What are the causes and treatment options for hypercalcemia?

Causes of Hypercalcemia

Hypercalcemia is most commonly caused by primary hyperparathyroidism and malignancy, which together account for approximately 90% of all cases. 1

Major Causes of Hypercalcemia

PTH-Dependent Causes

• Primary hyperparathyroidism - Most common cause in outpatients
• Tertiary hyperparathyroidism (in chronic renal failure)
• Familial hypocalciuric hypercalcemia (genetic disorder)
• Parathyroid carcinoma

Malignancy-Related Causes

• Humoral hypercalcemia of malignancy (PTHrP-mediated) - Common in solid tumors
• Osteolytic metastases - Direct bone destruction
• 1,25-Dihydroxyvitamin D production - Seen in some lymphomas
• Ectopic PTH production (rare)

Medication-Induced Causes

• Vitamin D supplements (excessive intake)
• Calcium supplements
• Thiazide diuretics
• Lithium
• Vitamin A excess
• Milk-alkali syndrome
• SGLT2 inhibitors
• Immune checkpoint inhibitors
• Denosumab discontinuation 1

Other Endocrine Causes

• Hyperthyroidism
• Adrenal insufficiency
• Pheochromocytoma (rare)

Granulomatous Disorders

• Sarcoidosis
• Tuberculosis
• Histoplasmosis
• Coccidioidomycosis
• Leprosy
• Berylliosis

Miscellaneous Causes

• Immobilization (especially with high bone turnover)
• Rhabdomyolysis (acute)
• Severe dehydration
• Extreme exercise
• Ketogenic diets 1

Clinical Presentation

Mild Hypercalcemia (Ca <12 mg/dL)

• Often asymptomatic (20% may have constitutional symptoms)
• Fatigue
• Constipation
• Polyuria
• Polydipsia
• Dry mouth (xerostomia) 2, 1

Severe Hypercalcemia (Ca ≥14 mg/dL)

• Nausea and vomiting
• Dehydration
• Confusion
• Lethargy
• Somnolence
• Coma
• Cardiac arrhythmias
• Renal dysfunction 2, 1

Diagnostic Approach

1. Confirm true hypercalcemia

   • Rule out pseudohypercalcemia (laboratory artifact)
   • Correct calcium for albumin or measure ionized calcium

2. Measure intact parathyroid hormone (PTH)

   • Elevated/normal PTH → Primary hyperparathyroidism
   • Suppressed PTH (<20 pg/mL) → Non-PTH mediated causes (malignancy, etc.)

3. Additional testing based on clinical suspicion

   • PTHrP for suspected malignancy
   • 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D
   • Serum and urine protein electrophoresis (multiple myeloma)
   • Thyroid function tests
   • Medication review
   • Urinary calcium/creatinine ratio (to identify familial hypocalciuric hypercalcemia) 2, 1, 3

Treatment Approach

Mild Asymptomatic Hypercalcemia

• Treat underlying cause
• Ensure adequate hydration
• Avoid medications that can worsen hypercalcemia
• Monitor serum calcium levels

Severe or Symptomatic Hypercalcemia

1. Aggressive IV fluid resuscitation

   • Normal saline (0.9% NaCl) to correct dehydration and promote calciuresis
   • Cornerstone of initial management 2, 4

2. Bisphosphonates

   • Zoledronic acid 4 mg IV over 15 minutes (preferred agent)
   • Response typically begins within 2-4 days
   • Check renal function before administration 2, 4

3. Denosumab

   • For hypercalcemia refractory to bisphosphonates
   • Preferred in patients with renal impairment
   • Dosage: 120 mg subcutaneously every 4 weeks with additional doses on days 8 and 15 of first month 2

4. Glucocorticoids

   • Effective for vitamin D-mediated hypercalcemia (sarcoidosis, lymphoma, vitamin D toxicity) 2, 5

5. Calcitonin

   • For immediate short-term management of severe symptomatic hypercalcemia
   • Rapid but modest effect 5

6. Loop diuretics

   • Only after adequate hydration
   • Enhances calcium excretion 2, 5

7. Hemodialysis

   • For severe refractory hypercalcemia, especially with renal failure 6

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, especially with denosumab 2

Monitoring

• Regular assessment of serum calcium, phosphate, magnesium, and renal function
• Check renal function before each dose of bisphosphonates
• Monitor for hypocalcemia, which can be severe, especially in patients on denosumab 2