Bisphosphonates breast cancer

For women whose breast cancer has metastasized to bone, bisphosphonates are recommended, in addition to chemotherapy or endocrine therapy, to reduce bone pain and fractures.28,64 Pamidronate (90 mg) and zoledronate (4 mg) can be given intravenously once each month. These bisphosphonates are given in combination with calcium and vitamin D. 

Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003 21 4042-4057. 

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]. 

AP23451 administration to mice inoculated with MDA-231 breast cancer cells effectively prevents metastasis-induced osteolysis similar to bisphosphonate zoledronic (Zometa ). However, it also significantly reduces the volirme of tumor cells inside the bone marrow cavities of the mice as opposed to a lack of inhibitory effect on tirmor cell volume in mice treated with zoledronic acid. AP23588 is also a bone-targeted Src kinase inhibitor which has been determined to possess both anti-resorptive and anabohc properties in vitro with respect to reducing osteoclast activity and stimulating osteoblast activity, respectively. 

Aromatase inhibitors increase bone turnover by near complete estrogen depletion, leading to reduced bone mineral density and an increased risk of fractures. Bisphosphonates plus calcium and vitamin D supplementation mitigate this (26). In an open, multicenter, randomized study in 602 women with early-stage breast cancer taking letrozole 2.5 mg/day, zoledronic acid 4 mg every 6 months prevented bone loss (27). 

Pavlakis N, Schmidt R, Stockier M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2005 CD003474. 

Continued treatment with bisphosphonate may also be appropriate to not only reduce the likelihood of recurrent hypercalcaemia but also to manage Mrs CR s bone metastases. Many guidelines (including the NICE Improving outcomes guidance for breast cancer, 2002a) recommend the use of bisphos-phonates to reduce the onset of skeletal complications such as skeletal fractures. An appropriate suggestion would be to continue one of the bisphosphonates previously outlined at three-weekly intervals (to coincide with chemotherapy administration). 

Walter, C., Al-Nawas, B., du Bois, A., Buch, L., Harter, P., and Grotz, K.A. (2009). Incidence of bisphosphonate-associated osteonecrosis of the jaws m breast cancer patients. Cancer 115 1631-1637. 

Senaratne, S.G., Mansi, J.L., and Colston, K.W. (2002). The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells. Br J Cancer 86 1479-1486. 

Sasaki, A., Boyce, B. R, Story, B., Wright, K. R., Chapman, M., Boyce, R., Mundy, G. R. and Yoneda, T. (1995). Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res. 55, 3551-3557. 

Bone pain, including cancer metastases, requires NSAIDs alone and with opioids. Bisphosphonates, e.g. sodium pamidronate, sodium clodronate, relieve pain from osteolytic bone metastases from breast cancer and multiple myeloma. 

Uses. Three bisphosphonates (alendronate, etidronate, risedronate) are currently licensed in the UK for the treatment of osteoporosis (zoledronate is also effective), and the others are used in Paget s disease of bone, and hypercalcaemia due to cancer (pamidronate, clodronate, zoledronate). Bisphosphonates may also provide benefit for neoplastic disease that has spread to bone evidence indicates that clodronate by mouth and pamidronate i.v. are effective in the secondary prevention of bone metastases due to multiple myeloma and breast cancer. 

Bisphosphonates are widely used for the prevention and treatment of osteopenia and osteoporosis and for the reduction of skeletal complications in patients with malignant bone disease. Several oral bisphosphonates, including alendronate, risedronate, and ibandronate, are approved worldwide for the treatment of osteoporosis in postmenopausal women, as are intravenous (i.v.) formulations of ibandronate (3 mg quarterly) and zoledronic acid (5 mg annually). Several i.v. bisphosphonates are available for the treatment of the skeletal complications that frequently occur in malignant disease, such as hypercalcaemia of malignancy (HCM), multiple myeloma, and bone metastases associated with solid tumours. Pamidronate is approved worldwide for the treatment of HCM, multiple myeloma, and breast cancer bone metastases. Although not registered for oncology indications in the United States, i.v. ibandronate is widely available elsewhere for HCM and breast cancer bone metastases. 

American Society of Clinical Oncology (ASCO) http //www.asco.org Clinical practice guidelines for chemotherapy and radiotherapy protectants, hematopoietic colony-stimulating factors, antiemetics, bisphosphonates in breast cancer, and treatment of selected neoplastic diseases. 

Several reviews have also been published regarding the management of pain caused by bone metastases. The most recent advances include the utilization of the bisphosphonates and new radioactive compounds. The American Society of Clinical Oncology (ASCO) published clinical guidelines for the use of bisphosphonates in breast cancer in 2000. " ... 

Clinical Oncology Guidelines on the role of bisphosphonates in breast cancer. J. Clin. Oncol. 2000, 18 (6), 1378-1391. 

Raloxifene adversely affects hot flnshes, but it is likely to be used for osteoporosis prevention. Eor women with a history of breast cancer or thromboembolic disease, alternative means of redncing the risk of osteoporosis, such as bisphosphonates, should be considered. 

Raloxifene is an alternative treatment option to prevent vertebral fractures, particularly in women who cannot tolerate or will not take bisphosphonates. It may also be useful for women who have a history of breast cancer or a significant risk for developing breast cancer (investigational). 

Oura S, Tanino H, Yoshimasu T, et al Bisphosphonate therapy for bone metastases from breast cancer ... 

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. 

Van Poznak CH. The use of bisphosphonates in patients with breast cancer. Cancer Control 2002 9 480-489. 

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). 

The prevalence of osteonecrosis of the jaw has been studied in 75 patients with breast cancer taking bisphosphonates for osseous metastases [14 ]. Four patients (5.3%) developed osteonecrosis three had used zoledronate only and one had first used pamidronate followed by zoledronate and ibandronate. Tooth extraction was identified as a trigger factor for osteonecrosis in two patients. 

The incidence and susceptibihty factors in cases of bisphosphonate-induced osteonecrosis of the jaw have been studied in patients with breast cancer and gynecological mahgnancies [16 ]. Of 345 patients, 10 (2.9%) developed osteonecrosis while taking bisphosphonates. Six had a history of... 

In general, the ideal patient for SIRT has liver-dominant disease only (Table 2.7.3). Extrahepatic disease may be present, but should not determine the patient s survival. Atypical example of this situation is a patient with hepatic breast cancer metastases - a rising indication beside the approved indications in HCC and colorectal cancer metastases - where often additional bone metastases are present but under clinical control by a bisphosphonate and hormone therapy for example. Nevertheless, one must always be aware that SIRT is a hepatic-directed treatment that does not affect extrahepatic disease (Fig. 2.7.1). 

Boissier, S., Ferreras, M., Peyruchaud, O., Magnetto, S., Ebetino, F.H., Colombel, M., Delmas, P., Delaisse, J.M., and Clezardin, P. (2000). Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60 2949-2954. 

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