Role of Parathyroid Hormone Related Peptide (PTHrP) in Hypercalcemia of Malignancy and the Development of Osteolytic Metastases.

Hypercalcemia of malignancy carries an extremely grim prognosis. The most common mechanism underlying hypercalcemia of malignancy is production by the tumor cells of cytokines responsible for osteoclastic differentiation and, therefore, lysis of the bone adjacent to the tumor. A minority of cases are attributable to increased renal reabsorption of calcium caused by a humoral factor, termed parathyroid hormone-related peptide, which is produced by some primary tumors. These two mechanisms can be involved in conjunction, particularly in patients with breast cancer. The development of osteolytic metastases initiates a vicious cycle in which bone degradation products, especially growth factors, stimulate the growth of the tumor cells located at the bone-tumor interface. Parathyroid hormone-related peptide is produced by many malignant tumors, most notably those of the breast. In addition to its endocrine effect on the kidney, it may have a paracrine effect consisting of enhancement of osteoclastic differentiation with osteolysis of the bone adjacent to the tumor. Other factors produced by primary tumor cells, such as proteases, intercellular adhesion molecules, or bone matrix proteins, may influence the propensity for the tumor to produce bone metastases. Bisphosphonates are usually effective in inducing a remission of hypercalcemia of malignancy and in improving the clinical manifestations of osteolytic metastases. Elucidation of the factors that influence the propensity for malignancies to metastasize to bone would improve our ability to use bisphosphonates optimally as adjuncts to tumor therapy.