically low in hyperparathyroidism
• Magnesium
• Renal function tests
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D
• PTHrP (if malignancy suspected)
• Urinary calcium/creatinine ratio 1

Additional Diagnostic Tests

• Chest radiography to evaluate for malignancy 1
• Renal ultrasound to detect nephrolithiasis 1
• Bone densitometry to assess bone density if hyperparathyroidism suspected 1

Treatment Algorithm

Step 1: Assess Severity

• Mild hypercalcemia (Ca <12 mg/dL): Often asymptomatic, may not require immediate intervention 2
• Moderate hypercalcemia (Ca 12-14 mg/dL): May present with constitutional symptoms
• Severe hypercalcemia (Ca ≥14 mg/dL): Requires urgent treatment due to risk of life-threatening complications 2, 3

Step 2: Initial Management

1. Aggressive IV fluid resuscitation with normal saline

   • Cornerstone of initial management 1
   • Corrects dehydration and promotes calciuresis
   • Target urine output of approximately 2 L/day 4
   • Avoid calcium-containing solutions 1

2. Avoid common pitfalls:

   • Do NOT use diuretics before correcting hypovolemia 1, 4
   • Do NOT overhydrate patients with cardiac failure 4
   • Do NOT delay treatment of severe hypercalcemia 1

Step 3: Pharmacological Management

1. Bisphosphonates (first-line pharmacological treatment) 1

   • Zoledronic acid: 4 mg IV over 15 minutes (preferred agent) 1, 4
   • Pamidronate: Alternative option
   • Dose adjustment required for renal impairment (see table below) 4

   Baseline CrCl (mL/min)	Zoledronic Acid Dose (mg)
   >60	4
   50-60	3.5
   40-49	3.3
   30-39	3

2. Denosumab

   • For hypercalcemia refractory to bisphosphonates
   • Preferred in patients with severe renal insufficiency 1
   • Dose: 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of first month) 1

3. Calcitonin

   • For immediate short-term management of severe symptomatic hypercalcemia 1, 3
   • Rapid but modest effect

4. Glucocorticoids

   • Effective for vitamin D toxicity, granulomatous disorders, or some lymphomas 1, 5

5. Loop diuretics (e.g., furosemide)

   • Only after adequate hydration to enhance calcium excretion 1, 4

Step 4: Monitoring and Follow-up

• Regular monitoring of serum calcium, phosphate, magnesium, and renal function 1
• Verify renal function before each dose of bisphosphonates 1
• Monitor for hypocalcemia, especially with denosumab therapy 1
• Administer oral calcium supplement (500 mg) and vitamin D (400 IU) daily 4

Special Considerations

Hypercalcemia of Malignancy

• Occurs in 10-25% of patients with lung cancer, most commonly in squamous cell carcinoma 1
• Poor prognosis with median survival of approximately 1 month after discovery 1
• Requires aggressive treatment 1, 6

Renal Impairment

• For patients with severe renal insufficiency, denosumab is preferred over bisphosphonates 1
• Consider hemodialysis for patients with advanced kidney disease and refractory severe hypercalcemia 3, 6

Retreatment Considerations

• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not normalize 4
• Allow minimum 7 days between treatments for full response 4
• Assess renal function prior to retreatment 4

Common Pitfalls to Avoid

• Using diuretics before correcting hypovolemia
• Failing to correct calcium for albumin
• Inadequate hydration before bisphosphonate administration
• Treating laboratory values without addressing the underlying cause
• Delaying treatment of severe hypercalcemia
• Administering bisphosphonates too rapidly
• Failing to monitor for hypocalcemia after treatment 1