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

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 supported by 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 cancer or through production of parathyroid hormone-related protein by tumors like lung and breast cancer
• Granulomatous diseases, such as sarcoidosis and tuberculosis, which produce excess vitamin D
• Excessive vitamin D supplementation
• Medications, such as thiazide diuretics, lithium, and theophylline
• Endocrine disorders, such as hyperthyroidism and adrenal insufficiency
• Familial hypocalciuric hypercalcemia
• Prolonged immobilization
• Milk-alkali syndrome from excessive calcium and antacid intake

Symptoms and Treatment

Symptoms of hypercalcemia typically appear when calcium levels exceed 12 mg/dL and include:

• Fatigue
• Confusion
• Constipation
• Nausea
• Increased urination
• Kidney stones
• In severe cases, coma Treatment depends on the underlying cause and may include:
• Hydration
• Bisphosphonates
• Calcitonin
• Surgery for parathyroid adenomas, as recommended in the study 1 It is essential to note that the treatment approach should be based on the underlying cause of hypercalcemia and should aim to reduce calcium levels to normal, as excessive calcium levels can lead to serious health complications, including kidney damage and cardiovascular disease, as highlighted in the studies 1.

From the FDA Drug Label

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. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease.

The causes of hypercalcemia include:

• Humoral hypercalcemia: caused by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically, commonly seen in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer.
• Hypercalcemia due to tumor invasion of bone: caused by local tumor products that stimulate bone resorption by osteoclasts, commonly seen in breast cancer and multiple myeloma.
• Osteoclastic hyperactivity: resulting in excessive bone resorption, which is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease 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
• Granulomatous disease, such as sarcoidosis 3, 6
• Endocrinopathies, such as thyroid disease 3, 6
• Immobilization 3, 6
• Genetic disorders, such as familial hypocalciuric hypercalcemia 4, 6
• Medications, including:
  • Thiazide diuretics 3, 6
  • Lithium 6
  • Vitamin D and calcium supplements 3, 5
  • Sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, and denosumab discontinuation 3
• Other causes, such as:
  • Chronic kidney disease 5
  • Chronic granulomatous diseases 5
  • Vitamin D toxicity 5
  • Malignant solid tumors and hematological malignancy 5

Less Common Causes

Less common causes of hypercalcemia include:

• Iatrogenic hypercalcemia due to overzealous use of vitamin D 5
• Ketogenic diets and extreme exercise 3
• SARS-CoV-2 infection 3

Diagnosis and Treatment

Diagnosis of hypercalcemia involves measuring serum intact parathyroid hormone (PTH) levels, which can distinguish between PTH-dependent and PTH-independent causes 3, 4, 6. Treatment of hypercalcemia depends on the underlying cause and severity of the condition, and may include:

• Hydration and intravenous bisphosphonates for severe hypercalcemia 3, 4, 7
• Parathyroidectomy for PHPT 3, 4, 7
• Chemotherapy for malignancy-associated hypercalcemia 7
• Glucocorticoids for hypercalcemia due to excessive intestinal calcium absorption 3