Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10 weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by μCT analysis and a three-point bending test of the femur, and vertebral bone strength was determined by compression testing. In the femur metaphysis and L6 vertebra, long-term diabetes (DM) induced deficits in trabecular bone microarchitecture. In the femur diaphysis, a decrease in cortical bone area, cortical thickness and minimal moment of inertia occurred in DM (p < 0.0001, for all) while cortical porosity was increased (p < 0.0001). These DM changes were associated with reduced fracture resistance (decreased material strength and toughness; decreased structural strength and rigidity; p < 0.001 for all). Significant increases in PTH (p < 0.0001), RatLAPs (p = 0.0002), and urine calcium concentration (p < 0.0001) were also seen in DM. Canagliflozin treatment improved BG in DM mice by ~35%, but did not improve microarchitectural parameters. Instead, in canagliflozin-treated diabetic mice, a further increase in RatLAPs was evident, possibly suggesting a drug-related intensification of bone resorption. Additionally, detrimental metaphyseal changes were noted in canagliflozin-treated control mice. Hence, diabetic bone disease was not favorably affected by canagliflozin treatment, perhaps due to insufficient glycemic improvement. Instead, in control mice, long-term exposure to SGLT2 inhibition was associated with adverse effects on the trabecular compartment of bone.

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Published in Bone, v. 82, p. 101-107.

Copyright © 2015 Elsevier Inc. All rights reserved.

This manuscript version is made available under the CC‐BY‐NC‐ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the author's post-peer-review final draft of the article.

A corrigendum to this article can be found at: https://doi.org/10.1016/j.bone.2016.11.021

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Funding Information

This work was supported by grants from the Children's University Medical Group fund of the Arkansas Children's Hospital Research Institute (to K.M.T.), the Arkansas Biosciences Institute (to J.L.F.), and in part by National Institutes of Health Grants R01DK055653 (to J.L.F.), and C06RR16517 (to ACHRI), as well as the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development 1I01BX001018 (to J.S.N.).