Bone Directed Therapies for Prostate Cancer

Purpose

Bone is the most common site of metastatic disease in prostate cancer and the lead cause of significant morbidity. Preclinical and clinical studies have provided insight into the pathophysiology of bone metastases and the changes that occur in the bone microenvironment that result in a favorable site of growth for prostate cancer. We provide an overview of recent advances in understanding bone biology, and bone targeted therapy research and development.

Materials and Methods

We reviewed recent research findings related to the biology of bone metastases, approaches to targeting osteoclast function, approaches to targeting osteoblasts and advances in assessing the treatment response to bone targeted therapies in the context of prostate cancer management.

Results

To date targeting some of the key players in the bone microenvironment has not been associated with a significant antitumor effect or with meaningful clinical benefit in phase III randomized trials. A significant limitation in the development of bone targeted therapy has been the inability to objectively assess treatment response. Investigation of improved imaging techniques are ongoing to provide better treatment assessment and, therefore, allow more rapid drug screening and development.

Conclusions

It is our recommendation that future therapy development should be combination based, focusing on simultaneous targeting of multiple relevant pathways. Most important of all is the direct targeting of prostate cancer cells.

Key Words: prostate, prostatic neoplasms, bone and bones, neoplasm metastasis

Abbreviations and Acronyms: ADC, apparent diffusion coefficient of tumor water, ET, endothelin, FDG, fludeoxyglucose ¹⁸F, fDM, functional diffusion mapping, HR, hormone refractory, ITT, intent to treat, MMP, matrix metalloproteinase, MMPI, MMP inhibitor, MRI, magnetic resonance imaging, OPG, osteoprotegerin, PCa, prostate cancer, PET, positron emission tomography, PSA, prostate specific antigen, RANK, receptor activator of nuclear factor-κB, RANKL, RANK ligand, SRE, skeletal related event, TTP, time to progression