title: A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep.
abstract: Large animals as sheep are often used as models for human osteoporosis. Our aim was therefore to determine how glucocorticoid treatment of ovariectomised sheep affects the cancellous bone, determining the cellular events within the bone remodelling process that contributes to their bone loss. Twenty female sheep were assigned for two groups; an untreated control group and an ovariectomised group treated with glucocorticoids (0.6 mg/kg/day, 5 times weekly) for 7 months. At 7 months the glucocorticoid-treated ovariectomised sheep showed a significant change in the bone microstructure revealed by a decreased trabecular bone volume and thickness compared to the control sheep. The treatment led to a temporary elevation of the bone resorption marker CTX (c-terminal collagen telopeptide), while the bone formation marker osteocalcin remained suppressed all 7 months. Histomorphometrically, the treated sheep had a complete absence of osteoid surfaces, and a 5-fold increase in the extent of eroded/reversal surfaces after 7 months. Most of these reversal surfaces were actually arrested reversal surfaces, defined as reversal surfaces without the presence of neighbouring osteoid surfaces or osteoclasts, which is classically observed next to active reversal surfaces. As in humans, these arrested reversal surfaces had compared to active reversal surfaces a reduced canopy coverage, a significantly decreased cell density, and a decreased immunoreactivity for the osteoblastic markers osterix, runx2 and smooth muscle actin in the mononuclear reversal cells colonising the surfaces. In conclusion, glucocorticoid treatment of ovariectomised sheep induced a significant bone loss, caused by an arrest of the reversal phase, resulting in an uncoupling of the bone formation and resorption during the reversal phase, as recently demonstrated in postmenopausal women with glucocorticoid-induced osteoporosis. This supports the relevance of the sheep model to the pathophysiology of glucocorticoid-induced osteoporosis in postmenopausal women, making it a relevant preclinical model for orthopaedic implant and biomaterial research.
authors.affiliation: Orthopaedic Research Laboratory, Department of Orthopaedics and Traumatology O, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, J. B. Winsloewsvej 15 ground floor, DK-5000 Odense C, Denmark. Electronic address: cmandreasen@health.sdu.dk.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Andreasen
authors.affiliation: Orthopaedic Research Laboratory, Department of Orthopaedics and Traumatology O, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, J. B. Winsloewsvej 15 ground floor, DK-5000 Odense C, Denmark. Electronic address: ming.ding@rsyd.dk.
authors.forename: Ming
authors.initials: M
authors.lastname: Ding
authors.affiliation: Orthopaedic Research Laboratory, Department of Orthopaedics and Traumatology O, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, J. B. Winsloewsvej 15 ground floor, DK-5000 Odense C, Denmark. Electronic address: soeren.overgaard@rsyd.dk.
authors.forename: Søren
authors.initials: S
authors.lastname: Overgaard
authors.affiliation: Biomedical Laboratory, University of Southern Denmark, J. B. Winsloewsvej 23, DK-5000 Odense C, Denmark. Electronic address: PBollen@health.sdu.dk.
authors.forename: Peter
authors.initials: P
authors.lastname: Bollen
authors.affiliation: Department of Clinical Cell Biology (KCB), Vejle Hospital - Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Kabbeltoft 25, DK-7100 Vejle, Denmark. Electronic address: thomas.levin.andersen@rsyd.dk.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andersen
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000633:toxicity; D006801:Humans; D007150:Immunohistochemistry; D010012:Osteogenesis / Q000502:physiology*; D015663:Osteoporosis, Postmenopausal / Q000139:chemically induced / Q000473:pathology*; D010052:Ovariectomy; D012756:Sheep
chemical_list: D005938:Glucocorticoids
keywords: Bone markers; Bone remodelling; Coupling; Glucocorticoid-induced osteoporosis; Reversal phase; Sheep model