Romosozumab Treatment Converts Trabecular Rods into Trabecular Plates in Male Cynomolgus Monkeys

Treatment with sclerostin antibody (romosozumab) increases bone formation while reducing bone resorption, leading to increases in bone volume and bone mineral density. Sclerostin antibody treatment may also provide beneficial changes in trabecular microarchitecture and strength that are not reflected in bone volume and density. Here we use three-dimensional dynamic histomorphometry to determine longitudinal changes in vertebral trabecular microarchitecture in adolescent male cynomolgus monkeys (4–5 years old) treated with sclerostin antibody. Animals were treated bi-weekly with either sclerostin antibody (30 mg/kg, sc, n = 6) or vehicle (n = 6) for 10 weeks. Animals were administered fluorochrome bone formation labels on days 14 and 24 (tetracycline) and on days 56 and 66 (calcein), followed by necropsy on day 70. Cylindrical specimens of cancellous bone from the 5th lumbar vertebrae were used to generate high-resolution, three-dimensional images of bone and fluorescent labels of bone formation (0.7 × 0.7 × 5.0 µm/voxel). The three-dimensional images of the bone formation labels were used to determine the bone volume formed between days 14 and 66 and the resulting alterations in trabecular microarchitecture within each bone. Treatment with sclerostin antibody resulted in a conversion of rod-like trabeculae into plate-like trabeculae at a higher rate than in vehicle-treated animals (p = 0.01). Plate bone volume fraction was greater in the sclerostin antibody group relative to vehicle (mean 43 vs. 30%, p < 0.05). Bone formation increased the thickness of trabeculae in all three trabecular orientations (axial, oblique, and transverse, p < 0.05). The volume of bone formed between days 14 to 66 was greater in sclerostin antibody-treated groups (9.0 vs. 5.4%, p = 0.02), and new bone formation due to sclerostin antibody treatment was associated with increased apparent stiffness as determined from finite element models. Our results demonstrate that increased bone formation associated with sclerostin antibody treatment increases plate-like trabecular morphology and improves mechanical performance.