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

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Abstract

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.

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Acknowledgements

Funding and specimens were provided by Amgen Inc. and UCB Pharma. Cornell’s National Science Foundation (NSF) Grant DGE-1,144,153, NSF Graduate Research Fellowship Program (to JBM), NSF Graduate Research Fellowship Program (to AMT), and a Cornell Colman fellowship (to AMT)

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Authors and Affiliations

  1. Sibley School of Mechanical and Aerospace Engineering, Cornell University, 355 Upson Hall, Ithaca, NY, 14853, USA

    Jonathan B. Matheny, Ashley M. Torres & Christopher J. Hernandez

  2. Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA

    Jonathan B. Matheny, Ashley M. Torres & Christopher J. Hernandez

  3. Department of Cardiometabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA

    Michael S. Ominsky

  4. Hospital for Special Surgery, New York, NY, USA

    Christopher J. Hernandez

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  1. Jonathan B. Matheny
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  2. Ashley M. Torres
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Correspondence to Christopher J. Hernandez.

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Conflicts of interest

Michael Ominsky reports personal fees from Amgen Inc during the conduct of the study; personal fees from Amgen Inc outside the submitted work. Jonathan Matheny and Ashley Torres report non-financial support from Amgen Inc, and UCB Pharma (supplied specimens) during the conduct of the study. Christopher Hernandez reports grants and non-financial support from Amgen Inc and UCB Pharma (supplied specimens) during the conduct of the study. The authors have full control of primary data and agree to journal review of the data if requested.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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223_2017_258_MOESM2_ESM.tif

Correlation Scatterplots for measurements of stiffness derived from high-resolution finite element models and traditional and ITS-based measurements of bone microstructure are shown (TIF 3040 KB)

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Matheny, J.B., Torres, A.M., Ominsky, M.S. et al. Romosozumab Treatment Converts Trabecular Rods into Trabecular Plates in Male Cynomolgus Monkeys. Calcif Tissue Int 101, 82–91 (2017). https://doi.org/10.1007/s00223-017-0258-3

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  • DOI: https://doi.org/10.1007/s00223-017-0258-3

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