VA AM Report 2.5.18: Hypercalcemia of malignancy

Case summary: Thanks to Max for presenting the case of a 64M with PMH squamous cell carcinoma of the lung s/p LUL lobectomy, who presented with several months of weight loss, fatigue, and mental “fuzziness.” He was found to have hypercalcemia with elevated PTHrp AND 1,25OH vit D, as well as new liver lesions and colonic narrowing on CT A/P.

Top pearls:

  1. Gerald Hsu pearl: in patients with prior cancer, especially lung, who have had only local therapy, the most likely site of recurrence is metastatic. Thus, in working up recurrence, these patients should get more extensive imaging (e.g. CT A/P and brain MRI–especially if ANY neurologic symptoms– in addition to local imaging like CT chest).
  2. Recall that there are multiple mechanisms of hypercalcemia in malignancy:  PTHrp (~80%, squamous cell cancers), bone osteolysis (~20%, extensive bone mets, especially multiple myeloma and breast), extrarenal 1,25(OH)2D (~1%, mostly lymphomas). Patients can have multiple mechanisms at once and can have non-malignant etiologies as well.
  3. Denosumab– a RANKL monoclonal antibody– is the new(ish) kid on the block for hypercalcemia, especially for patients with hypercalcemia refractory to bisphosphonates.

Hypercalcemia of malignancy: deep cuts

  • 1/3 of cancer patients develop hypercalcemia
    • 4x more common in stage IV cancer.
  • The most common malignancies associated with hypercalcemia are:
    • lung cancer
    • multiple myeloma
    • renal cell carcinoma.
    • breast
    • colorectal cancers
    • lowest rates are in prostate cancer
  • Hypercalcemia is associated with a very poor prognosis
    • Thirty-day mortality 50%
    • In-hospital mortality rate 6.8%
  • Lab patterns in malignancy-associated hypercalcemia (NB: this patient had BOTH mildly positive PTHrP and very elevated 1,25OH vit D– a rare combination):


Denosumab: the new(ish) kid on the block

  • Overarching schema for treating hypercalcemia: recall that treating the underlying driver (e.g. the malignancy) is also an important component in addition to calcium-targeted therapies.


  • Denosumab mechanism of action:
    • Tumors produce cytokines that impair the RANK/RANKL interaction and promote excess osteoclast activation and enhanced bone resorption
    • Denosumab is a human monoclonal antibody to RANKL; hence it will reduce the osteoclast activity and bone resorption.
  • Denosumab is more effective than zoledronic acid in delaying or preventing hypercalcemia of malignancy in patients with advanced cancer
  • It is also effective in hypercalcemia refractory to bisphosphonates.
  • It is dosed SQ and given ~1-2 weeks and then monthly
  • Unlike bisphosphonates, it’s safe to use in renal failure, as it’s not renally cleared, but should be dose-reduced to prevent hypocalcemia

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