What is the management of hypercalcemia?

From the Guidelines

Management of hypercalcemia should prioritize hydration, bisphosphonates, denosumab, steroids, and/or calcitonin, with zoledronic acid being the preferred bisphosphonate, as recommended by the most recent guidelines 1.

Key Considerations

• The approach to managing hypercalcemia should be stepwise, considering the severity and underlying cause of the condition.
• For mild hypercalcemia, addressing the underlying cause may be sufficient, while moderate to severe cases require more aggressive treatment.
• Initial treatment focuses on volume repletion with intravenous normal saline to enhance renal calcium excretion.
• Loop diuretics like furosemide can be used to prevent fluid overload and further promote calcium excretion.
• Bisphosphonates, particularly zoledronic acid, are the mainstay for treating hypercalcemia of malignancy, with calcitonin providing rapid but short-lived calcium reduction.
• Refractory cases may benefit from cinacalcet in hyperparathyroidism or denosumab in renal impairment when bisphosphonates are contraindicated.
• Glucocorticoids like prednisone can benefit vitamin D-mediated hypercalcemia, and hemodialysis remains an option for life-threatening hypercalcemia with renal failure.

Treatment Options

• Hydration with intravenous normal saline at 200-300 mL/hour
• Loop diuretics like furosemide 20-40 mg IV
• Bisphosphonates: zoledronic acid 4 mg IV over 15 minutes or pamidronate 60-90 mg IV over 2-4 hours
• Calcitonin 4-8 IU/kg subcutaneously every 12 hours
• Cinacalcet 30-90 mg daily for hyperparathyroidism
• Denosumab 120 mg subcutaneously for renal impairment when bisphosphonates are contraindicated
• Glucocorticoids like prednisone 40-60 mg daily for vitamin D-mediated hypercalcemia
• Hemodialysis for life-threatening hypercalcemia with renal failure

Guiding Principles

• Treatment should be based on the severity of hypercalcemia, underlying cause, and patient's symptoms and renal function.
• The choice of therapy depends on calcium level, symptoms, underlying etiology, and renal function, with treatment typically continuing until calcium normalizes or the primary cause is addressed.
• The most recent guidelines from the National Comprehensive Cancer Network (NCCN) should be consulted for the latest recommendations on managing hypercalcemia 1.

From the FDA Drug Label

Hypercalcemia of Malignancy Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in metastatic bone disease and hypercalcemia of malignancy 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 Correction of excessive bone resorption and adequate fluid administration to correct volume deficits are therefore essential to the management of hypercalcemia Patients who have hypercalcemia of malignancy can generally be divided into two groups, according to the pathophysiologic mechanism involved 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 management of hypercalcemia involves correction of excessive bone resorption and adequate fluid administration to correct volume deficits.

• Pamidronate disodium and zoledronic acid are two drugs that can be used to manage hypercalcemia of malignancy by inhibiting bone resorption.
• The choice of treatment depends on the underlying pathophysiologic mechanism involved, which can be either humoral hypercalcemia or hypercalcemia due to tumor invasion of bone.
• It is essential to monitor serum calcium levels and adjust treatment accordingly, taking into account the presence of hypoalbuminemia, which can affect the accuracy of serum calcium measurements 2 3.

From the Research

Management of Hypercalcemia

• Hypercalcemia is a common disorder that can be caused by primary hyperparathyroidism (PHPT) or malignancy, and its management is crucial to prevent significant mortality 4.
• The emergency management of hypercalcemia is based on intravenous rehydration with normal saline, and when this is inadequate, bisphosphonate therapy is used 4.
• A study found that saline hydration, furosemide, and zoledronic acid can be used to manage severe hypercalcemia secondary to PHPT, with zoledronic acid being more potent in reducing serum calcium levels 5.
• The use of intravenous bisphosphonates, such as pamidronate and zoledronic acid, is effective in treating hypercalcemia, but their safety in patients with preexisting renal dysfunction needs to be considered 6.
• A retrospective analysis found that the use of intravenous bisphosphonates in patients with baseline renal dysfunction was associated with increased rates of serum creatinine elevations, but the overall efficacy of the treatment was not significantly affected 6.

Treatment Options

• Normal saline hydration is the first line of treatment for hypercalcemia, and it can help reduce serum calcium levels 5.
• Furosemide can be used in conjunction with saline hydration, but its effectiveness in reducing serum calcium levels is limited 5.
• Zoledronic acid is a potent bisphosphonate that can be used to treat hypercalcemia, and it has been shown to be effective in reducing serum calcium levels and normalizing calcium levels in patients with PHPT 5.
• Denosumab is a novel anti-resorptive agent that has been shown to have a useful role in the treatment of hypercalcemia 4.

Special Considerations

• Patients with preexisting renal dysfunction need to be carefully monitored when treated with intravenous bisphosphonates, as they are at risk of developing serum creatinine elevations 6.
• The use of intravenous bisphosphonates in patients with renal dysfunction requires careful consideration of the potential risks and benefits, and alternative treatment options may need to be considered 6.