What are the causes and treatments of hypercalcemia and hypocalcemia?

Causes and Treatment of Hypercalcemia and Hypocalcemia

The management of hypercalcemia requires aggressive hydration with IV crystalloid fluids, bisphosphonates (preferably zoledronic acid), and addressing the underlying cause, while symptomatic hypocalcemia requires prompt calcium supplementation with calcium gluconate and correction of contributing factors. 1

Hypercalcemia

Causes

• Primary hyperparathyroidism: Most common cause in outpatient settings
• Malignancy: Most common cause in hospitalized patients
  • Parathyroid hormone-related protein (PTHrP) production
  • Increased active vitamin D (calcitriol)
  • Localized osteolytic hypercalcemia
• Other causes:
  • Granulomatous diseases (sarcoidosis)
  • Medications (thiazide diuretics, vitamin A, vitamin D)
  • Endocrinopathies (thyroid disease)
  • Immobilization
  • Genetic disorders

Clinical Presentation

• Mild to moderate hypercalcemia: Polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, myalgia
• Severe hypercalcemia (>14.0 mg/dL): Mental status changes, bradycardia, hypotension, dehydration, acute renal failure 1

Diagnostic Evaluation

• Serum calcium, albumin (for corrected calcium)
• Intact parathyroid hormone (iPTH)
• PTHrP
• 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D
• Magnesium and phosphorus levels 1

Treatment

1. Hydration:

   • First-line treatment for all hypercalcemia
   • IV crystalloid fluids not containing calcium
   • Corrects hypercalcemia-associated hypovolemia and promotes calciuresis 1

2. Bisphosphonates:

   • First-line pharmacologic treatment
   • Zoledronic acid (4 mg IV) preferred for hypercalcemia of malignancy
   • Pamidronate (90 mg IV) as alternative
   • Reserve 8 mg zoledronic acid dose for refractory cases 1

3. Denosumab:

   • Alternative for patients with renal impairment
   • Effective for hypercalcemia refractory to bisphosphonates
   • Monitor for hypocalcemia after treatment 1, 2

4. Loop diuretics (e.g., furosemide):

   • Use after correction of intravascular volume
   • Enhances calcium excretion 1

5. Additional options:

   • Glucocorticoids: Effective for hypercalcemia due to lymphoma or granulomatous diseases
   • Calcitonin: For immediate short-term management of severe symptomatic hypercalcemia
   • Dialysis: For severe hypercalcemia with renal failure 1, 3

Special Considerations

• Monitor calcium levels closely during treatment
• Treat the underlying cause
• For malignancy-related hypercalcemia, prognosis is poor (median survival ~1 month) 1
• Risk of osteonecrosis of jaw with bisphosphonates and denosumab 2

Hypocalcemia

Causes

• Hypoparathyroidism (surgical, autoimmune)
• Vitamin D deficiency
• Renal failure
• Acute pancreatitis
• Tumor lysis syndrome
• Medications (bisphosphonates, denosumab)
• Hypomagnesemia
• Hungry bone syndrome after parathyroidectomy

Clinical Presentation

• Neuromuscular irritability, tetany, seizures
• Paresthesias, especially perioral
• Chvostek's and Trousseau's signs
• QT prolongation on ECG
• In severe cases: laryngospasm, seizures, cardiac arrhythmias

Treatment

1. Symptomatic hypocalcemia:

   • Calcium gluconate 50-100 mg/kg IV for tetany and seizures
   • Can be cautiously repeated if necessary 1
   • Monitor ECG during administration 4

2. Asymptomatic hypocalcemia:

   • No immediate treatment required if asymptomatic 1
   • Oral calcium supplementation for mild cases

3. Magnesium replacement:

   • Essential in cases of hypomagnesemia
   • IV magnesium sulfate for severe cases 1

4. Vitamin D supplementation:

   • For chronic management
   • Monitor for hypervitaminosis D which can cause hypercalcemia 5

5. Treatment of underlying cause:

   • Address primary etiology (e.g., hypoparathyroidism, vitamin D deficiency)

Special Considerations in Tumor Lysis Syndrome

• Hypocalcemia often occurs with hyperphosphatemia
• Asymptomatic hypocalcemia does not require treatment
• For symptomatic hypocalcemia, administer calcium gluconate 50-100 mg/kg 1

Pitfalls and Caveats

1. For hypercalcemia:

   • Don't use thiazide diuretics (they increase calcium reabsorption)
   • Don't delay hydration while waiting for diagnostic tests
   • Monitor for renal dysfunction with bisphosphonate therapy
   • Watch for hypocalcemia after denosumab treatment 1

2. For hypocalcemia:

   • Don't treat asymptomatic hypocalcemia too aggressively
   • Don't forget to check and correct magnesium levels
   • Avoid rapid IV calcium administration (risk of cardiac arrhythmias)
   • Monitor for hypercalcemia when treating with vitamin D 5, 4

3. General:

   • Always identify and treat the underlying cause
   • Monitor electrolytes closely during treatment
   • Consider renal function when selecting treatments

By following these evidence-based approaches, clinicians can effectively manage both hypercalcemia and hypocalcemia while minimizing complications and addressing the underlying causes.