title: Time course of disassociation of bone formation signals with bone mass and bone strength in sclerostin antibody treated ovariectomized rats.
abstract: Sclerostin antibodies increase bone mass by stimulating bone formation. However, human and animal studies show that bone formation increases transiently and returns to pre-treatment level despite ongoing antibody treatment. To understand its mechanism of action, we studied the time course of bone formation, correlating the rate and extent of accrual of bone mass and strength after sclerostin antibody treatment. Ovariectomized (OVX) rats were treated with a sclerostin-antibody (Scle-ab) at 20mg/kg sc once weekly and sacrificed at baseline and 2, 3, 4, 6, and 8weeks post-treatment. In Scle-ab treated rats, serum PINP and OCN rapidly increased at week 1, peaked around week 3, and returned to OVX control levels by week 6. Transcript analyses from the distal femur revealed an early increase in bone formation followed by a sustained decrease in bone resorption genes. Lumbar vertebral (LV) osteoblast surface increased 88% by week 2, and bone formation rate (BFR/BS) increased 138% by week 4. Both parameters were below OVX control by week 8. Bone formation was primarily a result of modeling based formation. Endocortical and periosteal BFR/BS peaked around week 4 at 313% and 585% of OVX control, respectively. BFR/BS then declined but remained higher than OVX control on both surfaces through week 8. Histomorphometric analyses showed LV-BV/TV did not further increase after week 4, while BMD continued to increase at LV, mid femur (MF), and femoral neck (FN) through week 8. Biomechanical tests showed a similar improvement in bone strength through 8weeks in MF and FN, but bone strength plateaued between weeks 6 and 8 for LV. Our data suggest that bone formation with Scle-ab treatment is rapid and modeling formation dominated in OVX rats. Although transient, the bone formation response persists longer in cortical than trabecular bone.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: ma_linda@lilly.com.
authors.forename: Yanfei L
authors.initials: YL
authors.lastname: Ma
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hamang
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lucchesi
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Bivi
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Qianqiang
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Mary D
authors.initials: MD
authors.lastname: Adrian
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Raines
authors.affiliation: Indiana University-Purdue University, Indianapolis, IN, USA.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Li
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Kuhstoss
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Obungu
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Henry U
authors.initials: HU
authors.lastname: Bryant
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D001862:Bone Resorption / Q000097:blood / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D000071556:Cancellous Bone / Q000187:drug effects / Q000473:pathology; D003720:Densitometry; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005819:Genetic Markers / Q000276:immunology*; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000906:Antibodies; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat; D051153:Wnt Proteins
keywords: Bone formation; Bone histomorphometry; Osteoporosis; Sclerostin antibody