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Original Article | Open Access

Reversal of the diabetic bone signature with anabolic therapies in mice

Silvia Marino1,2, Nisreen Akel1,2, Shenyang Li2, Meloney Cregor1,2, Meghan Jones1, Betiana Perez1, Gaston Troncoso1, Jomeeka Meeks1, Scott Stewart3, Amy Y. Sato1,2, Intawat Nookaew4,5, Teresita Bellido1,2,5 ( )
Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Central Arkansas Veterans Healthcare System, John L. McClellan Little Rock, Little Rock, AR, USA
Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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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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Bone Research
Volume 11,
December 2023
Article number: 19
DOI: 10.1038/s41413-023-00261-0
Cite this article:
Marino S, Akel N, Li S, et al. Reversal of the diabetic bone signature with anabolic therapies in mice. Bone Research, 2023, 11: 19. https://doi.org/10.1038/s41413-023-00261-0

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Received: 10 January 2023
Revised: 01 March 2023
Accepted: 22 March 2023
Published: 19 April 2023
© The Author(s) 2023

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