Rotation Prep

Published July 10, 2019


Hypercalcemia occurs in 20% to 30% of patients with malignancy. Common cancer culprits include multiple myeloma, breast cancer, squamous-cell carcinoma, renal-cell carcinoma, bladder cancer, and lymphoma.

The four main etiologies of hypercalcemia of malignancy are:

  • increase in osteoclastic bone resorption

  • humoral hypercalcemia of malignancy (HHM) — caused by systemic secretion of parathyroid hormone (PTH)–related protein (PTHrP)

  • secretion of the active form of vitamin D (1,25-dihydroxyvitamin D [1,25(OH)2D]) by some lymphomas

  • ectopic secretion of authentic PTH (rare)

The following table lists types of hypercalcemia associated with cancer:



Hypercalcemia of malignancy is usually diagnosed with ionized calcium levels because total serum calcium levels are not always accurate, even after adjustment for albumin. PTH, phosphorous, and vitamin D (at least 25-hydroxyvitamin D, and possibly 1,25-dihydroxyvitamin D) should also be measured routinely. Make sure to consider nonmalignant causes (e.g., hyperparathyroidism, thiazide diuretics) that may be contributing to the condition.


Treatment of the underlying malignancy in addition to the following treatment for acute symptomatic hypercalcemia:

  • Aggressive intravenous fluid hydration is usually done at a rate of 200–500 mL/hr but depends on the patient’s hydration state (target urine output of approximately 2 mL/kg/hr).

  • Loop diuretics (furosemide) can also be used but only after the patient is adequately hydrated.

  • Intravenous (IV) bisphosphonates (zoledronic acid or pamidronate, adjusted for presence of renal dysfunction) should be given immediately because they can take up to 2 days to work.

  • Other medications include: glucocorticoids (however, these can obscure the diagnosis, so avoid use up front); calcitonin (beware of development of tachyphylaxis after several days of use; can be used as a “bridge” until bisphosphonates start working); and denosumab (a receptor activator of nuclear factor kappa-B [RANK]–ligand inhibitor).

  • Dialysis is the last resort.

The following table lists pharmacologic options for treating hypercalcemia associated with cancer:


This guideline provides guidance for the nonspecialist through the initial phase of assessment and management of acute hypercalcemia.

For information on management of hyponatremia, see Disorders of Sodium Concentration in the Endocrinology Rotation Guide.

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