What are the causes of hypercalcemia (elevated calcium)?

From the Guidelines

Elevated calcium levels require immediate attention, and the most effective treatment approach is to administer intravenous normal saline at 200-300 mL/hour, followed by furosemide 20-40 mg IV after adequate hydration, and bisphosphonates like zoledronic acid 4 mg IV for severe cases, particularly when caused by malignancy or hyperparathyroidism, as recommended by the NCCN Panel Members 1. The management of hypercalcemia depends on the severity and symptoms of the condition. For mild cases, increasing fluid intake to 2-3 liters daily and addressing the underlying cause may be sufficient. However, for moderate to severe hypercalcemia, more aggressive treatment is necessary.

• The treatment approach should include:
  • Intravenous normal saline at 200-300 mL/hour to promote calcium excretion
  • Furosemide 20-40 mg IV after adequate hydration to enhance calcium elimination
  • Bisphosphonates like zoledronic acid 4 mg IV or pamidronate 60-90 mg IV for severe cases
  • Calcitonin 4-8 IU/kg subcutaneously every 12 hours for rapid but short-term relief The underlying cause of hypercalcemia must be identified and treated, as primary hyperparathyroidism and malignancy account for 90% of cases, with symptoms including fatigue, confusion, bone pain, kidney stones, and cardiac abnormalities, summarized as "bones, stones, groans, and psychiatric overtones" 1. Regular monitoring of calcium, phosphate, and kidney function is essential during treatment.
• Key considerations in the treatment of hypercalcemia include:
  • The use of bisphosphonates, such as zoledronic acid, which is preferred by the NCCN Panel Members for the treatment of hypercalcemia 1
  • The importance of addressing the underlying cause of hypercalcemia, whether it be malignancy or primary hyperparathyroidism
  • The need for regular monitoring of calcium, phosphate, and kidney function during treatment to ensure effective management of the condition.

From the FDA Drug Label

Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate

Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations

Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy

The treatment of elevated calcium involves reducing excessive bone resorption and maintaining adequate fluid administration.

• Zoledronic acid and pamidronate are used to manage hypercalcemia of malignancy by inhibiting osteoclastic activity and reducing bone resorption.
• Monitoring of serum calcium levels and adjustment of treatment as needed is crucial in managing hypercalcemia.
• Adequate fluid administration is essential to correct volume deficits and prevent worsening of hypercalcemia 2 3.

From the Research

Definition and Classification of Hypercalcemia

• Hypercalcemia is defined as a serum calcium concentration >10.5 mg/dL 4
• It is classified into mild, moderate, and severe, depending on calcium values 4
• Mild hypercalcemia is usually asymptomatic, but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people 5
• Severe hypercalcemia can cause nausea, vomiting, dehydration, confusion, somnolence, and coma 5

Causes of Hypercalcemia

• Most cases of hypercalcemia are caused by primary hyperparathyroidism and malignancies 4, 5
• Other causes of hypercalcemia include granulomatous disease, endocrinopathies, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements like calcium, vitamin D, or vitamin A 5
• Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes 5

Diagnosis and Treatment of Hypercalcemia

• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, and distinguishes PTH-dependent from PTH-independent causes 5
• Initial treatment of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 4, 5, 6
• Zoledronic acid has been shown to be effective in reducing serum calcium levels in patients with severe hypercalcemia secondary to primary hyperparathyroidism 6, 7
• However, zoledronic acid can also cause hypocalcemia, and patients should be followed closely after infusion 7, 8
• Treatment of hypercalcemia should be individualized, and the underlying cause of hypercalcemia should be identified and treated 4, 5

Management of Severe Hypercalcemia

• Severe hypercalcemia is a life-threatening condition that should be managed urgently 6
• Normal saline hydration and intravenous bisphosphonates, such as zoledronic acid, are effective in reducing serum calcium levels in patients with severe hypercalcemia secondary to primary hyperparathyroidism 6
• Furosemide may not have a significant additional effect on calcium levels in patients with severe hypercalcemia secondary to primary hyperparathyroidism when compared with the effect of saline hydration alone 6