New bisphosphonates in the treatment of bone metastases

Abstract

Normal skeletal integrity is maintained by physiological bone turnover through a coupled process of bone resorption, mediated by osteoclasts, followed by new bone formation, mediated by osteoblasts. Major features of the pathogenesis of cancer‐associated skeletal destruction are enhanced osteoclast‐mediated bone resorption and disruption of normal bone formation. In this article, the literature on the pathogenesis and clinical manifestations of metastatic bone disease is discussed. Animal and clinical trials investigating novel bone targeted agents, emphasizing the bisphosphonates, are critically assessed. The most frequent clinical manifestations of bone metastases are pain, fracture, immobility, spinal cord compression, and hypercalcemia. New treatments under study for patients with bone metastases include agents specifically targeted to the skeleton such as bone‐seeking radioisotopes and bisphosphonates. Studies in animal models of metastatic bone disease show that these bisphosphonates are able to inhibit tumor‐induced osteolysis and are potentially useful in this condition. Bisphosphonates have been investigated in several clinical trials of patients with skeletal metastases from breast cancer, prostate cancer, and multiple myeloma. Overall, the studies investigating bone targeted radioisotopes or bisphosphonates for the treatment of morbidity due to skeletal metastases have been inconclusive. An improved understanding of the pathogenesis of metastatic bone disease and preclinical studies with hisphosphonates suggest that these agents may have a role in the treatment of this disorder. Additional trials of new generation bisphosphonates, employing a rigorously controlled, randomized study design with adequate numbers of subjects, are needed to demonstrate the safety and efficacy of this class of agents in this setting.

Comparative evaluation of markers of bone resorption in patients with breast cancer-induced osteolysis before and after bisphosphonate therapy

“…On the other hand, bisphosphonates have become the standard treatment of tumour-induced hypercalcaemia (TIH) (Body et al, 1987;Body, 1992;Ralston, 1992), and they are increasingly used for the treatment of bone metastases as the essential pathogenic role of osteoclasts in tumour-induced osteolysis (TIO) is now well demonstrated (Averbuch, 1993;Body, 1993). Optimum therapeutic schemes remain, however, largely unknown (Averbuch, 1993;Body, 1993), and the use of biochemical parameters of bone turnover could be quite useful in the determination of such schemes.…”

“…Optimum therapeutic schemes remain, however, largely unknown (Averbuch, 1993;Body, 1993), and the use of biochemical parameters of bone turnover could be quite useful in the determination of such schemes. Moreover, biochemical markers could help provide a better understanding of the pathophysiology of TIO, notably the possible uncoupling between bone formation and bone resorption (Body, 1992).…”

Trafficking of Metastatic Breast Cancer Cells in Bone

“…With expansion of bone lesions, osteoblast numbers decrease in MDA-MB-231 as well. 9 Assuming that the essential elements of osteolytic metastasis are observed in multiple breast carcinoma models, the findings reported here have significant implications with regard to control of bone metastasis in the clinic.…”

“…Current methods to detect bone metastases are insufficiently sensitive (e.g., radiography) or are impractical for adequately statistically powered experiments because of costs or laborintensiveness. Radiography can detect osteolytic lesions only after more than half of the calcified bone matrix has been degraded (9). Microcomputerized tomography is not widely available, but is likewise of insufficient resolution to recognize single tumor cells.…”

Preventing Bone Complications in Advanced Prostate Cancer

“…A combination of radionuclides (sodium-32 P-phosphate, 89 Sr-chloride, 153 Sm-lexidronam, 186 Re-hedp), pain medication, and bisphosphonates is a potential form of treatment for pca patients 31 , potentially allowing for simultaneous treatment of multiple sites and occult disease. A recent phase ii trial addressed the benefit of radionuclides associated with standard chemotherapy in pca 32 .…”