Hypercalcemia and Malignancy
Pp. 28-37 (10)
Umberto Basso, Anna Roma and Antonella Brunello
Hypercalcemia arising in cancer patients is usually referred to as malignancy-associated
hypercalcemia (MAH). It may complicate early or, more often, late phases of the disease with a
prevalence of around 5-30% of all patients with different types of cancer. However, the prophylactic
use of bisphosphonates to prevent skeletal events in patients with bone metastases, has probably
reduced the occurrence of clinically symptomatic MAH. The most frequent cause of MAH is
abnormal production of a parathyroid hormone-related protein (PTHrP), which mimics the effects of
parathyroid hormone, increasing bone resorption and, especially, renal tubular calcium reabsorption.
Other causes may be bone lysis due to several cytokines and mediators released by the cancer cells
in the bone or the ectopic production of 1,25(OH)2 vitamin D3 in tumor tissue. Periodical
monitoring of serum ions in cancer patients usually unveils the onset of MAH before the appearance
of the classical symptoms (headache, confusion, de-hydration), prompting adequate treatment
consisting in hydration, diuretics, bisphosphonates and, whenever possible, treatment of the
underlying cancer (usually with systemic chemotherapy). Bisphosphonates are a class of compounds
which have all shown to decrease serum calcium levels primarily by inhibition of PTH-dependent
osteoclast activation. Although, the antiresorptive potency is higher with late generation compounds
(pamidronate, zolendronate, ibandronate) compared to older oral compounds. Agents able to
interfere with the receptor activator of nuclear actor-κ ligand (RANKL) pathway such as the
monoclonal antibody denosumab represent novel and promising strategies for the treatment of MAH
which are currently undergoing experimental and clinical assessment.
Istituto Oncologico Veneto (IOV) IRCCS, 35128 Padova, Italy.