Gideon A. Rodan

Bone is a frequent site of metastases of the most common tumors, e.g., breast carcinoma and prostate carcinoma. The functions of the skeleton, calcium homeostasis and mechanical support, are carried out by the continuous destruction and rebuilding of small packets of this tissue called bone remodeling. Multinucleated, hemopoietically derived osteoclasts, which are related to macrophages, digest the bone, and mesenchymal-derived osteoblasts rebuild it. This process is kept in balance by finely regulated processes whereby osteoblast lineage cells respond to homeostatic signals and release factors that regulate osteoclast generation and activity. Cells that participate in inflammation and immunity also can stimulate osteoclast formation and lead to bone destruction. Tumor cells most likely subvert these physiologic processes to lodge in bone and cause metastases. Cancer 2003;97(3 Suppl):726–32. © 2003 American Cancer Society. DOI 10.1002/cncr.11147

The functions of bone(s) are (i) mechanical support of soft tissues, (ii) levers for muscle action, (iii) protection of the central nervous system, (iv) release of calcium and other ions for the maintenance of a constant ionic environment in the extracellular fluid, and (v) housing and support of hemopoiesis. The structure and amount of bone, both at the macroscopic and microscopic level, are determined by the genetic blueprint and by regulatory factors that help carry out bone functions. Genetic information is responsible for the highly conserved anatomical shape of bones and most likely for restoring that shape after fracture. To accomplish its functions, bone undergoes continuous destruction, called resorption, carried out by osteoclasts, and formation by osteoblasts. In the adult skeleton, the two processes are in balance, maintaining a constant, homeostatically controlled amount of bone. This fact, as well as the histological observation that osteoclastic bone resorption is followed by osteoblastic bone formation (1), led to the concept that the two processes are mechanistically “coupled” and to the search for “coupling factors.” No single factor has been proven to link the two processes. Existing evidence suggests that multiple factors probably are involved in the maintenance of bone homeostasis. Growth factors found in bone (2), such as IGFs or TGFβs, were proposed to be released during resorption and initiate local bone formation (3, 4). Factors deposited on the bone surface by osteoclasts at the end of the resorption phase were proposed to initiate the bone formation that follows (5). Humoral factors, such as parathyroid hormone and prostaglandin …

▪ Abstract Bisphosphonates (BPs) are pyrophosphate analogs in which the oxygen bridge has been replaced by carbon and diverse carbon side chains have generated a large family of compounds. Several are potent inhibitors of bone destruction (resorption) and are in clinical use for the treatment and prevention of osteoporosis, Paget's disease, hypercalcemia caused by malignancy, tumor metastases in bone, and other bone ailments. Selective action on bone is based on the binding of the BP moiety to the bone mineral. The molecular mode of action of BPs, which may differ from compound to compound, is unknown. However, at the tissue level, all BPs inhibit bone destruction and lead to an increase in bone mineral density by decreasing bone resorption and bone turnover. At the cellular level, the ultimate target of BP action is the osteoclast, the bone resorbing cell. In vitro evidence shows BP inhibition of osteoclast formation, via action on osteoblasts, and there is in vitro and in vivo evidence for BP inhibition of osteoclast activity. There is in vivo and in vitro evidence for increased apoptosis. The relative contribution of these various effects on the therapeutic action of BPs remains to be established. At the molecular level, it is not known if BPs act on a single or multiple targets. Enzymes in the cholesterol biosynthesis pathway and protein tyrosine phosphatases were shown to be inhibited by BPs.