What are the causes of hypercalcemia (elevated ionized calcium)?

From the Guidelines

Elevated ionized calcium, or hypercalcemia, should be managed with aggressive hydration, bisphosphonates, and loop diuretics to reduce calcium levels and prevent complications, as recommended by the most recent guidelines 1.

Causes and Symptoms of Hypercalcemia

Hypercalcemia can be caused by various factors, including primary hyperparathyroidism, malignancy, vitamin D toxicity, and certain medications like thiazide diuretics. Symptoms may include fatigue, weakness, confusion, bone pain, kidney stones, and cardiac arrhythmias. In patients with lung cancer, hypercalcemia is often associated with parathyroid hormone-related protein (PTHrP) production, increased active metabolite of vitamin D (calcitriol), and localized osteolytic hypercalcemia 1.

Management of Hypercalcemia

Initial management involves identifying and treating the underlying cause while ensuring adequate hydration. For severe hypercalcemia (>14 mg/dL or >3.5 mmol/L), intravenous normal saline at 200-300 mL/hour should be administered to promote calcium excretion, followed by bisphosphonates like zoledronic acid 4 mg IV or pamidronate 60-90 mg IV 1. Calcitonin 4 IU/kg every 12 hours can provide rapid but temporary reduction in calcium levels. Loop diuretics like furosemide may be added after adequate hydration to enhance calcium excretion.

Key Considerations

• Regular monitoring of calcium levels, renal function, and electrolytes is essential during treatment.
• Hypercalcemia requires prompt attention as it can lead to serious complications including renal failure, cardiac arrest, and coma if left untreated.
• Among the bisphosphonates, zoledronic acid is preferred for the treatment of hypercalcemia due to its efficacy and safety profile 1.
• Plasmapheresis may be used as adjunctive therapy for symptomatic hyperviscosity, but its use in renal dysfunction is institution-dependent 1.

From the FDA Drug Label

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

• Elevated ionized calcium is associated with hypercalcemia of malignancy (HCM), which can be managed with zoledronic acid injection.
• Zoledronic acid inhibits osteoclastic activity, reducing bone resorption and subsequently decreasing serum calcium levels.
• The drug label does not provide a direct answer to the question of how to manage elevated ionized calcium, but it implies that zoledronic acid can help reduce serum calcium levels in patients with HCM 2.

From the Research

Causes of Elevated Ionised Calcium

• Hypercalcemia can be caused by primary hyperparathyroidism (PHPT) or malignancy, which account for approximately 90% of cases 3
• Other causes of hypercalcemia include granulomatous disease, endocrinopathies, immobilization, genetic disorders, and certain medications or supplements 3
• Hypercalcemia can also be associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, although these account for less than 1% of cases 3

Symptoms of Elevated Ionised Calcium

• Mild hypercalcemia is usually asymptomatic, but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people 3
• Severe hypercalcemia can cause nausea, vomiting, dehydration, confusion, somnolence, and coma 3, 4
• Clinical manifestations of hypercalcemia are related to calcium levels, with higher values leading to more pronounced symptoms 4

Diagnosis of Elevated Ionised Calcium

• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, and distinguishes PTH-dependent from PTH-independent causes 3
• An elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level indicates another cause 3

Treatment of Elevated Ionised Calcium

• Mild hypercalcemia usually does not need acute intervention, but may require observation or parathyroidectomy depending on the underlying cause and severity 3
• Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 3, 5, 6
• Zoledronic acid has been shown to be effective in reducing serum calcium levels in patients with severe hypercalcemia secondary to PHPT 5 and in pediatric patients with severe hypercalcemia 7
• Treatment should also focus on identifying and treating the underlying cause of hypercalcemia 3, 4, 6