title: The prognostic role of bone turnover markers in multiple myeloma patients: The impact of their assay. A systematic review and meta-analysis.
abstract: BACKGROUND
  Multiple myeloma (MM) is characterized by the progressive destruction of bone tissue due to the uncontrolled proliferation of the immunoglobulins. The detection of bone turnover markers (BTMs) may represent a non-invasive method to assess the bone involvement and to predict the risk of bone morbidity. This systematic review evaluates clinical utility of changes in BTMs levels in MM patients and their prognostic role.
  
  
  METHODS
  We searched Medline, Embase, WOS and Scopus. All eligible articles were examined and the risk of bias was evaluated. Results about PICP, PINP, ICTP, OC, CTX, NTX, RANKL and OPG were extracted. Weighted mean difference, risk ratio and hazard ratio were pooled.
  
  
  RESULTS
  Thirty studies and more than 2500 patients were included in this systematic review. The majority of them (50%) used ELISA to quantify BTMs, 10 of them used RIA and only 4 did not report the information regarding the type of immunoassays. In MM patients, the concentration of NTX and ICTP increased, instead the concentrations of BAP and OC lowered when compared to healthy subjects. High levels of ICTP were predictive of bone events (RR 1.18) and they were associated to poor survival (HR 1.08). Most of the included studies were considered at high risk of bias, in fact the reporting of the results was often incomplete. Between-studies heterogeneity was high.
  
  
  CONCLUSIONS
  BTMs measurement may be very useful in the management of MM patients, especially to evaluate the bone disease progression. They could help clinicians to identify patients at high risk of bone events and to opt for more appropriate therapy; nevertheless their high biological and analytical variability limit their implementation in clinical practice.
authors.affiliation: Clinical Epidemiology Unit, IRCCS Galeazzi Orthopedic Institute, Via Riccardo Galeazzi, 4, 20161 Milan, Italy. Electronic address: valepecoraro@gmail.com.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pecoraro
authors.affiliation: Clinical Pathology and Endocrinology Laboratory, Azienda Unità Sanitaria Locale, Modena, Italy. Electronic address: l.roli@usl.mo.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Roli
authors.affiliation: Laboratorio Unilabs Ticino, Lugano, Switzerland. Electronic address: germagnoli.luca@alice.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Germagnoli
authors.affiliation: IRCCS Galeazzi Orthopedic Institute, Milan, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy. Electronic address: giuseppe.banfi1@unimi.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Banfi
mesh_terms: D015415:Biomarkers; D016723:Bone Remodeling; D024042:Collagen Type I / Q000032:analysis; D006801:Humans; D009101:Multiple Myeloma / Q000150:complications* / Q000378:metabolism; D010455:Peptides / Q000032:analysis; D011379:Prognosis
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide
keywords: Biological variability; Bone turnover markers; Clinical decision-making; Multiple myeloma; Systematic review