Skeletal effects of bazedoxifene paired with conjugated estrogens in ovariectomized rats.

A novel approach to menopausal therapy is the tissue selective estrogen complex (TSEC) that partners bazedoxifene (BZA) with conjugated estrogens (CE). We examined the effects of daily treatment with BZA 0.3mg/kg, CE 2.5mg/kg, or combined BZA/CE (BZA 0.1, 0.3, or 1.0mg/kg with CE 2.5mg/kg) over 12months on bone mass, bone architecture and strength, and biochemical markers of bone turnover in ovariectomized (OVX) female Sprague-Dawley rats vs OVX control rats. Total cholesterol and uterine weights were also evaluated. All BZA/CE dose combinations prevented ovariectomy-induced increases in bone turnover and significantly increased bone mineral density (BMD) at the lumbar spine, proximal femur, and tibia compared with OVX controls. All BZA/CE doses evaluated also prevented many of the ovariectomy-induced changes of the static and dynamic parameters of the cortical compartment of the tibia and the cancellous compartment of the L1 and L2 vertebrae. All BZA/CE doses increased biomechanical strength at the lumbar spine (L4) compared with OVX animals. The co-administration of BZA 0.3 and 1.0mg/kg/day with CE 2.5mg/kg/day showed a dose-dependent reduction in uterine wet weight compared with administration of CE alone. All BZA/CE doses significantly lowered total cholesterol levels compared with OVX controls. In conclusion, 12months of treatment with BZA/CE in OVX rats effectively maintained BMD, bone microstructure, and bone quality; and the pairing of BZA with CE prevented CE-induced uterine stimulation.

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

Therapeutic enhancement of fracture healing would help to prevent the occurrence of orthopedic complications such as nonunion and revision surgery. Sclerostin is a negative regulator of bone formation, and treatment with a sclerostin monoclonal antibody (Scl-Ab) results in increased bone formation and bone mass in animal models. Our objective was to investigate the effects of systemic administration of Scl-Ab in two models of fracture healing. In both a closed femoral fracture model in rats and a fibular osteotomy model in cynomolgus monkeys, Scl-Ab significantly increased bone mass and bone strength at the site of fracture. After 10 weeks of healing in nonhuman primates, the fractures in the Scl-Ab group had less callus cartilage and smaller fracture gaps containing more bone and less fibrovascular tissue. These improvements at the fracture site corresponded with improvements in bone formation, bone mass, and bone strength at nonfractured cortical and trabecular sites in both studies. Thus the potent anabolic activity of Scl-Ab throughout the skeleton also was associated with an anabolic effect at the site of fracture. These results support the potential for systemic Scl-Ab administration to enhance fracture healing in patients.

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

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.