What are the causes of hypercalcemia (elevated calcium)?

From the Guidelines

Elevated calcium levels, particularly in patients with lung cancer, necessitate immediate attention and treatment, with a focus on managing symptoms and addressing the underlying cause, as the median survival after discovery of hypercalcemia of malignancy is about 1 month 1.

Clinical Presentation and Diagnosis

The clinical symptoms of hypercalcemia depend on the severity and acuity of onset, ranging from mild symptoms such as polyuria, polydipsia, nausea, and confusion, to severe symptoms including mental status changes, bradycardia, and hypotension in cases of severe hypercalcemia (> 14.0 mg/dL) 1.

• The diagnostic evaluation should include measuring serum concentrations of intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, calcium, albumin, magnesium, and phosphorus.
• It is crucial to differentiate between the causes of hypercalcemia, as PTHrP-mediated hypercalcemia is characterized by a suppressed iPTH level and a low or normal calcitriol level, contrasting with primary hyperparathyroidism which presents with elevated iPTH and calcitriol levels 1.

Management and Treatment

For moderate to severe hypercalcemia, especially with symptoms, management includes rehydrating with IV crystalloid fluids not containing calcium and giving loop diuretics (e.g., furosemide) as needed after correction of intravascular volume, alongside bisphosphonates such as zoledronic acid or pamidronate, which are usually effective 1.

• Oral hydration may be sufficient for mild hypercalcemia.
• Additional therapeutic options such as glucocorticoids, gallium nitrate, and salmon calcitonin may be considered for specific cases 1.
• Identifying and treating the underlying cause of hypercalcemia is essential, as it significantly impacts the management strategy and patient outcomes.

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. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy

The treatment of elevated calcium involves reducing excessive bone resorption and maintaining adequate fluid administration.

• Zoledronic acid and pamidronate are two drugs that can be used to manage hypercalcemia of malignancy by inhibiting osteoclastic activity and reducing bone resorption 2, 3.
• The goal of treatment is to decrease serum calcium levels and prevent further complications.
• It is essential to monitor serum calcium levels and adjust treatment accordingly.
• Adequate fluid administration is also crucial in managing hypercalcemia of malignancy.

From the Research

Definition and Classification of Hypercalcemia

• Hypercalcemia is defined as a serum calcium concentration >10.5 mg/dL 4
• It is classified into mild, moderate, and severe, depending on calcium values 4
• Mild hypercalcemia is usually asymptomatic, but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people 5

Causes of Hypercalcemia

• Most cases of hypercalcemia are caused by primary hyperparathyroidism and malignancies 4, 5
• Other causes include granulomatous disease, endocrinopathies, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements like calcium, vitamin D, or vitamin A 5
• Hypercalcemia has also been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes 5

Diagnosis and Treatment of Hypercalcemia

• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, distinguishing PTH-dependent from PTH-independent causes 5
• Initial treatment involves vigorous intravenous hydration and drugs to reduce bone resorption such as bisphosphonates and, more recently, denosumab, in refractory cases 4
• Zoledronic acid is a highly potent bisphosphonate that has been shown to be effective in the treatment of hypercalcemia of malignancy, with a higher complete response rate and more durable responses compared to pamidronate 6, 7
• In patients with kidney failure, denosumab and dialysis may be indicated 5
• Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas) 4, 5

Clinical Manifestations of Hypercalcemia

• Clinical manifestations are related to calcium levels, with higher values leading to more pronounced symptoms 4
• Severe hypercalcemia can cause nausea, vomiting, dehydration, confusion, somnolence, and coma 5
• Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates 5