Reversal of the diabetic bone signature with anabolic therapies in mice

Abstract

The mechanisms underlying the bone disease induced by diabetes are complex and not fully understood; and antiresorptive agents, the current standard of care, do not restore the weakened bone architecture. Herein, we reveal the diabetic bone signature in mice at the tissue, cell, and transcriptome levels and demonstrate that three FDA-approved bone-anabolic agents correct it. Diabetes decreased bone mineral density (BMD) and bone formation, damaged microarchitecture, increased porosity of cortical bone, and compromised bone strength. Teriparatide (PTH), abaloparatide (ABL), and romosozumab/anti-sclerostin antibody (Scl-Ab) all restored BMD and corrected the deteriorated bone architecture. Mechanistically, PTH and more potently ABL induced similar responses at the tissue and gene signature levels, increasing both formation and resorption with positive balance towards bone gain. In contrast, Scl-Ab increased formation but decreased resorption. All agents restored bone architecture, corrected cortical porosity, and improved mechanical properties of diabetic bone; and ABL and Scl-Ab increased toughness, a fracture resistance index. Remarkably, all agents increased bone strength over the healthy controls even in the presence of severe hyperglycemia. These findings demonstrate the therapeutic value of bone anabolic agents to treat diabetes-induced bone disease and suggest the need for revisiting the approaches for the treatment of bone fragility in diabetes.

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Funding

U.S. Department of Veterans Affairs (Department of Veterans Affairs)(VA-IK6BX004596)

U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)(R01-AR059357)

American Society of Hematology (ASH)(Junior Faculty Scholar Award)

U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)(KL2TR003108)

U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)