Hypercalcemia: Key Investigations and Management
Key Investigations
Measure serum calcium (corrected for albumin or ionized calcium directly), intact PTH, PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, magnesium, albumin, creatinine, and BUN to determine the underlying cause. 1, 2, 3
Laboratory Workup
- Calculate corrected calcium: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 1, 3
- Classify severity: Mild (10-11 mg/dL), moderate (11-12 mg/dL), or severe (>14 mg/dL) 1, 3, 4
- PTH level distinguishes etiology: Elevated/normal PTH indicates primary hyperparathyroidism; suppressed PTH (<20 pg/mL) indicates other causes 3, 4
- PTHrP elevation suggests humoral hypercalcemia of malignancy 1, 3
- Vitamin D levels: Elevated 1,25-dihydroxyvitamin D in granulomatous disease/lymphoma; elevated 25-hydroxyvitamin D in vitamin D intoxication 3
Clinical Assessment
- Mild/moderate symptoms: Polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, fatigue, constipation 1, 3, 4
- Severe symptoms: Mental status changes, bradycardia, hypotension, dehydration, acute renal failure, somnolence, coma 1, 4
Medical Management
Immediate Treatment (All Patients with Symptomatic or Severe Hypercalcemia)
Administer IV normal saline immediately to correct hypovolemia and promote calciuresis, targeting urine output ≥100 mL/hour (3 mL/kg/hour in children <10 kg). 1, 2, 3
Hydration Protocol
- IV normal saline is the first-line intervention for all symptomatic hypercalcemia 1, 2, 3
- Loop diuretics (furosemide) only after volume repletion in patients with renal or cardiac insufficiency to prevent fluid overload 2, 3, 5
Bisphosphonate Therapy (Moderate to Severe Hypercalcemia)
Zoledronic acid 4 mg IV infused over no less than 15 minutes is preferred over pamidronate for initial treatment after hydration is initiated. 1, 2, 3
Bisphosphonate Dosing
- Zoledronic acid: 4 mg IV over ≥15 minutes, superior efficacy to pamidronate with longer duration of response (30-40 days vs 17 days) 2, 6
- Pamidronate: 30-90 mg IV over 4 hours if zoledronic acid unavailable; 90 mg dose achieves 100% normalization by day 7 7, 6
- Dose adjustment required for renal impairment; monitor serum creatinine before each dose 2
- Onset of action: 24-48 hours, with peak effect at 4-7 days 7, 6
Bisphosphonate Monitoring
- Monitor serum calcium, renal function, and electrolytes regularly 1, 2, 3
- Withhold treatment if renal deterioration occurs 2
- Watch for complications: Renal toxicity (2% with pamidronate), osteonecrosis of jaw with chronic use, transient fever/myalgias within 36 hours of first dose 3, 6
Adjunctive Pharmacologic Therapies
Calcitonin (Immediate Short-Term Management)
Calcitonin 100 IU subcutaneously or intramuscularly provides rapid onset within hours but limited efficacy; use as bridge until bisphosphonates take effect. 1, 2, 5
- Dosing: 200 IU/day nasal spray or 100 IU SC/IM every other day 2
- Advantage: Acute onset of hypocalcemic effect (within hours) 6
- Limitation: Poor long-term efficacy, tachyphylaxis develops 6
Glucocorticoids (Vitamin D-Mediated Hypercalcemia)
Glucocorticoids are the primary treatment for vitamin D-mediated hypercalcemia including sarcoidosis, lymphomas, vitamin D intoxication, and granulomatous disorders. 1, 2, 3
Denosumab (Refractory Hypercalcemia)
Denosumab 120 mg subcutaneously is indicated for refractory hypercalcemia, especially in patients with renal impairment where bisphosphonates are contraindicated. 1, 3
- Higher risk of hypocalcemia: Correct hypocalcemia before initiating; monitor serum calcium closely 2
- Supplementation during treatment: Oral calcium 500 mg plus vitamin D 400 IU daily 2
Dialysis (Severe Hypercalcemia with Renal Failure)
Dialysis with calcium-free or low-calcium solution is reserved for severe hypercalcemia complicated by renal insufficiency. 2, 3, 5
- Hemodialysis effectively removes calcium through diffusive therapy 2
Non-Medical Management
Dietary and Lifestyle Modifications
- Avoid vitamin D supplements in patients with hypercalcemia, particularly in early childhood 1, 2, 3
- Low-calcium diet for pediatric patients (e.g., Williams syndrome) under medical supervision 1
- Increased water intake to promote calciuresis 1
- Mobilization: Movement to greatest amount tolerated to reduce bone resorption 8
Medication Review
- Discontinue offending agents: Thiazide diuretics, calcium supplements, vitamin D, vitamin A 4
- Avoid NSAIDs and IV contrast in patients with renal impairment to prevent worsening renal function 1, 2
Definitive Management (Treat Underlying Cause)
Primary Hyperparathyroidism
Parathyroidectomy is indicated for symptomatic disease, osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age <50 years, or calcium >0.25 mmol/L above upper normal limit. 3, 4
- Observation acceptable in patients >50 years with calcium <1 mg above upper normal and no skeletal/kidney disease 4
Malignancy-Associated Hypercalcemia
Treat the underlying malignancy when possible, as this is essential for long-term control. 2, 3
- Plasmapheresis as adjunctive therapy for symptomatic hyperviscosity in multiple myeloma 2
- Continue bisphosphonates for up to 2 years in multiple myeloma or bone metastases 2
Tertiary Hyperparathyroidism
Parathyroidectomy is considered for persistent hypercalcemic hyperparathyroidism despite optimized medical therapy. 2
Critical Pitfalls to Avoid
- Do not restrict calcium intake without medical supervision in patients with normocalcemia 1, 2
- Hyperalbuminemia can mask true calcium status: Always calculate corrected calcium or measure ionized calcium 1
- Do not delay bisphosphonates in moderate to severe hypercalcemia; temporary measures provide only 1-4 hours benefit 2
- Avoid loop diuretics before volume repletion: Use only after adequate hydration in patients with renal/cardiac insufficiency 3, 5
- Asymptomatic hypocalcemia post-treatment does not require intervention: Only treat symptomatic hypocalcemia (tetany, seizures) with calcium gluconate 50-100 mg/kg 2