What are the causes of hypercalcemia?

From the Guidelines

Hypercalcemia is most commonly caused by primary hyperparathyroidism, where overactive parathyroid glands secrete excessive parathyroid hormone, leading to increased calcium absorption from bones and kidneys, as noted in the most recent study 1.

Causes of Hypercalcemia

The causes of hypercalcemia can be categorized into several groups, including:

• Primary hyperparathyroidism, which is the most common cause, accounting for approximately 80% of cases, as stated in the study 1
• Malignancy, which is the second most common cause, either through direct bone destruction by metastatic tumors or through production of parathyroid hormone-related protein by certain cancers like lung, breast, and kidney cancers, as mentioned in the study 1
• Granulomatous diseases, such as sarcoidosis and tuberculosis, which produce excess vitamin D, as noted in the study 1
• Excessive vitamin D intake or supplementation, as mentioned in the study 1
• Medications like thiazide diuretics and lithium, as stated in the study 1
• Endocrine disorders, such as hyperthyroidism and adrenal insufficiency, as mentioned in the study 1
• Familial hypocalciuric hypercalcemia, as noted in the study 1
• Prolonged immobilization, which releases calcium from bones, as mentioned in the study 1
• Milk-alkali syndrome from excessive calcium and antacid consumption, as stated in the study 1
• Certain rare genetic disorders, such as Williams syndrome, as mentioned in the study 1

Treatment of Hypercalcemia

Treatment of hypercalcemia depends on identifying and addressing the underlying cause, with severe cases requiring immediate intervention with:

• Intravenous fluids, as mentioned in the study 1
• Bisphosphonates, as stated in the study 1
• Calcitonin, as noted in the study 1
• Dialysis, as mentioned in the study 1 to prevent life-threatening complications.

Key Considerations

It is essential to note that the treatment of hypercalcemia should be individualized based on the underlying cause and the severity of the condition, as stated in the study 1. Additionally, the use of imaging studies, such as ultrasound and dual-phase 99mTc-sestamibi scintigraphy with SPECT/CT, can be helpful in localizing parathyroid adenomas, as mentioned in the study 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 Common tumors associated with hypercalcemia include:
• Squamous cell malignancies of the lung or head and neck
• Genitourinary tumors such as renal cell carcinoma or ovarian cancer
• Breast cancer
• Multiple myeloma 2

From the Research

Causes of Hypercalcemia

• Primary hyperparathyroidism (PHPT) and malignancy are the most common causes of hypercalcemia, accounting for approximately 90% of cases 3, 4, 5
• Other causes of hypercalcemia include:
  • Granulomatous disease such as sarcoidosis 3, 6
  • Endocrinopathies such as thyroid disease 3, 5
  • Immobilization 3
  • Genetic disorders 3
  • Medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A 3, 5
  • Vitamin D-mediated hypercalcemia, which can occur due to excessive ingestion of vitamin D, ectopic production of 1,25-dihydroxyvitamin D, or impaired degradation of 1,25-dihydroxyvitamin D 6
• Less common causes of hypercalcemia include:
  • Sodium-glucose cotransporter 2 protein inhibitors 3
  • Immune checkpoint inhibitors 3
  • Denosumab discontinuation 3
  • SARS-CoV-2 3
  • Ketogenic diets 3
  • Extreme exercise 3

Pathophysiology of Hypercalcemia

• Hypercalcemia can be caused by excessive parathyroid hormone (PTH) production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion 4
• Calcium homeostasis is regulated by three factors: calcitonin, vitamin D, and parathyroid hormone (PTH) 4
• Vitamin D-mediated hypercalcemia can occur due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] or 1,25-dihydroxyvitamin D [1,25(OH)2D] 6

Diagnosis and Treatment of Hypercalcemia

• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, and it can distinguish PTH-dependent from PTH-independent causes 3
• Treatment of hypercalcemia depends on the underlying cause and severity of the condition, and it may include hydration, intravenous bisphosphonates, glucocorticoids, and parathyroidectomy 3, 4, 7