Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading

• Published in: Journal of bone and mineral research Vol. 28; no. 4; pp. 865 - 874
• Main Authors: Spatz, Jordan M, Ellman, Rachel, Cloutier, Alison M, Louis, Leeann, van Vliet, Miranda, Suva, Larry J, Dwyer, Denise, Stolina, Marina, Ke, Hua Zhu, Bouxsein, Mary L
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-04-2013; Wiley Subscription Services, Inc
• Subjects: Animals; Antibodies - pharmacology; Biomarkers - metabolism; Biomechanical Phenomena - drug effects; Body Weight - drug effects; BONE; Bone and Bones - diagnostic imaging; Bone and Bones - drug effects; Bone and Bones - pathology; Bone and Bones - physiopathology; BONE DENSITY; Bone Density - drug effects; BONE LOSS; Bone Remodeling - drug effects; Female; Femur - diagnostic imaging; Femur - drug effects; Femur - pathology; Femur - physiopathology; Finite Element Analysis; Glycoproteins - blood; Glycoproteins - immunology; Hindlimb Suspension; HINDLIMB UNLOADING; Mice, Inbred C57BL; MOUSE; Muscles - drug effects; Muscles - pathology; Organ Size - drug effects; SCLEROSTIN ANTIBODY; Weight-Bearing - physiology; X-Ray Microtomography
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.1807

Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11–17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU‐SclAbII were at or above values of CON‐VEH mice. For example, hindlimb bone mineral density (BMD) decreased –9.2% ± 1.0% in HLU‐VEH, whereas it increased 4.2% ± 0.7%, 13.1% ± 1.0%, and 30.6% ± 3.0% in CON‐VEH, HLU‐SclAbII, and CON‐SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro–computed tomography (µCT) imaging of the distal femur, was lower in HLU‐VEH versus CON‐VEH (p < 0.05), and was 2‐ to 3‐fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three‐point bending, and distal femoral strength, assessed by micro–finite element analysis (µFEA), were significantly higher in SclAbII versus VEH‐groups in both loading conditions. Serum sclerostin was higher in HLU‐VEH (134 ± 5 pg/mL) compared to CON‐VEH (116 ± 6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse‐induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments. © 2013 American Society for Bone and Mineral Research.