Prostate cancer bisphosphonates

Bisphosphonates such as pamidronate and zoledronic acid may prevent skeletal morbidity, such as pathologic fractures and spinal code compression, when used for hormone-refractory prostate cancer in patients with clinically significant bone loss. Usual dosages are pamidronate, 90 mg every month, and zoledronic acid, 4 mg every 3 to 4 weeks. 

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]. 

Oades, G.M., Senaratne, S.G., Clarke, I.A., Kirby, R.S., and Colston, K.W. (2003). Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J Urol 170 246-252. 

English BC, Baum CE, Adelberg DE et al (2010) A SNP in CYP2C8 is not associated with the development of bisphosphonate-related osteonecrosis of the jaw in men with castrate-resistant prostate cancer. Ther Clin Risk Manag 6 579-583... 

Posadas EM, Dahut WL, Gulley J. The emerging role of bisphosphonates in prostate cancer. Am J Ther 2004 11 60—73. 

Miwa S., Mizokami A., Keller E. T., et al. (2005) The bisphosphonate YM529 inhibits osteolytic and osteoblastic changes and CXCR-4-induced invasion in prostate cancer. Cancer Res., 65, 8818-25. 

Zoledronic acid (zometa) is a bisphosphonate (see Chapter 61) indicated for the treatment of patients with bony metastases and for patients with MM. A direct antitumor effect on myeloma cells has been proposed some data suggest that inhibition of bone matrix-degrading proteinases may inhibit tumor ceU invasion in breast and prostate cancers. 

Our rationale is partly that prostate cancer is currently the most common non-skin cancer in America. It is estimated that in 2008, there will be 186,000 new cases of prostate cancer and 28,000 men will succumb to the disease (Prostate Cancer Foundation, 2008). Depending upon the staging of the disease, current therapies include hormonal treatments, radiotherapy, and radical prostatectomy. Those patients who have experienced relapse after hormonal therapy, are oftentimes in an advanced stage of disease and are treated with cytotoxics as docetaxel and mitox-antrone along with bisphosphonates (in the case of metastases) and radiation in case pain palliation is necessary. Unfortunately, these therapies can have major impacts on quality of life issues as side effects to therapies can often be severe (i.e. impotence). Clearly, new therapies directed towards managing or arresting the disease are necessary. 

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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