Hypercalcemia is a relatively common disorder. Primary hyperparathyroidism and
malignancy-associated hypercalcemia (MAH) are responsible for more than 90% of all causes of
hypercalcemia. General measures of treatment include rehydration and loop diuretics, when renal
insufficiency or heart failure is associated. Calcitonin is indicated for the short-term control of
severe hypercalcemia, while bisphosphonates are required in the long-term management. The
antireabsorptive action of bisphosphonates has been considered the most effective in the disorders
characterized by an excessive bone resorption. Both clodronate and pamidronate have been widely
used in the past. Recently controlled clinical trials demonstrated the superiority of zoledronate
compared with previous treatments. The use of calcimimetic agents has been recently introduced to
control hypercalcemia in selected cases of primary hyperparathyroidism. They are used when
patients do not meet surgical criteria or surgery is not possible or accepted. Recent studies on
cancer-induced bone disease have highlighted the role of receptor activator of nuclear factor-κ
ligand (RANKL) as a critical effector of skeletal complications of malignancy. RANKL inhibitors
may reduce bone resorption in patients with bone metastases and multiple myeloma. Malignancyassociated
hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic
MAH. The former refers to the paraneoplastic release of humoral factors, mainly parathyroid
hormone-related peptide (PTHrP). A humanized monoclonal antibody against human PTHrP has
been generated. It is able to neutralize the PTHrP effects, reducing hypercalcemia in human tumor
xenograft animal models.
