title: Sclerostin antibody prevented progressive bone loss in combined ovariectomized and concurrent functional disuse.
abstract: Osteoporosis is characterized by low bone mass and compromised trabecular architecture, and is commonly occurred in post-menopausal women with estrogen deficiency. In addition, prolonged mechanical unloading, i.e., long term bed rest, can exaggerate the bone loss. Sclerostin is a Wnt signaling antagonist and acts as a negative regulator for bone formation. A sclerostin-neutralizing antibody (Scl-Ab) increased bone mineral density in women with postmenopausal osteoporosis and healthy men. The objective of this study was to characterize the condition of bone loss in ovariectomized (OVX) rats with concurrent mechanical unloading and evaluate the effect of sclerostin antibody treatment in mitigating the prospective severe bone loss conditions in this model. Four-month-old OVX- or sham-operated female SD rats were used in this study. They were subjected to functional disuse induced by hind-limb suspension (HLS) or free ambulance after 2days of arrival. Subcutaneous injections with either vehicle or Scl-Ab at 25mg/kg were made twice per week for 5weeks from the time of HLS. μCT analyses demonstrated a significant decrease in distal metaphyseal trabecular architecture integrity with HLS, OVX and HLS+OVX (bone volume fraction decreased by 29%, 71% and 87% respectively). The significant improvements of various trabecular bone parameters (bone volume fraction increased by 111%, 229% and 297% respectively as compared with placebo group) with the administration of Scl-Ab are associated with stronger mechanical property and increased bone formation by histomorphometry. These results together indicate that Scl-Ab prevented the loss of trabecular bone mass and cortical bone strength in OVX rat model with concurrent mechanical unloading. The data suggested that monoclonal sclerostin-neutralizing antibody represents a promising therapeutic approach for severe osteoporosis induced by estrogen deficiency with concurrent mechanical unloading.
authors: Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States.
authors: Dongye
authors: D
authors: Zhang
authors: Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States.
authors: Minyi
authors: M
authors: Hu
authors: Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States.
authors: Timothy
authors: T
authors: Chu
authors: Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States.
authors: Liangjun
authors: L
authors: Lin
authors: Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States.
authors: Jingyu
authors: J
authors: Wang
authors: Dept. of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, United States.
authors: Xiaodong
authors: X
authors: Li
authors: UCB Pharma, Slough, UK.
authors: Hua Zhu
authors: HZ
authors: Ke
authors: Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States. Electronic address: yi-xian.qin@stonybrook.edu.
authors: Yi-Xian
authors: YX
authors: Qin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D001862:Bone Resorption / Q000150:complications* / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005819:Genetic Markers / Q000276:immunology*; D007091:Image Processing, Computer-Assisted; D020966:Muscular Disorders, Atrophic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D010052:Ovariectomy; D017207:Rats, Sprague-Dawley; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D000906:Antibodies; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Histomorphometry; Mechanical unloading; Post-menopause; Sclerostin antibody; Severe osteoporosis