NEJM: How to Treat Cancer-Associated Hypercalcem

Written by Laura Murphy

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Cancer-associated hypercalcemia requires prompt recognition and treatment in the ED, starting with aggressive rehydration +/- loop diuretics as well as coordination of initiation of bone resorption inhibition, which can take up to 48 or longer hours to have a full effect.

Why does this matter?
Hypercalcemia complicates the course of ~30% of patients with cancer, and it portends a poor prognosis. It is important for emergency physicians to recognize this condition and initiate treatment for these patients in the ED.

Breaking the vicious cycle
Hypercalcemia is most common with non-small cell lung cancer, breast cancer, multiple myeloma, squamous cell head and neck cancer, urothelial cancers or ovarian cancers; it occurs late in solid tumor progression and is associated with a poor prognosis. The mechanism is generally increased osteoclastic resorption as a result of tumor factors overwhelming calcium and bone homeostasis. Humoral mechanisms are most common in squamous tumors of lung, head, and neck, urothelial carcinomas, breast cancers, often with few or no bone metastases. Tumors secrete cytokines, most commonly parathyroid hormone related peptide (PTHrP), which increase bone resorption and renal tubular reabsorption. In cancers with extensive metastatic bone disease or multiple myeloma, local cytokines lead to bony infiltration and increase osteoclastic bone resorption and cause hypercalcemia.

In patients presenting with hypercalcemia, it is important to determine the cause and suspect malignancy. Remember to correct calcium levels for albumin or use ionized calcium level and to consider other causes. Common symptoms include nausea, vomiting, anorexia, constipation, weakness, bone pain, and in severe cases, confusion and altered mental status.


  1. Hydration and Saline NatriuriesisSignificant dehydration/volume depletion results from symptoms of nausea, vomiting, anorexia and nephrogenic diabetes insipidus. Administration of IV hydration (usually normal saline) is the first step, as delivery of saline to renal tubules increases calcium excretion. The use of loop diuretics has not been shown to reduce calcium levels faster than use of fluids alone and may worsen dehydration, so they should be used cautiously only after aggressive fluid resuscitation. These may be important for patients at risk of volume overload. This can lower serum calcium levels by 1-2 mg/dL, but the effect is only transient unless other therapies are initiated.
  2. Inhibition of Bone ResorptionThis is the mainstay of therapy but can take 24 hours or more to be effective. Bisphosphonates are generally the first line treatment; 4 mg of IV zolendronate is the preferred regimen and is administered every 3-4 weeks. These medications can worsen renal insufficiency, so do not start these in patients who are volume depleted or have low creatinine clearance. There are alternative therapies which can be used in patients with bisphosphonate resistance or who need additional therapies (e.g. denosumab, glucocorticoids, calcitonin, cinacalcet). Calcitonin is sometimes used for very high levels while awaiting for more prolonged onset of action of antiresorptive agents.

Take-home: Cancer-associated hypercalcemia is a dangerous finding and requires initiation of treatment in the ED. Many of these patients will require admission for initiation of longer-term antiresorptive therapy so that more definitive cancer treatment can be initiated.

Cancer-Associated Hypercalemia. N Engl J Med 2022; 386: 1443-51. DOI 10.1056/NEJMcp2113128

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