ABSTRACT
Sclerostin antibody (Scl-Ab) restored bone mass and strength in the ovariectomized rat model of postmenopausal osteoporosis. Increased bone mineral density (BMD) and decreased skeletal fragility fracture risk have been reported in postmenopausal osteoporotic women receiving Scl-Ab. In males, loss of androgen leads to rapid decreases in BMD and an increased risk of fragility fractures. We hypothesized that Scl-Ab could reverse the loss of bone mass and strength caused by androgen ablation in the orchiectomized (ORX) rat model of male osteoporosis. We treated 9-month-old ORX Sprague Dawley rats (3 months after ORX) subcutaneously twice weekly with vehicle or Scl-Ab (5 or 25 mg/kg) for 6 weeks (n = 10 per group). Both doses of Scl-Ab fully reversed the BMD deficit in the lumbar spine and femur and tibia in ORX rats. Microcomputed tomography showed that the bone mass in the fifth lumbar vertebral body, femur diaphysis, and femoral neck were dose-dependently restored by Scl-Ab. The bone strength at these sites increased significantly with Scl-Ab to levels matching those of sham-operated controls and correlated positively with improvements in bone mineral content, demonstrating bone quality maintenance. Dynamic histomorphometry of the tibial diaphysis and second lumbar vertebral body demonstrated that Scl-Ab significantly increased bone formation on periosteal, endocortical, and trabecular surfaces and significantly decreased bone resorption on endocortical and trabecular surfaces. The effects of Scl-Ab on increasing bone formation and decreasing bone resorption led to restoration of bone mass and strength in androgen-deficient rats. These findings support the ongoing evaluation of Scl-Ab as a potential therapeutic agent for osteoporosis in men.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Bone Density Conservation Agents/therapeutic use , Bone Morphogenetic Proteins/immunology , Bone and Bones/drug effects , Disease Models, Animal , Genetic Markers/immunology , Osteogenesis/drug effects , Osteoporosis/drug therapy , Absorptiometry, Photon , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Bone Density/drug effects , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/adverse effects , Bone Morphogenetic Proteins/metabolism , Bone Resorption/prevention & control , Bone and Bones/diagnostic imaging , Bone and Bones/pathology , Dose-Response Relationship, Drug , Injections, Subcutaneous , Male , Molecular Targeted Therapy , Orchiectomy , Organ Size/drug effects , Osteoporosis/diagnostic imaging , Osteoporosis/pathology , Prostate/drug effects , Prostate/pathology , Rats, Sprague-Dawley , Seminal Vesicles/drug effects , Seminal Vesicles/pathology , Shear Strength/drug effects , Weight Gain/drug effects , X-Ray MicrotomographyABSTRACT
Sclerostin (Scl) is an osteocyte protein that decreases bone formation, and its inhibition by neutralizing antibodies (Scl-Ab) increases bone formation, mass and strength. We investigated the effects of Scl-Ab in mature ovariectomized (OVX) rats with a mechanistic focus on longer-term responses of osteoclasts, osteoblasts and osteocytes. Four-month-old Sprague-Dawley rats had OVX or sham surgery. Two months later, sham controls received sc vehicle while OVX rats received vehicle (OVX-Veh) or Scl-Ab (25mg/kg) once weekly for 6 or 26weeks followed by necropsy (n=12/group). Terminal blood was collected for biochemistry, non-adherent marrow cells were harvested from femurs for ex vivo osteoclast formation assays, and vertebrae and tibiae were collected for dynamic histomorphometry and mRNA analyses. Scl-Ab treatment led to progressively thicker but fewer trabeculae in the vertebra, leading to increased trabecular bone volume and reduced trabecular surfaces. Scl-Ab also increased cortical bone volume in the tibia, via early periosteal expansion and progressive endocortical contraction. Scl-Ab significantly reduced parameters of bone resorption at week 6 relative to OVX-Veh controls, including reduced serum TRACP-5b, reduced capacity of marrow cells to form osteoclasts ex vivo, and >80% reductions in vertebral trabecular and tibial endocortical eroded surfaces. At week 26, serum TRACP-5b and ex vivo osteoclast formation were no longer reduced in the Scl-Ab group, but eroded surfaces remained >80% lower than in OVX-Veh controls without evidence for altered skeletal mRNA expression of opg or rankl. Scl-Ab significantly increased parameters of bone formation at week 6 relative to OVX-Veh controls, including increases in serum P1NP and osteocalcin, and increased trabecular, endocortical and periosteal bone formation rates (BFRs). At week 26, surface-referent trabecular BFR remained significantly increased in the Scl-Ab group versus OVX-Veh controls, but after adjusting for a reduced extent of trabecular surfaces, overall (referent-independent) trabecular BFR was no longer significantly elevated. Similarly, serum P1NP and osteocalcin were no longer significantly increased in the Scl-Ab group at week 26. Tibial endocortical and periosteal BFR were increased at week 6 in the Scl-Ab group versus OVX-Veh controls, while at week 26 only endocortical BFR remained increased. The Scl-Ab group exhibited significant increments in skeletal mRNA expression of several osteocyte genes, with sost showing the greatest induction in both the tibia and vertebra. We propose that Scl-Ab administration, and/or the gains in bone volume that result, may have increased osteocytic expression of Scl as a possible means of regulating gains in bone mass.
