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Hypercalcemia Associated with Malignancy

Hypercalcemia Associated with Malignancy is a topic covered in the 5-Minute Clinical Consult.

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  • Hypercalcemia associated with malignancy is the most common cause of severe hypercalcemia diagnosed in a hospital setting.
  • Often a very poor prognostic sign
  • Occurs with both solid tumors and hematologic malignancies; most commonly associated with multiple myeloma and breast and lung cancer; also associated with metastases to bone


Hypercalcemia is diagnosed in 10–30% of all cancer patients during the course of illness, with an in-hospital mortality rate of 6.8%.

Etiology and Pathophysiology

  • Increased bone resorption is involved in most cases, caused by either extensive local bone destruction or humoral factors.
  • Nephrogenic diabetes insipidus induced by the hypercalcemia (1)
  • Osteolytic metastases-induced hypercalcemia: most commonly in breast cancer, multiple myeloma, lymphoma, and leukemia
  • Humoral hypercalcemia is most commonly associated with cancer, due to tumor secretion of parathyroid hormone (PTH)–related protein (rP), calcitriol, and prostaglandins, transforming growth factors, tumor necrosis factor (TNF), colony-stimulating factors, and interleukins.
  • PTH-rP increases expression of receptor activator of nuclear factor κB ligand (RANKL) in bone. RANKL binds to RANK on the surfaces of osteoclast precursors, resulting in differentiation into osteoclasts and leading to bone resorption and the development of hypercalcemia.
  • Ectopic PTH secretion is very rare but reported in ovarian carcinoma, neuroectodermal tumor, thyroid papillary carcinoma, lung cancer, rhabdomyosarcoma, and pancreatic cancer.
  • Calcitriol production: mostly reported in lymphoma and ovarian dysgerminomas
  • In multiple myeloma, the elevated serum calcium may be due to the binding of the monoclonal protein with calcium. Multiple myeloma also may cause impaired renal function that decreases calcium excretion.
  • In patients with active disease, ~20% have another cause of hypercalcemia than cancer itself.

Risk Factors

  • Dehydration
  • Immobilization

General Prevention

  • Encourage adequate hydration and activity, especially in patients with multiple myeloma.
  • In advanced cancer patients with bone metastasis, denosumab 120 mg subcutaneously every 4 weeks is more efficacious than zoledronic acid 4 mg IV every 4 weeks in delaying or preventing hypercalcemia of malignancy (2)[A].

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Stephens, Mark B., et al., editors. "Hypercalcemia Associated With Malignancy." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816100/all/Hypercalcemia_Associated_with_Malignancy.
Hypercalcemia Associated with Malignancy. In: Stephens MB, Golding J, Baldor RA, et al, eds. 5-Minute Clinical Consult. 27th ed. Wolters Kluwer; 2019. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816100/all/Hypercalcemia_Associated_with_Malignancy. Accessed April 19, 2019.
Hypercalcemia Associated with Malignancy. (2019). In Stephens, M. B., Golding, J., Baldor, R. A., & Domino, F. J. (Eds.), 5-Minute Clinical Consult. Available from https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816100/all/Hypercalcemia_Associated_with_Malignancy
Hypercalcemia Associated With Malignancy [Internet]. In: Stephens MB, Golding J, Baldor RA, Domino FJ, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2019. [cited 2019 April 19]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816100/all/Hypercalcemia_Associated_with_Malignancy.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Hypercalcemia Associated with Malignancy ID - 816100 ED - Stephens,Mark B, ED - Golding,Jeremy, ED - Baldor,Robert A, ED - Domino,Frank J, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816100/all/Hypercalcemia_Associated_with_Malignancy PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -