title: Myeloma bone disease: pathogenesis, current treatments and future targets.
abstract: BACKGROUND
  Patients with myeloma develop localized and generalized bone loss leading to hypercalcaemia, accelerated osteoporosis, vertebral wedge fractures, other pathological fractures, spinal cord compression and bone pain. Bone loss is mediated by a variety of biological modifiers including osteoclast-activating factors (OAF) and osteoblast (OB) inhibitory factors produced either directly by malignant plasma cells (MPCs) or as a consequence of their interaction with the bone marrow microenvironment (BMM). Raised levels of OAFs such as receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage inflammatory protein 1 alpha, tumour necrosis factor-alpha and interleukin 6 stimulate bone resorption by recruiting additional osteoclasts. Via opposing mechanisms, increases in OB inhibitory factors, such as dickkopf-1 (Dkk-1), soluble frizzled-related protein-3 and hepatocyte growth factor (HGF), suppress bone formation by inhibiting the differentiation and recruitment of OBs. These changes result in an uncoupling of physiological bone remodelling, leading to myeloma bone disease (MBD). Moreover, the altered BMM provides a fertile ground for the growth and survival of MPCs. Current clinical management of MBD is both reactive (to pain and fractures) and preventive, with bisphosphonates (BPs) being the mainstay of pharmacological treatment. However, side effects and uncertainties associated with BPs warrant the search for more targeted treatments for MBD. This review will summarize recent developments in understanding the intimate relationship between MBD and the BMM and the novel ways in which they are being therapeutically targeted.
  
  
  METHODS
  All data included were sourced and referenced from PubMed.
  
  
  RESULTS
  The clinical utility of BP therapy is well established. However, there is general acknowledgement that BPs are only partially successful in the treatment of MBD. The number of skeletal events attributable to myeloma are reduced by BPs but not totally eliminated. Furthermore, existing damage is not repaired. It is widely recognized that more effective treatments are needed.
  
  
  RESULTS
  There remains controversy concerning the duration of BP therapy. Whether denosumab is a viable alternative to BP therapy is also contested. Many of the new therapeutic strategies discussed are yet to translate to clinical practice and demonstrate equal efficacy or superiority to BP therapy. It also remains controversial whether reported anti-tumour effects of bone-modulating therapies are clinically significant.
  
  
  CONCLUSIONS
  The potential clinical utility of bone anabolic therapies including agents such as anti-Dkk-1, anti-sclerostin and anti-HGF is becoming increasingly recognized.
  
  
  CONCLUSIONS
  Further research effectively targeting the mediators of MBD, targeting both bone resorption and bone formation, is urgently needed. This should translate promptly to clinical trials of combination therapy comprising anti-resorptives and bone anabolic therapies to demonstrate efficacy and improved outcomes over BPs.
authors.affiliation: Sheffield Myeloma Research Team (SmaRT), Department of Oncology, University of Sheffield, Sheffield, UK Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Walker
authors.affiliation: Sheffield Myeloma Research Team (SmaRT), Department of Oncology, University of Sheffield, Sheffield, UK Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lawson
authors.affiliation: Sheffield Myeloma Research Team (SmaRT), Department of Oncology, University of Sheffield, Sheffield, UK Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: Clive H
authors.initials: CH
authors.lastname: Buckle
authors.affiliation: Sheffield Myeloma Research Team (SmaRT), Department of Oncology, University of Sheffield, Sheffield, UK Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Snowden
authors.affiliation: Sheffield Myeloma Research Team (SmaRT), Department of Oncology, University of Sheffield, Sheffield, UK Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK a.d.chantry@sheffield.ac.uk.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Chantry
mesh_terms: D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001847:Bone Diseases / Q000209:etiology* / Q000628:therapy; D015815:Cell Adhesion Molecules / Q000502:physiology; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000150:complications* / Q000628:therapy; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology; D010024:Osteoporosis / Q000209:etiology / Q000628:therapy
chemical_list: D050071:Bone Density Conservation Agents; D015815:Cell Adhesion Molecules; D007155:Immunologic Factors; C013065:cell aggregation factors
keywords: bone disease; myeloma; therapeutic targets