What are the causes and treatment options for hypercalcemia?

Causes and Treatment of Hypercalcemia

Primary hyperparathyroidism and malignancy account for approximately 90% of hypercalcemia cases, with other causes including granulomatous diseases, endocrinopathies, medications, and genetic disorders. 1

Major Causes of Hypercalcemia

PTH-Dependent Causes

• Primary hyperparathyroidism - characterized by elevated or inappropriately normal parathyroid hormone (PTH) levels with hypercalcemia 2
• Tertiary hyperparathyroidism - often seen in chronic renal failure patients receiving calcium and vitamin D metabolite treatment 3
• Familial hypocalciuric hypercalcemia - a genetic disorder that should be considered in the differential diagnosis 4

Malignancy-Associated Causes

• Solid tumors with bone metastases - commonly seen in breast cancer and prostate cancer 5
• Humoral hypercalcemia of malignancy - mediated by parathyroid hormone-related protein (PTHrP), often in squamous cell carcinomas and renal cell carcinoma 2, 6
• Multiple myeloma - causes osteolytic lesions leading to hypercalcemia 7
• Lymphomas - can cause hypercalcemia through various mechanisms including vitamin D-mediated processes 2

Other Important Causes

• Granulomatous disorders (sarcoidosis, tuberculosis) - due to increased 1,25-dihydroxyvitamin D production 2
• Vitamin D intoxication - excessive supplementation or treatment 8
• Medications - thiazide diuretics, lithium, milk-alkali syndrome 3
• Thyrotoxicosis - increased bone turnover 3
• Immobilization - particularly in patients with high bone turnover 1
• Williams syndrome - associated with idiopathic infantile hypercalcemia 9

Clinical Presentation

• Mild hypercalcemia (total calcium <12 mg/dL) - often asymptomatic or with constitutional symptoms like fatigue and constipation 1
• Moderate hypercalcemia - presents with polyuria, polydipsia, nausea, vomiting, abdominal pain, and myalgia 2
• Severe hypercalcemia (>14 mg/dL) - associated with mental status changes, bradycardia, hypotension, dehydration, and acute renal failure 2
• In Williams syndrome - may present with extreme irritability, vomiting, constipation, and muscle cramps in infants 9

Diagnostic Approach

• Measure serum intact parathyroid hormone (iPTH) - the most important initial test to distinguish PTH-dependent from PTH-independent causes 1
• Check parathyroid hormone-related protein (PTHrP) - elevated in many cases of malignancy-associated hypercalcemia 10
• Measure vitamin D metabolites - 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels 10, 2
• Evaluate renal function - with serum creatinine and urinary calcium excretion 8
• Calculate corrected calcium - when albumin is abnormal, using the formula: cCa in mg/dL = Ca in mg/dL + 0.8 (4.0 g/dL - patient albumin [g/dL]) 5
• Consider malignancy markers - if PTH is suppressed 8

Treatment Approach

Mild Asymptomatic Hypercalcemia

• Ensure adequate hydration 8
• Maintain normal calcium intake (minimum 1g per day) and avoid excessive supplementation 8
• Monitor serum calcium regularly 8
• For primary hyperparathyroidism, consider parathyroidectomy based on age, calcium level, and evidence of kidney or skeletal involvement 1

Moderate to Severe Symptomatic Hypercalcemia

1. Hydration

   • Administer IV normal saline to correct hypovolemia and promote calciuresis 10
   • Restore urine output to approximately 2 L/day 5
   • Avoid overhydration in patients with cardiac failure 5

2. Pharmacologic Therapy

   • Bisphosphonates - first-line treatment for moderate to severe hypercalcemia, especially malignancy-associated 2

     • Zoledronic acid 4 mg IV over no less than 15 minutes 5
     • Pamidronate IV for treatment of moderate or severe hypercalcemia associated with malignancy 7
     • Dose adjustments needed for patients with renal impairment 5

   • Glucocorticoids - effective for vitamin D-mediated hypercalcemia (sarcoidosis, lymphomas, vitamin D intoxication) 2

   • Calcitonin - has a more rapid but modest hypocalcemic effect; can be combined with bisphosphonates for enhanced rate of calcium reduction 11

3. Special Considerations

   • For malignancy-associated hypercalcemia, treatment of the underlying cancer is essential 8
   • In patients with kidney disease, careful monitoring of renal function is necessary when using bisphosphonates 8
   • For Williams syndrome with hypercalcemia, consider low-calcium diet and increased water intake under medical supervision 9
   • Avoid vitamin D supplements in patients with hypercalcemia 10

Follow-up and Monitoring

• Monitor serum calcium, renal function, and electrolytes regularly 8
• For retreatment with zoledronic acid, wait at least 7 days to allow for full response to the initial dose 5
• Assess serum creatinine prior to each bisphosphonate treatment 5

Prognosis

• Asymptomatic primary hyperparathyroidism has excellent prognosis with either medical or surgical management 1
• Hypercalcemia of malignancy is associated with poor survival, with median survival of approximately 1 month in some cancers 2, 1