title: Sclerostin inhibition prevents spinal cord injury-induced cancellous bone loss.
abstract: Spinal cord injury (SCI) results in rapid and extensive sublesional bone loss. Sclerostin, an osteocyte-derived glycoprotein that negatively regulates intraskeletal Wnt signaling, is elevated after SCI and may represent a mechanism underlying this excessive bone loss. However, it remains unknown whether pharmacologic sclerostin inhibition ameliorates bone loss subsequent to SCI. Our primary purposes were to determine whether a sclerostin antibody (Scl-Ab) prevents hindlimb cancellous bone loss in a rodent SCI model and to compare the effects of a Scl-Ab to that of testosterone-enanthate (TE), an agent that we have previously shown prevents SCI-induced bone loss. Fifty-five (n = 11-19/group) skeletally mature male Sprague-Dawley rats were randomized to receive: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe (250 kilodyne) SCI, (C) 250 kilodyne SCI + TE (7.0 mg/wk, im), or (D) 250 kilodyne SCI + Scl-Ab (25 mg/kg, twice weekly, sc) for 3 weeks. Twenty-one days post-injury, SCI animals exhibited reduced hindlimb cancellous bone volume at the proximal tibia (via μCT and histomorphometry) and distal femur (via μCT), characterized by reduced trabecular number and thickness. SCI also reduced trabecular connectivity and platelike trabecular structures, indicating diminished structural integrity of the remaining cancellous network, and produced deficits in cortical bone (femoral diaphysis) strength. Scl-Ab and TE both prevented SCI-induced cancellous bone loss, albeit via differing mechanisms. Specifically, Scl-Ab increased osteoblast surface and bone formation, indicating direct bone anabolic effects, whereas TE reduced osteoclast surface with minimal effect on bone formation, indicating antiresorptive effects. The deleterious microarchitectural alterations in the trabecular network were also prevented in SCI + Scl-Ab and SCI + TE animals, whereas only Scl-Ab completely prevented the reduction in cortical bone strength. Our findings provide the first evidence indicating that sclerostin inhibition represents a viable treatment to prevent SCI-induced cancellous and cortical bone deficits and provides preliminary rationale for future clinical trials focused on evaluating whether Scl-Ab prevents osteoporosis in the SCI population.
authors.affiliation: Research Service, Department of Veterans Affairs Medical Center, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA; Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Beggs
authors.forename: Fan
authors.initials: F
authors.lastname: Ye
authors.forename: Payal
authors.initials: P
authors.lastname: Ghosh
authors.forename: Darren T
authors.initials: DT
authors.lastname: Beck
authors.forename: Christine F
authors.initials: CF
authors.lastname: Conover
authors.forename: Alexander
authors.initials: A
authors.lastname: Balaez
authors.forename: Julie R
authors.initials: JR
authors.lastname: Miller
authors.forename: Ean G
authors.initials: EG
authors.lastname: Phillips
authors.forename: Nigel
authors.initials: N
authors.lastname: Zheng
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Williams
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Aguirre
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wronski
authors.forename: Prodip K
authors.initials: PK
authors.lastname: Bose
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Borst
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Yarrow
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D005819:Genetic Markers; D008297:Male; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications* / Q000503:physiopathology; D013739:Testosterone / Q000097:blood; D055114:X-Ray Microtomography
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat; D013739:Testosterone
keywords: ANABOLIC; HISTOMORPHOMETRY; MICROCOMPUTED TOMOGRAPHY; OSTEOPOROSIS; PRECLINICAL STUDIES