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

Initial Management and Workup of Hypercalcemia

Begin immediate IV normal saline hydration targeting urine output ≥100 mL/hour while simultaneously obtaining intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, albumin, phosphorus, magnesium, and creatinine to determine the underlying cause. 1, 2

Immediate Assessment and Severity Classification

Measure ionized calcium directly rather than relying solely on corrected calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling. 2, 3 If only total calcium is available, calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)]. 2

Classify severity to guide urgency:

• Mild: 10-11 mg/dL (usually asymptomatic) 2, 4
• Moderate: 11-13.5 mg/dL (constitutional symptoms in ~20% of patients) 2, 4
• Severe: ≥14 mg/dL (nausea, vomiting, confusion, somnolence, coma) 2, 4

Essential Laboratory Workup

The PTH level is the single most important test to distinguish PTH-dependent from PTH-independent causes. 1, 4

Obtain the following labs simultaneously:

• Intact PTH: Elevated/normal suggests primary hyperparathyroidism; suppressed (<20 pg/mL) indicates malignancy or other causes 1, 3, 4
• PTHrP: Elevated in humoral hypercalcemia of malignancy (squamous cell carcinomas, renal cell carcinoma) 1, 3
• 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together: Must measure both for diagnostic accuracy in vitamin D-mediated causes 1, 3
• Phosphorus: Low in hyperparathyroidism, elevated in vitamin D intoxication 1
• Magnesium, creatinine, BUN: Assess renal function and electrolyte status 1
• Albumin: Required for corrected calcium calculation 2

If PTH is suppressed, check malignancy markers and consider imaging for occult malignancy. 1

Medication and Exposure History

Specifically inquire about:

• Thiazide diuretics and lithium (increase calcium) 3
• Calcium supplements >500 mg/day 3
• Vitamin D supplements >400 IU/day 3
• Vitamin A intake 3
• Recent denosumab discontinuation, immune checkpoint inhibitors, or SGLT2 inhibitors 4

Clinical Symptom Assessment

Moderate hypercalcemia: Look for polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, constipation, and fatigue. 1, 3

Severe hypercalcemia: Assess for mental status changes, dehydration, bradycardia, hypotension, and acute renal failure. 3 Obtain ECG to evaluate for QT interval prolongation. 1

Immediate Treatment Algorithm

Step 1: Aggressive Hydration (Start Immediately)

Administer IV normal saline to achieve urine output 100-150 mL/hour (or 3 mL/kg/hour in children <10 kg). 1, 2 Ideally begin hydration 48 hours before tumor-specific therapy when possible. 2

Critical pitfall: Monitor fluid status carefully in patients with cardiac or renal insufficiency; use loop diuretics (furosemide) after volume repletion to prevent fluid overload. 1 However, furosemide provides no additional calcium-lowering benefit beyond saline alone and may actually increase calcium levels. 5

Step 2: Bisphosphonate Therapy (Administer Early)

Do not delay bisphosphonate administration in moderate to severe hypercalcemia. 1

Zoledronic acid 4 mg IV infused over no less than 15 minutes is superior to pamidronate and should be the first-choice bisphosphonate. 1, 2, 4 It normalizes calcium in approximately 50% of patients by day 4 with longer response duration. 2

Dose adjustments required for creatinine clearance <60 mL/min. 1 Monitor serum creatinine before each dose and withhold if renal deterioration occurs. 1

Before initiating bisphosphonates: Correct any pre-existing hypocalcemia and provide oral calcium supplement 500 mg plus vitamin D 400 IU daily during treatment. 1

Step 3: Adjunctive Therapies for Specific Situations

Calcitonin 100 IU subcutaneously or intramuscularly: Provides rapid onset within hours but limited efficacy; use as a bridge until bisphosphonates take effect in severe symptomatic cases. 1, 4 Calcitonin also provides analgesic benefit for bone pain from metastases. 1

Glucocorticoids (prednisone 1 mg/kg/day orally): Use specifically for vitamin D-mediated hypercalcemia including sarcoidosis, granulomatous diseases, some lymphomas, and vitamin D intoxication. 1, 3, 4 Taper over 2-4 months depending on response. 1

Cause-Specific Diagnostic Patterns

Primary hyperparathyroidism (90% of outpatient cases): Elevated or inappropriately normal PTH with hypercalcemia, typically mild (<12 mg/dL), chronic duration (>6 months), may have kidney stones, hyperchloremic metabolic acidosis, no anemia. 3, 4, 6

Malignancy-associated hypercalcemia (most common inpatient cause): Suppressed PTH, elevated PTHrP, rapid onset, higher calcium levels (often >12 mg/dL), marked anemia, no kidney stones or metabolic acidosis, median survival ~1 month. 1, 2, 3, 6

Granulomatous disorders (sarcoidosis): Suppressed PTH, elevated 1,25-dihydroxyvitamin D due to extrarenal production. 3

Refractory Cases

Denosumab 120 mg subcutaneously is indicated for bisphosphonate-refractory hypercalcemia or patients with renal insufficiency, reducing calcium in 64% of refractory cases. 2 Monitor calcium levels closely post-treatment due to significant hypocalcemia risk. 2

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, 4, 6

Critical Monitoring Parameters

• Serum calcium, creatinine, and electrolytes: Monitor regularly to assess treatment effectiveness 1
• Discontinue bisphosphonates if: Unexplained albuminuria >500 mg/24 hours OR serum creatinine increases >0.5 mg/dL OR absolute creatinine >1.4 mg/dL in patients with normal baseline 2
• Baseline dental examination: Required before chronic bisphosphonate use to monitor for osteonecrosis of the jaw 2

Medications to Avoid

Discontinue nephrotoxic medications, NSAIDs, and intravenous contrast media in patients with renal impairment to prevent further deterioration. 1

Stop vitamin D supplements immediately in all patients with hypercalcemia. 1, 3