What are the causes of hypercalcemia?

From the Guidelines

Hypercalcemia is most commonly caused by primary hyperparathyroidism and malignancy, which together account for about 90% of cases, with primary hyperparathyroidism typically resulting from a benign parathyroid adenoma that overproduces parathyroid hormone, as reported in the most recent study 1. The causes of hypercalcemia can be categorized into several main groups, including:

• Primary hyperparathyroidism, which is usually due to a single parathyroid adenoma (80%), but can also occur from multiple adenomas, parathyroid hyperplasia, or, rarely, parathyroid carcinoma (<1%) 1
• Malignancy-related hypercalcemia, which occurs through direct bone destruction by metastases or through production of parathyroid hormone-related protein (PTHrP) by tumors like lung and breast cancer
• Other important causes, including:
  • Medications such as thiazide diuretics, lithium, and excessive vitamin A or D supplementation
  • Granulomatous diseases like sarcoidosis and tuberculosis, which can cause hypercalcemia through increased vitamin D production
  • Endocrine disorders including thyrotoxicosis, adrenal insufficiency, and acromegaly, which may also elevate calcium levels
  • Less common causes, such as familial hypocalciuric hypercalcemia, milk-alkali syndrome from excessive calcium intake, prolonged immobilization leading to bone resorption, and recovery phase of acute kidney injury It is worth noting that the study 1 on secondary hyperparathyroidism in chronic renal failure and the guidelines for multiple myeloma 1 also mention hypercalcemia as a complication, but the most relevant and recent information on the causes of hypercalcemia is provided in the study 1. The symptoms of hypercalcemia typically appear when calcium levels exceed 12 mg/dL and include fatigue, confusion, constipation, polyuria, and in severe cases, cardiac arrhythmias and coma. In summary, primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia, and it is essential to identify the underlying cause to provide appropriate treatment and improve patient outcomes, as supported by the most recent evidence 1.

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. Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts.

The causes of hypercalcemia include:

• Osteoclastic hyperactivity resulting in excessive bone resorption
• Humoral hypercalcemia: osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein
• Hypercalcemia due to tumor invasion of bone: extensive invasion of bone by tumor cells resulting in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with hypercalcemia include:
• Breast cancer
• Multiple myeloma
• Squamous-cell malignancies of the lung or head and neck
• Genitourinary tumors such as renal-cell carcinoma or ovarian cancer 2 3

From the Research

Causes of Hypercalciemia

• Primary hyperparathyroidism (PHPT) and malignancy are the most common causes of hypercalciemia, accounting for approximately 90% of cases 4
• Other causes of hypercalciemia include:
  • Granulomatous disease such as sarcoidosis 4, 5
  • Endocrinopathies such as thyroid disease 4, 6
  • Immobilization 4
  • Genetic disorders 4
  • Medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A 4, 6
  • Vitamin D intoxication 7, 5
  • Hypercalcemia of malignancy, which can be caused by tumor production of parathyroid hormone-related protein, osseous metastases, or increased production of 1,25-dihydroxyvitamin D (1,25(OH)2D) 5, 8

Less Common Causes of Hypercalciemia

• Sodium-glucose cotransporter 2 protein inhibitors 4
• Immune checkpoint inhibitors 4
• Denosumab discontinuation 4
• SARS-CoV-2 4
• Ketogenic diets 4
• Extreme exercise 4
• Familial hypocalciuric hypercalcemia 6
• Milk-alkali syndrome 6
• Lithium therapy 6

Diagnosis and Treatment of Hypercalciemia

• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, distinguishing PTH-dependent from PTH-independent causes 4
• Treatment of hypercalciemia depends on the underlying cause and severity of the condition, and may include hydration, intravenous bisphosphonates, glucocorticoids, and parathyroidectomy 4, 7