From the Guidelines
The treatment for hypercalcemia of malignancy should start with aggressive hydration using intravenous normal saline, followed by the administration of zoledronic acid (4 mg IV over 15-30 minutes) as the preferred bisphosphonate, as recommended by the NCCN MM Panel members 1. This approach is based on the most recent and highest quality evidence available. The use of zoledronic acid is preferred due to its efficacy in reducing calcium levels and its safety profile.
- Initial therapy typically includes:
- Aggressive hydration with intravenous normal saline to dilute serum calcium and increase renal calcium excretion
- IV bisphosphonates, such as zoledronic acid, to inhibit bone resorption by osteoclasts
- Alternative treatments include:
- Denosumab (120 mg subcutaneously) for patients with renal impairment or those who don't respond to bisphosphonates, as it has been shown to lower serum calcium in 64% of patients within 10 days 1
- Calcitonin (4-8 IU/kg subcutaneously or IM every 12 hours) for rapid but short-term calcium reduction
- Loop diuretics like furosemide to enhance calcium excretion after adequate hydration is achieved
- Glucocorticoids, which are particularly effective in certain malignancies such as multiple myeloma and lymphomas
- In severe cases (calcium >14 mg/dL with neurological symptoms), hemodialysis may be necessary, and treating the underlying malignancy is crucial for long-term management, as emphasized in the NCCN guidelines 1. The approach works because hydration dilutes serum calcium and increases renal calcium excretion, while bisphosphonates and denosumab prevent further bone breakdown that releases calcium into the bloodstream.
From the FDA Drug Label
Zoledronic acid injection is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] 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. Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. 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).
Treatment for Hypercalcemia of Malignancy:
- Zoledronic Acid: 4 mg dose given as a single-dose intravenous infusion over no less than 15 minutes 2
- Denosumab: 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, for patients refractory to bisphosphonate therapy 3
- Conservative Measures: saline hydration, with or without loop diuretics, for mild or asymptomatic hypercalcemia
- Key Considerations:
- Vigorous saline hydration to restore urine output
- Monitoring of serum creatinine and calcium levels
- Avoidance of overhydration, especially in patients with cardiac failure
- Consideration of the severity and symptoms of tumor-induced hypercalcemia
From the Research
Treatment Options for Hypercalcemia of Malignancy
The treatment of hypercalcemia of malignancy is aimed at lowering serum calcium levels and managing symptoms. The following are some of the treatment options:
- Aggressive hydration with isotonic fluids to enhance renal calcium excretion 4, 5, 6, 7
- Bisphosphonate therapy, such as zoledronic acid, to inhibit bone resorption 4, 5, 7, 8
- Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand, for refractory disease or bisphosphonate-refractory hypercalcemia 4, 5, 7
- Calcitonin and corticosteroids as adjunctive therapies 5, 6
- Cinacalcet, a calcimimetic, for refractory disease 4
Mechanism of Treatment
The treatment of hypercalcemia of malignancy is based on the underlying cause of the condition. The majority of cases are humoral in etiology and related to parathyroid hormone-related protein (PTHrP) 4. Treatment is aimed at inhibiting bone resorption and increasing urinary calcium excretion.
Importance of Early Treatment
Early and appropriate treatment is key to successful outcomes in patients with hypercalcemia of malignancy 6. Continuous monitoring is also important to prevent potential adverse effects of treatment.
Prognosis
Despite the efficacy of treatment, hypercalcemia of malignancy portends an ominous prognosis, indicating advanced and often refractory cancer with survival on the order of months 4. The ultimate resolution of hypercalcemia of malignancy comes only from the treatment of the underlying malignancy 6.