title: Serum osteoprotegerin is increased in Crohn's disease: a population-based case control study.
abstract: BACKGROUND
  There is a potential interface between osteoporosis and the chronic inflammation of inflammatory bowel disease (IBD), and the osteoprotegerin (OPG)/receptor for activated nuclear factor-kappaB (RANK)/RANK ligand (RANKL) signaling pathway may be an important mediator, although data are limited.
  
  
  METHODS
  We conducted a population-based case-control seroassay study to look for alterations in serum OPG and soluble RANKL (sRANKL). The study population included IBD patients who were 18 to 50 years old with Crohn's disease (CD; n = 287) or ulcerative colitis (UC; n = 166), age-matched healthy controls (n = 368), and nonaffected siblings of IBD patients (n = 146). Serum OPG and sRANKL were measured by enzyme-linked immunoassay. Sex-specific reference ranges were derived from the healthy controls.
  
  
  RESULTS
  Analysis of variance (ANOVA) confirmed significant group differences in women for mean serum OPG (P = 0.018). CD women had higher values of OPG than UC women (P = 0.028) or healthy controls (P = 0.045), whereas the other groups were similar. OPG levels were above the reference range in 13/173 (8%) of CD women, exceeding the expected proportion (P = 0.032). In contrast, no differences in OPG were seen in men between controls, CD, or UC. Estrogen use in women (P = 0.000002) and corticosteroid use in men (P = 0.026) were associated with higher OPG levels. In multivariate analysis, CD diagnosis (P = 0.031) and estrogen use (P = 0.000002) were independently associated with higher OPG levels. No group differences were seen in mean serum sRANKL measurements.
  
  
  CONCLUSIONS
  An OPG:sRANKL imbalance with OPG exceeding sRANKL should inhibit osteoclastogenesis and promote bone formation. CD is associated with increased fracture risk, and possibly, the paradoxically higher OPG is a counterregulatory response to factors such as inflammatory cytokines, promoting high bone turnover. Alternatively, elevated OPG in CD may reflect T-cell activation.
authors.affiliation: Department of Medicine, University of Manitoba, Manitoba, Canada. cbernst@cc.umanitoba.ca
authors.forename: Charles N
authors.initials: CN
authors.lastname: Bernstein
authors.forename: Michael
authors.initials: M
authors.lastname: Sargent
authors.forename: William D
authors.initials: WD
authors.lastname: Leslie
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000097:blood*; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000097:blood*; D003424:Crohn Disease / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D015914:Estrogen Replacement Therapy; D005260:Female; D005938:Glucocorticoids; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000097:blood*; D008875:Middle Aged; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood*; D018124:Receptors, Tumor Necrosis Factor; D012737:Sex Factors; D012907:Smoking
chemical_list: D002352:Carrier Proteins; D005938:Glucocorticoids; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human