title: Identification of serological biomarker profiles associated with total joint replacement in osteoarthritis patients.
abstract: Establish a biomarker panel associated with all-cause total joint replacement (TJR) through identification of patients with osteoarthritis (OA) who do or do not progress to TJR and investigate effects of nonsteroidal anti-inflammatory drugs (NSAIDs).
  
  
  
  Serum samples from patients enrolled in phase III trials of tanezumab who experienced TJR (n = 174) or matched patients who did not (n = 321) were analyzed for bone, cartilage, soft tissue, and inflammation markers. Classification and Regression Tree (CART) analysis was used to identify biomarker phenotypes associated with TJR.
  
  
  
  At baseline, biomarker combinations for patients who did not use NSAIDs before starting tanezumab and used NSAIDs during tanezumab treatment <90 days ("nonNSAID"), identified 77% (95% confidence interval [CI]: 71-84%) of patients who experienced TJR and 77% (95% CI: 65-86%) who did not over a 6-month study period (on average). These biomarker combinations increased odds of identifying patients to remain free of a TJR by 3.3-fold. In patients who used NSAIDs continuously (during screening and ≥90 days during tanezumab treatment), 64% (95% CI: 54-73%) who had TJR and 75% (95% CI: 68-83%) who did not were identified by biomarker combinations different from nonNSAID patients, with an increase in odds of identifying patients to remain free of a TJR by two-fold.
  
  
  
  Although validation on other cohorts is necessary, biomarkers may assist in identifying patients who will need TJR. The profiles suggest NSAID use increases importance of bone metabolism in TJR pathology.
authors.affiliation: Pfizer Inc, 445 Eastern Point Road, Groton, CT 06340, United States. Electronic address: Rosalin.Arends@pfizer.com.
authors.forename: R H G P
authors.initials: RHGP
authors.lastname: Arends
authors.affiliation: Nordic Bioscience, Herlev Hovedgade, DK-2730, Herlev, Denmark. Electronic address: mk@nordicbioscience.com.
authors.forename: M A
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Pfizer Inc, 445 Eastern Point Road, Groton, CT 06340, United States. Electronic address: Kenneth.M.Verburg@pfizer.com.
authors.forename: K M
authors.initials: KM
authors.lastname: Verburg
authors.affiliation: Pfizer Inc, 445 Eastern Point Road, Groton, CT 06340, United States. Electronic address: Christine.West@pfizer.com.
authors.forename: C R
authors.initials: CR
authors.lastname: West
authors.affiliation: Nordic Bioscience, Herlev Hovedgade, DK-2730, Herlev, Denmark. Electronic address: acbj@Nordicbioscience.com.
authors.forename: A C
authors.initials: AC
authors.lastname: Bay-Jensen
authors.affiliation: Pfizer Inc, 445 Eastern Point Road, Groton, CT 06340, United States. Electronic address: David.S.Keller@pfizer.com.
authors.forename: D S
authors.initials: DS
authors.lastname: Keller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D019644:Arthroplasty, Replacement, Hip; D019645:Arthroplasty, Replacement, Knee; D015415:Biomarkers / Q000097:blood*; D019485:Bone Morphogenetic Proteins / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein / Q000097:blood; D024042:Collagen Type I / Q000097:blood; D024043:Collagen Type II / Q000097:blood; D024061:Collagen Type III / Q000097:blood; D018450:Disease Progression; D005260:Female; D005819:Genetic Markers; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016015:Logistic Models; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000097:blood* / Q000628:therapy; D020370:Osteoarthritis, Knee / Q000097:blood* / Q000628:therapy; D015675:Osteocalcin / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D010455:Peptides / Q000097:blood; D011347:Procollagen / Q000097:blood; D011379:Prognosis; D057216:Propensity Score; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D002097:C-Reactive Protein; D064236:Cartilage Oligomeric Matrix Protein; D024042:Collagen Type I; D024043:Collagen Type II; D024061:Collagen Type III; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D020780:Matrix Metalloproteinase 9; D015675:Osteocalcin; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; D042461:Vascular Endothelial Growth Factor A; C501126:DKK1 protein, human; C508600:IL6 protein, human; C422903:SOST protein, human; C467484:VEGFA protein, human; C052929:collagen type I trimeric cross-linked peptide; C047202:procollagen Type I N-terminal peptide; C579270:MMP9 protein, human; C549319:tanezumab; C577553:TSP5 protein, human
keywords: Biomarker; Bone turnover; Connective tissue; NSAID; Osteoarthritis; Total joint replacement