title: Raloxifene pharmacodynamics is influenced by genetic variants in the RANKL/RANK/OPG system and in the Wnt signaling pathway.
abstract: BACKGROUND
  Raloxifene is a selective estrogen receptor (ER) modulator (SERM) used for the treatment of osteoporosis. However, its efficacy and also its safety vary greatly among treated patients, and it might be influenced by the individuals' genetic background. As the receptor activator of the nuclear factor κB (RANK) ligand (RANKL)/RANK/osteoprotegerin (OPG) system is essential for osteoclastogensis and Wnt signaling pathway for osteoblastogenesis, we decided to evaluate the raloxifene treatment in regard to selected polymorphisms in key genes of these two main bone regulatory pathways.
  
  
  METHODS
  Fifty-six osteoporotic postmenopausal women treated with raloxifene were genotyped for 11 polymorphisms located in six genes: -290C>T, -643C>T, and -693G>C in tumor necrosis factor receptor superfamily member 11 (TNFSF11), +34694C>T, +34901G>A, and +35966insdelC in tumor necrosis factor receptor superfamily member 11A (TNFRSF11A), K3N and 245T>G in tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), A1330V in LRP5, I1062V in LRP6, and -1397_-1396insGGA in SOST. For evaluation of treatment efficacy, bone mineral density (BMD) and biochemical markers of bone turnover were measured.
  
  
  RESULTS
  One-year change in total hip BMD was associated with +34901G>A in TNFRSF11A (p=0.040), whereas, for lumbar spine BMD, the association was shown for -1397_-1396insGGA in SOST (p=0.015). C-terminal crosslinking telopeptides of type I collagen (CTX) concentrations showed significant association with -643C>T single nucleotide polymorphism (SNP) in TNFSF11 (p=0.049) and +34694C>T in TNFRSF11A (p=0.022). No other association was found between 1-year change in BMDs or biochemical markers and the studied SNPs.
  
  
  CONCLUSIONS
  We have shown that, in postmenopausal osteoporotic women treated with raloxifene, the efficacy of raloxifene treatment might be influenced by +34901G>A in TNFRSF11A gene and -1397_-1396insGGA in the SOST gene as well as -643C>T in TNFSF11 gene and +34694C>T in TNFRSF11A gene. However, these findings need additional functional and clinical confirmation for potential pharmacogenetic use in the future.
authors.forename: Simona
authors.initials: S
authors.lastname: Mencej-Bedrač
authors.forename: Janja
authors.initials: J
authors.lastname: Zupan
authors.forename: Simona Jurković
authors.initials: SJ
authors.lastname: Mlakar
authors.forename: Andrej
authors.initials: A
authors.lastname: Zavratnik
authors.forename: Janez
authors.initials: J
authors.lastname: Preželj
authors.forename: Janja
authors.initials: J
authors.lastname: Marc
mesh_terms: D015502:Absorptiometry, Photon; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects; D005260:Female; D006801:Humans; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D053244:Osteoprotegerin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053245:RANK Ligand / Q000235:genetics*; D020849:Raloxifene Hydrochloride / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D020845:Selective Estrogen Receptor Modulators / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics
chemical_list: D015415:Biomarkers; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020845:Selective Estrogen Receptor Modulators; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D020849:Raloxifene Hydrochloride