From the Guidelines
Hypercalcemia is most commonly caused by primary hyperparathyroidism and malignancy, which account for approximately 90% of cases, as supported by recent studies 1. The etiology of elevated hypercalcemia can be multifactorial, involving various underlying conditions and mechanisms.
Common Causes of Hypercalcemia
- Primary hyperparathyroidism: typically results from a parathyroid adenoma causing excessive parathyroid hormone (PTH) secretion
- Malignancy: can occur through direct bone destruction or production of parathyroid hormone-related protein (PTHrP)
- Medications: thiazide diuretics, lithium, vitamin A or D toxicity
- Granulomatous diseases: sarcoidosis, tuberculosis
- Endocrine disorders: hyperthyroidism, adrenal insufficiency
- Familial hypocalciuric hypercalcemia
- Immobilization
- Renal failure: can contribute through reduced calcium excretion
Laboratory Evaluation and Treatment
Laboratory evaluation should include serum calcium (ionized and total), phosphorus, PTH, vitamin D levels, and renal function tests. Treatment depends on severity and underlying cause, ranging from hydration and bisphosphonates for acute management to addressing the specific etiology, such as parathyroidectomy for primary hyperparathyroidism or treating underlying malignancy, as recommended by recent guidelines 1. Understanding the pathophysiology involves recognizing that calcium homeostasis depends on the balanced actions of PTH, vitamin D, and calcitonin on bone, kidneys, and intestines.
Recent Guidelines and Recommendations
Recent studies and guidelines suggest that hypercalcemia may be harmful in all GFR categories of CKD, prompting the recommendation to avoid inappropriate calcium loading in adults whenever possible 1. The use of calcium-based phosphate binders should also be restricted in patients with hyperphosphatemia across the CKD spectrum. In patients with multiple myeloma, hypercalcemia should be treated with hydration, bisphosphonates, denosumab, steroids, and/or calcitonin, with zoledronic acid being the preferred bisphosphonate for treatment of 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 etiology of elevated hypercalcemia is osteoclastic hyperactivity resulting in excessive bone resorption, which can be caused by two main mechanisms:
- Humoral hypercalcemia: osteoclasts are activated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically.
- Hypercalcemia due to tumor invasion of bone: extensive invasion of bone by tumor cells results in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts 2.
From the Research
Etiology of Elevated Hypercalcemia
The etiology of elevated hypercalcemia can be attributed to various causes, including:
- Primary hyperparathyroidism (PHPT) and malignancy, which account for approximately 90% of cases 3
- Granulomatous disease, such as sarcoidosis, and endocrinopathies, such as thyroid disease 3
- Immobilization, genetic disorders, and certain medications, including thiazide diuretics and supplements like calcium, vitamin D, or vitamin A 3
- Other less common causes, such as sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, which account for less than 1% of cases 3
Pathophysiology of Hypercalcemia
The pathophysiology of hypercalcemia involves various mechanisms, including:
- Excessive parathyroid hormone (PTH) production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion 4
- Impaired renal calcium excretion resulting from a combination of volume contraction and calcium-induced renal injury (nephrocalcinosis) 5
Clinical Presentation and Diagnosis
Hypercalcemia can present with various symptoms, including:
- Mild hypercalcemia, which is usually asymptomatic, but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people 3
- Severe hypercalcemia, which can cause nausea, vomiting, dehydration, confusion, somnolence, and coma 3, 5, 6
- Diagnosis is typically made by measuring serum calcium levels, and the underlying cause should be identified and treated 3, 4
Treatment and Management
Treatment of hypercalcemia depends on the underlying cause and severity of the condition, and may include:
- Hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate, for symptomatic or severe hypercalcemia 3, 5, 7
- Glucocorticoids for hypercalcemia associated with high levels of vitamin D, such as sarcoidosis, some lymphomas, or vitamin D intoxication 3, 5
- Denosumab and dialysis for patients with kidney failure 3
- Parathyroidectomy for patients with primary hyperparathyroidism, depending on age, serum calcium level, and kidney or skeletal involvement 3