What is the treatment for Hypercalcemia?

From the Guidelines

Hypercalcemia should be treated with hydration, bisphosphonates, denosumab, steroids, and/or calcitonin, with zoledronic acid being the preferred bisphosphonate. The treatment approach depends on the severity and underlying cause of hypercalcemia. For mild cases, increasing fluid intake and addressing the underlying cause may be sufficient. However, for moderate to severe hypercalcemia, initial management includes aggressive IV fluid rehydration with normal saline at 200-300 mL/hour to promote calcium excretion, followed by loop diuretics like furosemide 20-40 mg IV after adequate hydration to enhance calcium elimination 1.

Bisphosphonates are first-line medications for hypercalcemia of malignancy, with zoledronic acid 4 mg IV over 15 minutes being the most effective option, as preferred by the NCCN MM Panel members 1. Calcitonin 4-8 IU/kg SC/IM every 12 hours provides rapid but short-term calcium reduction. For severe or refractory cases, dialysis may be necessary. Cinacalcet 30-90 mg daily is useful for hyperparathyroidism-related hypercalcemia. Glucocorticoids like prednisone 40-60 mg daily can help in cases caused by granulomatous diseases or certain malignancies.

The importance of treating hypercalcemia cannot be overstated, as elevated calcium levels can cause cardiac arrhythmias, kidney stones, neurological symptoms, and in severe cases, coma and death. Definitive treatment always requires addressing the underlying cause, which commonly includes hyperparathyroidism, malignancy, or medication effects. The NCCN guidelines provide a comprehensive approach to managing hypercalcemia, emphasizing the need for prompt and effective treatment to prevent long-term complications 1.

Key considerations in the treatment of hypercalcemia include:

• Aggressive hydration and diuresis to enhance calcium excretion
• Use of bisphosphonates, such as zoledronic acid, as first-line therapy for malignancy-related hypercalcemia
• Consideration of calcitonin, cinacalcet, and glucocorticoids in specific clinical contexts
• Addressing the underlying cause of hypercalcemia to prevent recurrence and long-term complications.

From the FDA Drug Label

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3. 0 mmol/L]) is 4 mg. The 4 mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i. e., saline hydration, with or without loop diuretics).

Hypercalcemia Treatment with Zoledronic Acid:

• The recommended dose is 4 mg as a single-dose intravenous infusion over no less than 15 minutes.
• Patients should be adequately rehydrated prior to administration.
• Serum creatinine should be assessed prior to each treatment.
• Conservative measures such as saline hydration, with or without loop diuretics, may be used for mild or asymptomatic hypercalcemia.
• Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment, with a minimum of 7 days between treatments 2, 2.

From the Research

Hypercalcemia Treatment Overview

• Hypercalcemia is a condition that affects approximately 1% of the worldwide population, with mild cases often being asymptomatic and severe cases causing symptoms such as nausea, vomiting, and confusion 3.
• The treatment of hypercalcemia depends on the underlying cause, with primary hyperparathyroidism (PHPT) and malignancy being the most common causes, accounting for approximately 90% of cases 3, 4, 5.

Treatment Approaches

• Mild hypercalcemia usually does not require acute intervention, but in cases of PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement 3.
• Initial therapy for symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate 3, 4, 5, 6.
• Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption, such as in vitamin D intoxication, granulomatous disorders, or some lymphomas 3, 4, 5.
• Denosumab and dialysis may be indicated in patients with kidney failure 3, 4.

Specific Treatment Options

• Zoledronic acid has been shown to be effective in reducing serum calcium levels in patients with severe hypercalcemia secondary to PHPT, with a mean maximal reduction of 0.57 ± 0.27 mmol/L 6.
• Furosemide may not have a significant additional effect on calcium levels in patients with severe hypercalcemia secondary to PHPT when compared to saline hydration alone 6.
• Calcitonin is preferable for short-term control of severe hypercalcemia, while bisphosphonates are considered the drugs of choice for long-term management 4, 5.

General Principles

• Treatment of hypercalcemia should be started with hydration, and loop diuretics may be required in individuals with renal insufficiency or heart failure to prevent fluid overload 4, 5.
• The underlying cause of hypercalcemia should be identified and treated, and treatment reduces serum calcium and improves symptoms, at least transiently 3, 4, 5.