Hypercalcemia Associated with Malignancy



  • 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, renal, and lung cancer; also associated with metastases to bone


Hypercalcemia is diagnosed in 10–30% of all cancer patients during the course of illness depending on the type of tumor, with an in-hospital mortality rate of 6.8% (1).

Etiology and Pathophysiology

  • Increased bone resorption is involved in most cases, caused by either extensive local bone destruction or humoral factors.
  • Osteolytic metastases-induced hypercalcemia: This is commonly mediated by osteoclasts that are stimulated by many factors including cytokines produced by tumor cells; most commonly seen in breast cancer, multiple myeloma, other solid tumors with bone metastases, lymphoma, and leukemia
  • Humoral hypercalcemia of malignancy is most commonly due to tumor secretion of parathyroid hormone (PTH)-related protein (rP).
  • 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 among others.
  • Increased 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. In such cases, ionized calcium should be measured. 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 SC every 4 weeks is more efficacious than zoledronic acid 4 mg IV every 4 weeks in delaying or preventing hypercalcemia of malignancy (2).

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