Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength

Abstract

The development of bone-rebuilding anabolic agents for treating bone-related conditions 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. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis. ß

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.…”

“…(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). An increase in serum CTX with Scl-Ab was not observed previously in female nonhuman primates (21) and may have been related to increased bone turnover at the fracture site and the greater callus size in the Scl-Ab group. Patients with tibia fractures were reported to have greater postfracture increases in serum CTX than patients with smaller malleolar fractures.…”

“…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). (21) Scl-Ab significantly increased DXA-determined BMD at the lumbar spine, total hip, femoral neck, and distal radius. The increase in lumbar spine BMD was associated with significant improvement in peak compressive load of the lumbar vertebrae.…”

“…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.…”

Sclerostin: A gem from the genome leads to bone-building antibodies

“…In gonad-intact female cynomolgus monkeys, shortterm dosing of Scl-Ab produced a strong anabolic response in both trabecular and cortical bone. (90) In this study, a oncemonthly administration of Scl-Ab for 2 months resulted in marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Significant increases in bone mineral content and/or bone mineral density were found at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis).…”