title: Metastatic Prostate Cancer and the Bone: Significance and Therapeutic Options.
abstract: BACKGROUND
  Skeletal involvement is common in metastatic prostate cancer (PCa) and is associated with skeletal-related events (SREs). The interaction of PCa with the bone microenvironment contributes to self-perpetuating progression of cancer in bone. Bone-targeted agents (BTAs) are available for use in metastatic castration-resistant prostate cancer (mCRPC).
  
  
  OBJECTIVE
  To review the biology of bone metastases in PCa and to review the clinical trial data for BTAs in PCa.
  
  
  METHODS
  A literature search was conducted in October 2014. Keywords included clinical trial, prostate cancer, denosumab, bisphosphonates, zoledronic acid, radium-223, bone turnover markers, skeletal-related events, and symptomatic skeletal events.
  
  
  RESULTS
  The biology of bone metastases in PCa is summarized. Data supporting the use of BTAs in PCa are reviewed, and issues related to the combination and sequencing of available agents are discussed.
  
  
  CONCLUSIONS
  The osteoclast-targeted agents zoledronic acid and denosumab decrease SREs in mCRPC, and the α-emitting radiopharmaceutical agent radium-223 improves survival and decreases symptomatic skeletal events. Limited data are available to guide the sequence and combination of BTAs with disease-modifying agents, although data support the use of osteoclast-targeted drugs with chemotherapy, androgen-targeted agents, and radium-223. Zoledronic acid does not reduce SREs when started prior to castration resistance, although osteoclast-targeted agents do improve outcomes when used in patients with asymptomatic to minimally symptomatic chemotherapy-naive mCRPC. The optimal sequence of radium-223 with chemotherapy is uncertain, although data suggest the efficacy and tolerability of radium-223 is similar with either sequence. Clinical trials evaluating the combination of BTAs with other agents are under way. The optimization of sequence and combination strategies will guide the best use of available agents.
  
  
  RESULTS
  The literature pertaining to bone metastases in prostate cancer (PCa) was reviewed, and the current understanding of the biology of PCa having spread to bone and the agents available to reduce skeletal complications was discussed.
authors.affiliation: Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address: bgartrel@montefiore.org.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Gartrell
authors.affiliation: Academic Unit of Clinical Oncology, Weston Park Hospital, CR-UK/YCR Sheffield Cancer Research Centre, Sheffield, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Coleman
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA; Department of Clinical Therapeutics, University of Athens, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.affiliation: Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Department of Internal Medicine, Section of Medical Oncology, UAB Medical Center, Birmingham, AL, USA.
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
authors.affiliation: Department of Medicine and Urology, Tulane University, New Orleans, LA, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.affiliation: Centre Hospitalier de I'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
mesh_terms: D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D000069448:Denosumab / Q000627:therapeutic use; D004164:Diphosphonates / Q000627:therapeutic use; D005598:Fractures, Spontaneous / Q000517:prevention & control*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D011868:Radioisotopes / Q000627:therapeutic use; D011883:Radium / Q000627:therapeutic use; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D011868:Radioisotopes; D000069448:Denosumab; D000077211:Zoledronic Acid; C581106:radium Ra 223 dichloride; D011883:Radium
keywords: Bone metastases; Bone-targeted agents; Prostate cancer; Skeletal-related events; Symptomatic skeletal events