Breast cancer cells frequently metastasize to the bone, where they cause severe degradation of bone tissue. Metastatic cancer affects more than half of all women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcemia (abnormally high levels of calcium in blood plasma), and spinal cord compression. The bisphosphonates, including alendronate (Fosamax), tiludronate (Skelid), pamidronate (Aredia), etidronate (Didronel), risedronate (Actonel), ibandronate, and zoledronic acid (Zometa), are a class of drugs that protect against the degradation of bone, primarily by inhibiting osteoclast-mediated bone resorption (bone breakdown).
Bisphosphonates are analogs of a naturally occurring compound, called pyrophosphate, which serves to regulate calcium and prevent bone breakdown. Bisphosphonates are a major class of drugs used for the treatment of bone diseases as they have a marked ability to inhibit bone resorption. Bisphosphonates are considered standard care for tumor-associated hypercalcemia and have been shown to reduce bone pain, improve quality of life, and to delay and reduce skeletal events (Hortobagyi 1996; Roemer-Becuwe et al. 2003).
The renewal of bone is responsible for bone strength throughout our life. Old bone is removed (resorption) and new bone is created (formation). This process is called bone remodeling. Healthy bone is continually being remodeled. Two main types of cells are responsible for bone renewal: the osteoblasts involved in bone formation and the osteoclasts involved in bone resorption. There are several stages involved in bone remodeling. The first is activation. This process involves preosteoclasts that are stimulated and differentiated under the influence of cytokine and growth factors to mature into active osteoclasts. The next step is resorption, in which osteoclasts digest mineral matrix (old bone). The third step is reversal, which ends resorption and signals for the final phase, formation. During this stage, osteoblasts are responsible for bone matrix synthesis (collagen production). Two other noncollagenous proteins are also formed: osteocalcin and osteonectin, together they form new bone.
In patients with bone metastases, bone resorption by the osteoclasts is increased and exceeds bone reformation. Calcium lost from the bones appears in increased amounts in the patient's blood serum and urine. This increase in bone resorption may result in pain, bone fractures, spinal cord compression, and hypercalcemia.
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