title: Bisphosphonate treatment of postmenopausal osteoporosis is associated with a dose dependent increase in serum sclerostin.
abstract: The benefits coming from long-term treatment of postmenopausal osteoporosis with bisphophonates are limited by a coupled decrease in bone formation. The objective of this study is to determine whether this decrease in bone formation is associated with changes in serum levels of the WNT signaling antagonist sclerostin or Dickkopf-1 (DKK1). This is an ancillary observation from patients participating in a 12 months, phase 2, randomized clinical trial. We analyzed 107 patients given either monthly intramuscular neridronate (12.5, 25 or 50 mg) or placebo. Serum C-terminal telopeptide of type I collagen (sCTX, a bone-resorption marker) decreased by 61%, 75% and 73% in the 12.5, 25 and 50 mg dose groups, respectively. Mean changes in bone alkaline phosphatase (bAP) at 12 months were -47%, -60.0% and -52.6% in the groups receiving 12.5, 25 or 50 mg neridronate, respectively. Serum DKK1 remained unchanged at all time points in the 3 groups. Serum sclerostin increased versus placebo group gradually and significantly only in patients treated with 25 or 50 mg neridronate monthly, reaching 138-148% of baseline values (P<0.001). Changes in serum sclerostin at 12 months were negatively correlated with changes in bAP (P<0.001) even when data were adjusted for sCTX changes and only treated patients were included. In conclusions, decreased bone formation after several months of bisphosphonate therapy is associated with increased serum levels of sclerostin. This might suggest that Wnt signaling may play a role in the coupling between resorption and formation.
authors.affiliation: Rheumatology Unit, Department of Medicine, University of Verona, Italy. Davide.Gatti@univr.it
authors.forename: Davide
authors.initials: D
authors.lastname: Gatti
authors.forename: Ombretta
authors.initials: O
authors.lastname: Viapiana
authors.forename: Silvano
authors.initials: S
authors.lastname: Adami
authors.forename: Luca
authors.initials: L
authors.lastname: Idolazzi
authors.forename: Elena
authors.initials: E
authors.lastname: Fracassi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rossini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019485:Bone Morphogenetic Proteins / Q000097:blood*; D024042:Collagen Type I / Q000097:blood; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000097:blood* / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050071:Bone Density Conservation Agents; D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; D004164:Diphosphonates; D005819:Genetic Markers; C422903:SOST protein, human; C053389:6-amino-1-hydroxyhexane-1,1-diphosphonate; D000469:Alkaline Phosphatase