BONE AND CANCER - PATHOPHYSIOLOGY AND TREATMENT OF METASTASES

The variability of different primary tumors in the susceptibility to metastatic bone disease is poorly understood, Factors that determine the viability of metastatic cells are also poorly understood, but may depend in part upon gene expression of PTHrP and the vitamin D receptor, In contrast, much more is known of the manner in which metastatic disease affects bone remodeling to induce osteolytic bone disease, Mechanisms include a generalized increase in activation frequency at sites close to metastatic tissue, an imbalance between the amount of bone formed and that resorbed within resorption cavities, and uncoupling of bone formation from bone resorption, The greatest morbidity from metastatic bone disease arises from osteolytic disease and gives rise to hypercalcemia, bone pain, and fractures, Because osteolysis is primarily mediated by the activation of osteoclasts, there has been a great deal of interest in the use of agents which primarily affect bone metabolism to alter the natural history of metastatic bone disease, Nonsteroidal antiinflammatory agents and cytotoxic agents are capable of inducing responses in bone, but are limited by their toxicity when effective doses are utilized, The use of calcitonin in the longterm suppression of osteolysis has also been disappointing, The bisphosphonates are, however, capable of inducing sustained decreases in osteoclast activity and numbers in patients with osteolytic bone disease, There are now several studies which have examined the effects of the bisphosphonates on skeletal morbidity in breast cancer, Both clodronate and pamidronate decrease the incidence of hypercalcemia, bone pain, and pathological fractures, but do not significantly alter mortality, Given, however, the unchanging survival in patients with metastatic bone disease, significant improvements in the quality of remaining life is an important therapeutic effect.