What are the causes and treatments of hypercalcemia?

Causes and Treatment of Hypercalcemia

Primary hyperparathyroidism and malignancy are responsible for over 90% of all hypercalcemia cases, with specific treatment approaches required for each cause. 1, 2

Major Causes of Hypercalcemia

PTH-Dependent Causes

• Primary hyperparathyroidism is characterized by elevated or inappropriately normal parathyroid hormone (PTH) levels with hypercalcemia 1
• Tertiary hyperparathyroidism can occur in patients with kidney disease despite optimized medical therapy 3

PTH-Independent Causes

• Malignancy-associated hypercalcemia, often mediated by parathyroid hormone-related protein (PTHrP), commonly seen in squamous cell carcinomas and renal cell carcinoma 1
• Granulomatous disorders (e.g., sarcoidosis) cause hypercalcemia due to increased 1,25-dihydroxyvitamin D production 1
• Vitamin D intoxication from excessive supplementation or treatment 1
• Williams syndrome is associated with idiopathic infantile hypercalcemia 1
• Medications such as thiazide diuretics, calcium supplements, and vitamin supplements 2
• Endocrinopathies such as thyroid disease 2
• Immobilization and genetic disorders 2

Diagnostic Approach

First-Line Laboratory Tests

• Serum calcium (total and ionized) measurement is essential 4
• Albumin levels for corrected calcium calculation 4
• Intact parathyroid hormone (iPTH) is the most important initial test to distinguish PTH-dependent from PTH-independent causes 4, 2
• Serum creatinine, blood urea nitrogen, phosphorus, and magnesium should be measured 4

Second-Line Laboratory Tests

• If PTH is elevated or inappropriately normal with hypercalcemia, measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 4
• If PTH is suppressed, measure parathyroid hormone-related protein (PTHrP) to evaluate for malignancy 4
• Consider malignancy markers if PTH is suppressed 1

Treatment Approach

Mild Asymptomatic Hypercalcemia

• Observation may be appropriate for patients older than 50 years with serum calcium levels less than 1 mg/dL above the upper normal limit and no evidence of skeletal or kidney disease 2
• Ensure adequate hydration and avoid medications that can worsen hypercalcemia 2

Moderate to Severe Hypercalcemia

• Intravenous saline hydration is the first step to correct hypovolemia and promote calciuresis 3, 2
• Maintain urine output of at least 100 ml/hour (3 ml/kg/hour in children <10 kg) 3
• Loop diuretics may be necessary in patients with renal or cardiac insufficiency to prevent fluid overload 3, 5

Pharmacological Interventions

• Bisphosphonates are the first-line treatment for moderate to severe hypercalcemia, especially malignancy-associated 1, 6
• Zoledronic acid 4 mg IV is preferred for hypercalcemia of malignancy, administered over no less than 15 minutes 6
• Dose adjustments of zoledronic acid are necessary for patients with renal impairment 6
• Calcitonin can be used for immediate short-term management of severe symptomatic hypercalcemia 3, 5
• Glucocorticoids are effective for vitamin D-mediated hypercalcemia, such as in sarcoidosis, lymphomas, and vitamin D intoxication 1, 3

Cause-Specific Treatment

• Treatment of the underlying cancer is essential for malignancy-associated hypercalcemia 1
• Parathyroidectomy is indicated for symptomatic patients with primary hyperparathyroidism and patients with osteoporosis, impaired kidney function, kidney stones, hypercalciuria, age ≥50 years, or calcium increased by more than 0.25 mmol/L above the upper limit of normal 7
• For Williams syndrome with hypercalcemia, a low-calcium diet and increased water intake under medical supervision are recommended 1

Severe Cases and Special Considerations

• Dialysis is generally reserved for patients with severe hypercalcemia complicated by renal insufficiency 3, 5
• In patients with kidney disease, careful monitoring of renal function is necessary when using bisphosphonates 1
• Vitamin D supplements should be avoided in patients with hypercalcemia 1, 3

Monitoring and Follow-up

• Serum calcium, renal function, and electrolytes should be monitored regularly 1
• For zoledronic acid treatment, renal function must be carefully monitored and serum creatinine assessed prior to each treatment 6
• Retreatment with zoledronic acid 4 mg may be considered if serum calcium does not return to normal, with a minimum of 7 days between treatments 6