Osteolytic bone diseases

Osteolytic bone diseases or bone resorption the most important clinical application of BPs is as inhibitors of osteolytic bone diseases, including osteoporosis, tumor-related bone destruction, and Paget s disease. These are discussed in detail in the next section. 

Van Rooijen N (1993) Extracellular and intracellular action of clodronate in osteolytic bone diseases a hypothesis. Calcif Tissue Int 52 407... 

Bisphosphonates (BPs) are compounds belonging to an important therapeutic class for bone disease treatment (Paget s disease, metastatic and osteolytic bone disease and osteoporosis). Since the beginning of their clinical use in the late 1960s, the... 

Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that interfere with effector binding and thereby disrupt signal transduction. AP-22408 decreases bone resorption in animal studies and may be a promising drug to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Bone disease is a common manifestation of multiple myeloma. Bisphosphonates should be initiated in symptomatic patients with bone lesions to slow osteopenia and reduce the fracture risk associated with the disease. Pamidronate and zolendronic acid have equivalent efficacy in the management of osteolytic lesions, but because of relative ease of administration, zolendronic acid is used most frequently.43 The use of zolendronic acid decreases pain and bone-related complications and improves quality of life. The suggestion that bisphosphonates have direct antimyeloma activity, based on the ability to inhibit NF-kB signaling, remains controversial. Recent cases of osteonecrosis of the jaw have been a major concern. Risk factors are unclear, but osteonecrosis of the jaw is more common in patients receiving intravenous administration of bisphosphonates and having dental procedures performed. It is recommended that patients... 

Metastatic bone disease (MBD) is characterized by very high levels of bone turnover in regions proximal to the tumour [33]. Bone resorption inhibitors such as bisphosphonates represent the current standard of care for the treatment of bone metastases primarily due to breast or prostate cancer and multiple myeloma. It has been proposed that other strong anti-resorptives such as a Cat K inhibitor could be useful in the treatment of bone metastases. Evidence for this has been presented in the form of a preclinical MBD model in which human breast cancer cells are implanted into nude mice. Treatment with a Cat K inhibitor gave a significantly lower area of breast cancer-mediated osteolytic lesions in the tibia [34]. In a separate study, the efficacy of a Cat K inhibitor in the reduction in tumour-induced osteolysis was found to be enhanced in the presence of the bisphosphonate zolendronic acid [35,36]. When prostate cancer cells were injected into the tibia of SCID mice, treatment with a Cat K inhibitor both prevented and diminished the progression of cancer growth in bone [37]. 

Osteolytic tumors may induce bone destruction either through local invasion, or by a secondary metastatic bone disease. The most frequent types of primary tumors that develop into metastatic bone disease are, in the order of prevalence breast, prostate, thyroid, kidney, and bronchial tumors, whereas esophageal, gastrointestinal and rectal tumors are much less metastatic [11]. Very often, the destruction of bone in a metastatic bone disease leads to hypercalcemia of malignancy, which also responds to BPs. In addition, hematological cancers such as... 

This class of drugs is used to treat hypercalcemia in osteolytic bone cancer and metastasis in breast cancer, multiple myeloma, and Paget disease of the bone. It is used more frequently to inhibit bone resorption in postmenopausal women and therefore has the potential for widespread effects despite a relatively low risk of ADRs. 

Clodronate is a bisphosphonate that has demonstrated efficacy in patients with a variety of disorders of enhanced bone resorption, including Paget s disease, osteolytic bone metastases, and hypercalcemia of malignancy (8,9). In preclinical studies, clodronate prevented bone loss during immobilization (10). 

Pamidronate, a second-generation bisphosphonate, is 100-fold more potent than etidronate (Fig. 35.7) (6). It has been approved for the treatment of hypercalcemia of malignancy, for Paget s disease, and for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. When used to treat bone metastases, pamidronate decreases osteoclast recruitment, decreases osteoclast activity and increases osteoclast apoptosis (53). Erosive esophagitis has been reported with the use of pamidronate sodium. 

Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor used to treat hypercalcemia associated with malignancy and osteolytic bone lesions associated with multiple myeloma, metastatic breast cancer, and moderate to severe Paget s disease of bone. Aredia, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-l-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD). 

Pamidronate is one of the first drugs that has been proven to reduce the incidence of skeletal complications of metastatic breast cancer and prostate cancer. It also relieves bone pain caused by metastatic bone lesions. Other indications include treatment of osteolytic bone lesions of multiple myeloma, moderate-to-severe hypercalcemia of malignancy, and moderate-to-severe bone lesions due to Paget s disease. 

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