title: Temporal changes in systemic and local expression of bone turnover markers during six months of sclerostin antibody administration to ovariectomized rats.
abstract: Sclerostin (Scl) is an osteocyte protein that decreases bone formation, and its inhibition by neutralizing antibodies (Scl-Ab) increases bone formation, mass and strength. We investigated the effects of Scl-Ab in mature ovariectomized (OVX) rats with a mechanistic focus on longer-term responses of osteoclasts, osteoblasts and osteocytes. Four-month-old Sprague-Dawley rats had OVX or sham surgery. Two months later, sham controls received sc vehicle while OVX rats received vehicle (OVX-Veh) or Scl-Ab (25mg/kg) once weekly for 6 or 26weeks followed by necropsy (n=12/group). Terminal blood was collected for biochemistry, non-adherent marrow cells were harvested from femurs for ex vivo osteoclast formation assays, and vertebrae and tibiae were collected for dynamic histomorphometry and mRNA analyses. Scl-Ab treatment led to progressively thicker but fewer trabeculae in the vertebra, leading to increased trabecular bone volume and reduced trabecular surfaces. Scl-Ab also increased cortical bone volume in the tibia, via early periosteal expansion and progressive endocortical contraction. Scl-Ab significantly reduced parameters of bone resorption at week 6 relative to OVX-Veh controls, including reduced serum TRACP-5b, reduced capacity of marrow cells to form osteoclasts ex vivo, and >80% reductions in vertebral trabecular and tibial endocortical eroded surfaces. At week 26, serum TRACP-5b and ex vivo osteoclast formation were no longer reduced in the Scl-Ab group, but eroded surfaces remained >80% lower than in OVX-Veh controls without evidence for altered skeletal mRNA expression of opg or rankl. Scl-Ab significantly increased parameters of bone formation at week 6 relative to OVX-Veh controls, including increases in serum P1NP and osteocalcin, and increased trabecular, endocortical and periosteal bone formation rates (BFRs). At week 26, surface-referent trabecular BFR remained significantly increased in the Scl-Ab group versus OVX-Veh controls, but after adjusting for a reduced extent of trabecular surfaces, overall (referent-independent) trabecular BFR was no longer significantly elevated. Similarly, serum P1NP and osteocalcin were no longer significantly increased in the Scl-Ab group at week 26. Tibial endocortical and periosteal BFR were increased at week 6 in the Scl-Ab group versus OVX-Veh controls, while at week 26 only endocortical BFR remained increased. The Scl-Ab group exhibited significant increments in skeletal mRNA expression of several osteocyte genes, with sost showing the greatest induction in both the tibia and vertebra. We propose that Scl-Ab administration, and/or the gains in bone volume that result, may have increased osteocytic expression of Scl as a possible means of regulating gains in bone mass.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: mstolina@amgen.com.
authors.forename: Marina
authors.initials: M
authors.lastname: Stolina
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: ddwyer@amgen.com.
authors.forename: Denise
authors.initials: D
authors.lastname: Dwyer
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: qniu@amgen.com.
authors.forename: Qing-Tian
authors.initials: QT
authors.lastname: Niu
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: kwarming@amgen.com.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Villasenor
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: kurimoto@amgen.com.
authors.forename: Pam
authors.initials: P
authors.lastname: Kurimoto
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: grisanti@amgen.com.
authors.forename: Mario
authors.initials: M
authors.lastname: Grisanti
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: ehan@amgen.com.
authors.forename: Chun-Ya
authors.initials: CY
authors.lastname: Han
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: minl@amgen.com.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: xli@amgen.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: mominsky@amgen.com.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ominsky
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: hke@amgen.com.
authors.forename: Hua Z
authors.initials: HZ
authors.lastname: Ke
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA. Electronic address: paulk@amgen.com.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostenuik
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology*; D015519:Bone Density / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D005260:Female; D005819:Genetic Markers / Q000276:immunology*; D010010:Osteoclasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000906:Antibodies; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat
keywords: Bone formation; Bone resorption; Bone turnover markers; DKK-1; Osteoporosis; Sclerostin