Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength in a Rat Model of Postmenopausal Osteoporosis

Abstract

The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Sixmonth-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

“…The anabolic effect was less pronounced on the periosteal surface, and the decrease in BFR/BS in both groups during the study suggested that the surgery may have resulted in transient changes in periosteal bone formation independent of treatment. Consistent with the previous reports of the effects of Scl-Ab in rats (20) and cynomolgus monkeys, (21) bone formed during Scl-Ab treatment in this study was of normal lamellar architecture with no evidence of woven bone accumulation.…”

“…These results differ from the anabolic effects of intermittent parathyroid hormone (PTH), which were associated with dose-dependent increases in cortical porosity in older OVX nonhuman primates. (33,34) Although the mechanism by which Scl-Ab reduced osteoclastic resorption is unclear, similar evidence for an antiresorptive effect with Scl-Ab administration was observed in OVX rats (20) and in healthy men and postmenopausal women. (22) However, inconsistent with the changes in histologic resorption, serum CTX was significantly increased in the Scl-Ab group at the end of the study (3.2 AE 0.3 ng/mL versus 2.5 AE 0.1 ng/mL, p < .05).…”

“…In male rats, Scl-Ab increased serum markers of bone formation, as well as bone mass and strength of the femoral midshaft, similar to a previous report in aged ovariectomized (OVX) rats. (20) Increases in bone mass in the femoral neck and trabecular distal femur also were observed. This study in male cynomolgus monkeys provided a larger sample size (n ¼ 18 to 21/group) to evaluate the skeletal effects of Scl-Ab in a remodeling species, complementing the anabolic effects reported previously in female cynomolgus monkeys (n ¼ 2 to 4/group).…”

“…Treatment with a murine Scl-Ab significantly increased bone formation on trabecular, periosteal, endocortical, and intracortical bone surfaces in a rat model of osteoporosis, leading to an increase in bone mass and bone strength. (20) Similarly, treatment with a humanized Scl-Ab resulted in increased bone formation, bone mass, and bone strength in intact nonhuman primates (21) and increased biochemical markers of bone formation in healthy men and postmenopausal women. (22) This study investigated the effects of systemic administration of Scl-Ab in two models used previously to assess the effects of therapeutic agents on fracture healing: the rat closed femoral fracture model (23) and the cynomolgus monkey fibular osteotomy model.…”

“…(17) Although the mechanism by which sclerostin negatively regulates bone formation is an area of continuing investigation, one body of research supports the hypothesis that sclerostin binds to LRP5/6 to inhibit Wnt/bcatenin signaling, (18) thus impairing osteoblast differentiation and function. Sclerostin antibodies (Scl-Abs) have been shown to neutralize the inhibitory effects of sclerostin on Wnt/b-catenin signaling in vitro (19,20) and to have significant bone anabolic activity in various species in vivo. Treatment with a murine Scl-Ab significantly increased bone formation on trabecular, periosteal, endocortical, and intracortical bone surfaces in a rat model of osteoporosis, leading to an increase in bone mass and bone strength.…”