What are the causes of hypercalcemia?

From the Guidelines

Hypercalcemia is primarily caused by excess bone resorption from bone disease, leading to the release of calcium into the blood, and can also be caused by primary hyperparathyroidism, which is typically due to a single parathyroid adenoma. The most common causes of hypercalcemia include bone disease, such as multiple myeloma, and primary hyperparathyroidism (PHPT), which is usually caused by a single parathyroid adenoma 1. Other causes of hypercalcemia may include hyperparathyroidism due to multiple adenomas, parathyroid hyperplasia, or parathyroid carcinoma. Symptoms of hypercalcemia include polyuria, gastrointestinal disturbances, progressive dehydration, and decreases in glomerular filtration rate 1.

Causes of Hypercalcemia

• Excess bone resorption from bone disease, such as multiple myeloma
• Primary hyperparathyroidism (PHPT), typically due to a single parathyroid adenoma
• Multiple adenomas, parathyroid hyperplasia, or parathyroid carcinoma
• Other rare causes, such as familial hyperparathyroidism or multiple endocrine neoplasia types 1 and 2A

Treatment of Hypercalcemia

• Hydration
• Bisphosphonates, such as zoledronic acid, pamidronate, or ibandronate
• Denosumab
• Steroids
• Calcitonin
• Treatment of the underlying cause, such as surgery for primary hyperparathyroidism

According to the most recent evidence, the treatment of hypercalcemia should prioritize hydration, bisphosphonates, and treatment of the underlying cause 1. In cases of primary hyperparathyroidism, surgical excision of the abnormally functioning parathyroid tissue is typically indicated, even in asymptomatic patients, due to the potential negative effects of long-term hypercalcemia 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 These causes are commonly associated with certain types of cancer, including:
• 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 2

From the Research

Causes of Hypercalcemia

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

• Primary hyperparathyroidism (PHPT) and malignancy, which account for approximately 90% of cases 3, 4, 5, 6
• Granulomatous disease, such as sarcoidosis 3, 7
• Endocrinopathies, such as thyroid disease 3, 7
• Immobilization 3, 7
• Genetic disorders, such as familial hypocalciuric hypercalcemia 4, 7
• Medications, including:
  • Thiazide diuretics 3, 7
  • Supplements, such as calcium, vitamin D, or vitamin A 3
  • Sodium-glucose cotransporter 2 protein inhibitors 3
  • Immune checkpoint inhibitors 3
  • Denosumab discontinuation 3
• Other causes, including:
  • SARS-CoV-2 3
  • Ketogenic diets 3
  • Extreme exercise 3
  • Vitamin D toxicity 6
  • Chronic kidney disease 7, 6
  • Chronic granulomatous diseases 6

Diagnosis and Evaluation

The diagnosis and evaluation of hypercalcemia involve measuring serum intact parathyroid hormone (PTH) levels, which can distinguish between PTH-dependent and PTH-independent causes 3, 4, 7. Other tests, such as ionized calcium and vitamin D metabolites, may also be useful in diagnosing and evaluating hypercalcemia 7.

Malignant and Non-Malignant Causes

Malignant causes of hypercalcemia include solid tumors, such as oral cavity carcinoma, and hematological malignancies, such as multiple myeloma 6. Non-malignant causes include primary hyperparathyroidism, vitamin D toxicity, and chronic kidney disease 6.