Effects of sclerostin antibodies in animal models of osteoporosis

• Published in: Bone (New York, N.Y.) Vol. 96; pp. 63 - 75
• Main Authors: Ominsky, Michael Stuart, Boyce, Rogely Waite, Li, Xiaodong, Ke, Hua Zhu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2017
• Subjects: Animal models; Animals; Antibodies - therapeutic use; Bone and Bones - pathology; Bone and Bones - physiopathology; Bone formation; Bone Morphogenetic Proteins - immunology; Bone quality; Bone Resorption - drug therapy; Disease Models, Animal; Humans; Orthopedics; Osteoporosis; Osteoporosis - drug therapy; Osteoporosis - physiopathology; Romosozumab; Sclerostin antibody; procollagen type 1 N-terminal-propeptide; TNFα; ALN; chronic kidney disease-mineral and bone disorder; Op.N; CTX; remodeling-based bone formation; DMP1; osteoblast number; laser capture microdissection; tartrate-resistant acid phosphatase type 5b; AUC; tumor necrosis factor-alpha; bone mineral density; Osteoporosis; runt-related transcription factor 2; dual-energy x-ray absorptiometry; human tumor necrosis factor transgenic mice; polycystic kidney disease; Zucker Diabetic Fatty; bone formation rate per bone surface; RBF; Romosozumab; Fourier-transform infrared microspectroscopy; MM; parathyroid hormone; multiple myeloma; W.Th; osteoprotegerin-Fc; pQCT; sclerostin antibodies; PKD; hTNFtg; DXA; DKK1; osteoprogenitor number; RUNX2; anti-drug antibody; bSEM; Ob.N; FTIRM; LCM; Bone quality; human parathyroid hormone; Animal models; Bone formation; PTH; fibroblast growth factor 23; peripheral quantitative computed tomography; P1NP; LRP4; periodontal ligament; ovariectomized; backscattered scanning electron microscopy; CKD-MBD; Dikkopf-1; lipoprotein receptor-related protein-4; MBF; OVX; area under curve; BFR/BS; Sclerostin antibody; OPG-Fc; wall thickness; BMD; PDL; alendronate; glucocorticoids; GC; FGF23; ZDF; dexamethasone; TRACP-5b; hPTH; modeling-based bone formation; carboxy-terminal collagen crosslinks; Scl-Ab; DEX; dentin matrix protein 1; ADA
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2016.10.019

Abstract There is an unmet need for therapies that can restore bone strength and reduce fracture risk among patients at high risk of osteoporotic fracture. To address this need, bone-forming therapies that increase osteoblast activity are required to help restore bone structure and strength. Sclerostin is now recognized as a target for osteoporosis therapy. Sclerostin is predominantly secreted by the osteocyte and acts as an extracellular inhibitor of canonical Wnt signaling by binding to the receptors lipoprotein receptor-related protein-4, 5 and 6. Monoclonal antibodies to sclerostin (Scl-Ab) have been used in both clinical and in preclinical studies of osteoporosis with beneficial outcomes for bone density, structure, strength and fracture risk reduction. In this review paper, we summarize the current literature describing the effects of Scl-Ab in animal models of osteoporosis. In addition, we report new pharmacologic data from three animal studies of Scl-Ab: 1) a 12-month study evaluating bone quality in ovariectomized (OVX) rats; 2) a 6-month study evaluating bone structure and strength in adolescent cynomolgus monkeys; and 3) the effects of transition from Scl-Ab to vehicle or the RANKL inhibitor osteoprotegerin-Fc in OVX rats. Together, these results demonstrate that inhibition of sclerostin by Scl-Ab increased bone formation, and decreased bone resorption, leading to improved bone structure, bone mass and bone strength while maintaining bone quality in multiple animal models of osteoporosis. Further, gains in bone mass induced by Scl-Ab treatment were preserved by antiresorptive agents such as a RANKL inhibitor as a follow-on therapy. The bone-forming effects of Scl-Ab were unaffected by pre- or co-treatment with a bisphosphonate, and were restored following a treatment-free period after initial dosing. These data support the clinical development of Scl-Ab for treatment of conditions with low bone mass such as postmenopausal and male osteoporosis.