Diagnose and Treat Hypercalcemia of Malignancy

July 15, 2021 by Zac Pitts MSN, NP-C

Hypercalcemia of malignancy (HCM) is a common (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505545/) paraneoplastic syndrome associated (https://www.sciencedirect.com/science/article/abs/pii/S000991201200210X?via%3Dihub=) with poor prognosis that affects (https://www.najms.org/article.asp?issn=1947-2714%3Byear%3D2015%3Bvolume%3D7%3Bissue%3D11%3Bspage%3D483%3Bepage%3D493%3Baulast%3DMirrakhimov) approximately 20%–30% of patients with cancer. It’s most often seen (https://onlinelibrary.wiley.com/doi/10.1002/cam4.749) in patients with breast, lung, renal, or ovarian cancers; squamous cell carcinoma of the head and neck; multiple myeloma; and certain lymphomas.


Elevated calcium levels can result in life-threatening outcomes, but HCM is typically manageable with early diagnosis. Regularly monitoring calcium levels is critical, but practitioners must recognize (https://www.ncbi.nlm.nih.gov/books/NBK482423) that it may fluctuate with albumin levels because 40%–45% of serum calcium is bound to albumin, so measure serum albumin or ionized calcium levels as well.

Oncology nurses and advanced practice RNs (ARPNs) alike should be familiar with the four most common etiologies that lead to HCM: humoral, osteolytic, vitamin D–secreting lymphomas, and ectopic parathyroidism. Humoral HCM accounts for an estimated 80% of cases and is attributed (https://www.nejm.org/doi/full/10.1056/NEJMcp042806) to malignant tumors secreting parathyroid hormone–related protein (PTHrP). Elevated PTHrP increases osteoclast activity and bone resorption with subsequent release of calcium into the blood.

Osteolytic HCM is behind an estimated 20% of HCM cases and is related to malignant cells in the bone marrow. Inflammation in the marrow increases osteoclast activity and leads to an excess of calcium. Osteolytic HCM is common in malignancies with bone metastasis and multiple myeloma.

Vitamin D–secreting lymphomas are rare (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505545/) with incidence rates of less than 1%. They cause hypercalcemia by increasing absorption in the gastrointestinal tract and decreasing renal calcium excretion. HCM from ectopic hyperparathyroidism stems (https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21489) from increased PTH levels, and its pathway (https://www.nejm.org/doi/full/10.1056/NEJMcp042806) is very similar to humoral HCM.

Diagnosis and Work-Up

HCM can affect (https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21489) multiple organ systems through several clinical manifestations. Kidney involvement can lead to nephrolithiasis and chronic renal insufficiency. Patients may develop polyuria from calciuresis that can lead to hypovolemia when compounded by decreased oral intake.

Cardiac manifestations range from electrocardiogram abnormalities to cardiac arrest. Gastrointestinal symptoms include nausea, vomiting, and constipation; the latter may be a result of calcium’s influence on smooth muscle. Effects on the central nervous system can range from confusion to coma. Mild neurocognitive dysfunction occurs (https://www.najms.org/article.asp?issn=1947-2714%3Byear%3D2015%3Bvolume%3D7%3Bissue%3D11%3Bspage%3D483%3Bepage%3D493%3Baulast%3DMirrakhimov) more frequently in hyperparathyroidism and may result (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505545/) from the effects of parathyroid hormone on the brain. When hypercalcemia is caused by a resorptive process, patients may present (https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21489) with pathologic fractures.

Because an incidental finding of hypercalcemia may be the first sign of an undiagnosed cancer, the work-up should not stop after HCM diagnosis. APRNs should take relevant history (https://www.najms.org/article.asp?issn=1947-2714%3Byear%3D2015%3Bvolume%3D7%3Bissue%3D11%3Bspage%3D483%3Bepage%3D493%3Baulast%3DMirrakhimov) and ask about recent or persistent cough, weight loss, or new masses. Zagzag et al. developed an algorithm (https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21489) to aid clinicians in the initial work-up of a patient presenting with hypercalcemia.

Clinical Management

Because patients presenting with HCM are typically hypovolemic, the first step is IV hydration, usually with normal saline. Either concurrently or after, initiate (http://journal.fk.unpad.ac.id/index.php/mkb/article/view/283) bisphosphonate therapy. Zoledronic acid 4 mg IV over 15–30 minutes is the bisphosphonate of choice; it inhibits (https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21489) osteoclasts from attaching to actin-binding sites, promotes apoptosis, decreases osteoclast recruitment and development, and increases expression of a RANKL decoy receptor.

Onset of action may take one to three days, with a calcium nadir occurring in four to seven days. Bisphosphonates are associated with nephrotoxicity and may need to be delayed in patients with impaired renal function secondary to HCM until it improves.

Denosumab was approved by the U.S. Food and Drug Administration in 2014 for the treatment of HCM and works by decreasing osteoclast resorption of bone. Other options for therapy include corticosteroids, calcitonin, and dialysis.

In 2021, O’Callaghan and Yau proposed (https://ec.bioscientifica.com/view/journals/ec/10/1/EC-20-0487.xml) cinacalcet as potential agent in the treatment of HCM. Although not approved for the indication, it can safely reduce calcium levels in patients with compromised renal function. Cinacalcet was approved in 2004 for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, hypercalcemia in patients with parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are ineligible for parathyroidectomy. The researchers cited PTH and PTHrP’s shared homology and hypothesized that cinacalcet’s ability to control PTH-mediated hypercalcemia may also translate to HCM, particularly humoral.

HCM in patients with cancer can be from the malignancy itself or other benign etiologies. PTH lab values are critical to guide treatment. Although palliative IV fluids and bisphosphonate therapy is the mainstay of initial treatment, addressing the underlying malignancy is the best chance at long-term management.

Copyright © 2021 by the Oncology Nursing Society. User has permission to print one copy for personal or unit-based educational use. Contact pubpermissions@ons.org for quantity reprints or permission to adapt, excerpt, post online, or reuse ONS Voice content for any other purpose.