Oral implant osseointegration is delayed by hyperglycemia-generated oxidative stress (OS). Forkhead transcription factor 1 (FoxO1) is known to be viewed as a sensor to OS since reactive oxide species like H2O2 regulates its activity. We previously demonstrated that 1,25(OH)(2)D-3 favored glucose homeostasis and implant osseointegration in diabetic rats. In this study, we investigated the role of FoxO1(OB) in the regulation process of 1,25(OH)(2)D-3 on glycometabolism and bone metabolism. We show herein that, with the treatment of 1,25(OH)(2)D-3, mice lacking FoxO1 in osteoblasts (FoxO1(OB)(-/-)) exhibited decreased serum glucose that was gradually elevated in untreated diabetic mice. An optimal increase of bone mass and bone-implant contact (BIC) was observed in 1,25(OH)(2)D-3 treated FoxO1(OB)(-/-) mice after 2-month healing. Surprisingly, FoxO1(OB)(-/-) mice without 1,25(OH)(2)D-3 treatment also showed an improvement on bone formation and BIC. Same effect could be found in the expression of bone-related markers Runx2, Osterix and BSP, which elevated in 1,25(OH)(2)D-3 treated FoxO1(OB)(-/-) mice as compared to untreated WT mice. In addition, in vitro study showed that high glucose induced FoxO1 nuclear localization while the effect was ameliorated by 1,25(OH)(2)D-3 treatment. These results suggest that FoxO1(OB) might be involved in the regulation of 1,25(OH)(2)D-3 on glucose homeostasis and bone formation, and that FoxO1(OB) might act as a key modulator of the capacity of the skeleton regulating metabolic homeostasis. Our study also provides a new idea that a combination of systemic 1,25(OH)(2)D-3 and local FoxO1 inhibitor may be a new approach to enhance implant osseointegration. (C) 2017 Elsevier Inc. All rights reserved.