. 2022 Aug 4;18(1):196–206. doi: 10.1016/j.jtumed.2022.07.003

Table 3.

General characteristics and outcomes of the included animal studies. DM, diabetes mellitus; BV, bone volume; BF, bone fill, BIC, bone-implant contact; BA, bone area; TV trabecular volume; TT, trabecular thickness; and immunohistochemistry.

Study	Animal model (n)	Groups		DM inclusion criteria	Implant details	Duration of study	Method of metformin administration	Metformin dose	Method of osseointegration assessment	Other variables assessed	DM outcomes	Osteointegration outcomes
Study	Animal model (n)	Test (n)	Control (n)	DM inclusion criteria	Implant details	Duration of study	Method of metformin administration	Metformin dose	Method of osseointegration assessment	Other variables assessed	DM outcomes	Osteointegration outcomes
Inouye et al. 2014³²	Wistar-Kyoto rats (non-DM) (n = 12) Goto-Kakizaki DM rats (24)	DM + MET (n = 12) DM (n = 12)	Non-DM, no treatment (n = 12)	Not defined	3 × 1 mm, Ti; replacing right maxillary molars	4 weeks	Fed in water	100 mg/kg/day	Micro-CT: BIC, BV, TN, BMD at weeks 1 and 4	Blood glucose, HbA1c, and pyridinoline	MET reduced glucose levels in diabetic mice.	No significant effect of MET observed on BIC and TN in diabetic rats. MET improved BV in diabetic rats.
Bastos et al. 2017²⁹	Wistar rats (n = 20)	MET (n = 10)	No treatment (n = 10)	N/A	4.0 × 2.2 mm, Ti; placed in tibia	30 days	Gavage	40 mg/kg/day	Histo: BIC, BA	IHC: RANKL-and OPG-positive cells	Not measured	MET reduced BIC and BA, and increased number of RANKL+ cells.
Serrão et al. 2017³¹	Diabetic rats (n = 30)	DM (n = 10) DM + MET (n = 10)	Non-diabetic, no treatment (n = 10)	>300 mg/dL	4.0 × 2.2 mm, Ti; placed in tibia	30 days	Gavage	100 mg/kg/day	Histo: BIC, BA	IHC: RANKL-and OPG-positive cells	Not measured	MET did not have significant effect on BIC and BA but increased OPG+ cells, decreasing RANKL/OPG ratio.
Lin et al. 2020³³	Sprague Dawley rats (n = 30)	Sham surgery (n = 10) OVX + MET (n = 10) OVX only (n = 10)	Not specified	None	3 × 1.5 mm, Ti; replacing right maxillary molars	14 days	Injected into implant site (in PBS)	20 mg/ml/day	Micro-CT: BV/TV %, TT, TS, TN	IHC: Calcified bone matrix	Not measured	MET accelerated osseointegration and bone formation in osteoporotic rat model.
Yıldırım et al. 2020²⁸	Sprague Dawley rats (n = 20)	MET (n = 10)	No treatment (n = 10)	N/A	4 × 2.5 mm, Ti; placed in tibia	28 days	Gavage	40 mg/kg/day	Histological: BF ratios	None	Not measured	MET induced higher periimplant BF ratios.
Sun et al. 2021³⁰	Wistar rats (n = 18)	MET-50 (n = 6) MET-100 (n = 6)	No treatment (n = 6)	N/A	3 × 2 mm, Ti; placed in femur	4 weeks	Gavage	MET-50: 50 mg/kg/day MET-100: 100 mg/kg/day	Histo: BIC	None	Not measured	MET increased BIC. 100 mg/kg/day Met had higher impact on BIC than 50 mg/kg/day.