Metastatic bone disease (MBD) in advanced-stage cancer increases the risk of intractable bone pain, pathological skeletal fracture, spinal-cord compression and decreased survival. The disease manifestation course during MBD is largely driven by homotypic and heterotypic cellular interactions between invading tumor cells, osteoblasts and osteoclasts. The outcome is a sustained vicious cycle of bone matrix remodeling. Osteoclast-mediated bone degradation and subsequent bone loss are the hallmarks of secondary bone metastases from most solid tumors. An additional complication in prostate cancer is the predominance of osteosclerotic lesions typified by inappropriate bone production. Successful therapeutic strategies for the treatment of osteolytic MBD include the administration of intravenous bisphosphonates or subcutaneous inhibitors of receptor activator of nuclear factor κB ligand (RANKL). Inhibitors of SRC and cABL kinases and cathepsin K are under clinical investigation as potential anti-osteolytics. In contrast to the rapid progress being made in the development of anti-osteolytic therapies, the treatment of osteosclerotic MBD remains restricted to palliative radiotherapy for symptomatic solitary lesions and systemic taxane-based chemotherapy for widespread multiple lesions. This Review discusses the complex pathology of bone lesions in metastatic castration-resistant prostate cancer and focuses on new therapeutic strategies and targets that are emerging in preclinical studies.
Treatment of metastatic bone disease (MBD) in men with castration-resistant prostate cancer (CRPC) is complicated by osteolytic (bone-degrading), osteosclerotic (bone-forming) and mixed osteolytic and osteosclerotic lesions
It is essential to study the complex interactions between tumor cells, osteoblasts and osteoclasts in the bone metastatic niche using clinically relevant models to allow development of targeted treatments
Bisphosphonates are used as a palliative treatment to protect against the osteolytic effects of MBD; to date, clodronate has been shown to improve survival of CRPC patients with MBD
Denosumab, the RANKL inhibitor, has been approved for the treatment of MBD that originate from solid tumors; however, its efficacy in MBD associated with CRPC is unclear
Inhibition of Endothelin A receptor and systemic radionuclide therapy target osteoblast activity and are under investigation for their clinical impact in CRPC
Improved understanding of the molecular mechanisms of dysregulated type-I collagen deposition in MBD will open up new avenues for therapeutic exploitation
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The authors would like to acknowledge funding support from The Prostate Cancer Charity (Grant 110632), The Prostate Cancer Charity and the Milly Apthorp Charitable Trust (Grant 110854), The Association of International Cancer Research (Grant 08-0803), The Rosetrees Trust (Grant JS16/M59), Tony & Rita Gallagher, Imperial College NHS Healthcare Trust Special Trustees and The Fundação para a Ciência e Tecnologia. We thank A. V. Fonseca for her help in the schematic design.
The authors declare no competing financial interests.
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Sturge, J., Caley, M. & Waxman, J. Bone metastasis in prostate cancer: emerging therapeutic strategies. Nat Rev Clin Oncol 8, 357–368 (2011). https://doi.org/10.1038/nrclinonc.2011.67
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