Agents That Cause Hypercalcemia
The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy, which together account for approximately 90% of all cases. 1
Primary Causes
Endocrine Disorders
- Primary hyperparathyroidism: Excessive parathyroid hormone secretion
- Hyperthyroidism: Increased bone turnover
- Adrenal insufficiency: Altered calcium homeostasis
- Acromegaly: Growth hormone excess affecting calcium metabolism 2
Malignancy-Related
- Humoral hypercalcemia of malignancy: Mediated by parathyroid hormone-related protein (PTHrP)
- Common in squamous cell carcinomas of lung/head/neck
- Renal cell carcinoma
- Ovarian cancer 3
- Direct bone invasion: Local osteolytic factors
- Breast cancer
- Multiple myeloma 3
- 1,25-dihydroxyvitamin D production: Typically in lymphomas 2
Medication-Induced Hypercalcemia
Vitamin-Related
- Vitamin D preparations: Both nutritional (D2/D3) and active forms (calcitriol)
- Vitamin D analogs (tacalcitol, calcipotriol, 22-oxacalcitriol) used in psoriasis 4
- Vitamin A excess: Increases bone resorption 4
Diuretics and Other Medications
- Thiazide diuretics: Increase renal calcium reabsorption 5
- Lithium: Alters calcium sensing receptor function 2
- Foscarnet: Direct calcium release from bone 2
- Sodium-glucose cotransporter 2 inhibitors: Mechanism unclear 1
- Immune checkpoint inhibitors: Immune-mediated endocrinopathies 1
- Denosumab discontinuation: Rebound effect after stopping anti-resorptive therapy 1
Genetic and Congenital Disorders
- Williams syndrome: Idiopathic infantile hypercalcemia 6
- 22q11.2 deletion syndrome: Associated with hypoparathyroidism but can have hypercalcemia 6
- Jansen's metaphyseal chondrodysplasia: Gain-of-function mutation in PTHR1 2
Other Causes
- Granulomatous disorders:
- Sarcoidosis
- Tuberculosis
- Increased 1,25-dihydroxyvitamin D production 1
- Immobilization: Increased bone resorption, especially in patients with high bone turnover 1
- Milk-alkali syndrome: Excessive intake of calcium and absorbable alkali 2
- Parenteral nutrition: Especially in preterm infants 2
- Extreme exercise: Rare cause 1
- SARS-CoV-2 infection: Mechanism unclear 1
- Ketogenic diets: Altered calcium metabolism 1
Management Approach
For symptomatic or severe hypercalcemia (total calcium ≥14 mg/dL):
- Aggressive IV fluid resuscitation with normal saline to correct hypovolemia and enhance renal calcium excretion 7
- Bisphosphonates (e.g., zoledronic acid 4 mg IV over 15 minutes) to inhibit osteoclastic bone resorption 7, 3
- Denosumab for refractory cases or patients with severe renal impairment 7
- Glucocorticoids for vitamin D toxicity, granulomatous disorders, or some lymphomas 7
- Calcitonin for immediate short-term management of severe symptomatic hypercalcemia 7
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 7
Clinical Pearls
- Rapidly developing hypercalcemia typically causes more severe symptoms than gradually increasing levels 7
- In humoral hypercalcemia, skeletal metastases may be absent or minimal 3
- Hypercalcemia of malignancy is associated with poor survival 1
- Thiazide diuretics can cause severe hypercalcemia, with cases reported as high as 19.8 mg/dL 5
Understanding the specific agent causing hypercalcemia is crucial for targeted treatment and improving patient outcomes, particularly in terms of morbidity, mortality, and quality of life.