Therapeutic strategies for bone metastases and their clinical sequelae in prostate cancer

Abstract

Skeletal metastases threaten quality of life, functionality, and longevity in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapeutic strategies for bone metastases in prostate cancer can palliate pain, delay/prevent skeletal complications, and prolong survival. Pharmacologic agents representing several drug classes have demonstrated the ability to achieve these treatment goals in men with mCRPC. Skeletal-related events such as fracture and the need for radiation can be delayed using drugs that target the osteoclast/osteoblast pathway. Cancer-related bone pain can be palliated using beta-emitting bone-seeking radiopharmaceuticals such as samarium-153 EDTMP and strontium-89. Also, prospective randomized studies have demonstrated that cytotoxic chemotherapy can palliate bone pain. For the first time, bone-directed therapy has been shown to prolong survival using the novel alpha-emitting radiopharmaceutical radium-223. Given these multifold clinical benefits, treatments targeting bone metabolism, tumor-bone stromal interactions, and bone metastases themselves are now central elements of routine clinical care. Decisions about which agents, alone or in combination, will best serve the patient's and clinician's clinical goals is contingent on the treatment history to date, present disease manifestations, and symptomatology. Clinical trials exploring novel agents such as those targeting c-Met and Src are under way, using endpoints that directly address how patients feel, function, and survive.

Figure 1

Simplified schema of bone directed therapies and their primary targets. Osteoblasts produce receptor activator of nuclear factor kappa b ligand (RANKL) which binds to its receptor (RANK) on osteoclast precursors, stimulating osteoclast activity. Regulation of such stimulation is exerted by osteoblast production of osteoprotegerin, a soluble decoy receptor of RANKL. Available treatments utilize these pathways. Denosumab binds to RANKL, preventing it from binding to its receptor on osteoclast precursors. Bisphosphonates prevent osteoclast activity by binding to hydroxyapatite in bone. Radiopharmaceuticals deliver ionized radiation to bone metastases. The impact of alpha and beta emitters on surrounding bone marrow are not drawn to scale.