Diabetic bone fragility through advanced glycation end product-collagen axis: Mechanisms and therapy of sodium glucose cotransporter 2 inhibitors

Table 5 Research progress on anti-glycation compounds

Intervention	Model and type	Dosage and duration	Evaluation indicators	Summary of main findings	Ref.
Aminoguanidine (AGE formation inhibitor)	db/db genetic T2DM mice (in vivo)	100 mg/kg/day, intraperitoneal injection, 8 weeks (estimated)	Femoral BMD, microarchitecture, biomechanical strength	Reduced AGE accumulation in bone matrix; increased BMD and trabecular number; significantly improved 3-point bending load	[8]
Pyridoxamine (AGE formation inhibitor)	STZ-induced T1DM bone defect model (in vivo); MC3T3-E1 osteoblasts (in vitro)	1 g/L in drinking water for 4 weeks; 50-500 μM for cells	Bone defect CT imaging, histology; ALP activity	Accelerated bone defect healing; increased bone density in defect site within 7-14 days; rescued MGO-induced ALP suppression in vitro	[91]
Metformin (AGE inhibition/antihyperglycemic)	db/db T2DM mice (in vivo)	200 mg/kg/day, oral gavage, 12 weeks (estimated)	Bone volume fraction (BV/TV), biomechanical strength	Increased trabecular bone volume and cortical thickness; improved bending strength; inhibited AGE accumulation in bone	[8]
ALT-711 (AGE crosslink breaker)	Cy/+ chronic kidney disease rats (diabetic osteoporosis-like, in vivo)	3 mg/kg/day, intraperitoneal injection, 10 weeks	Bone AGE content, porosity, mechanical strength	Decreased total bone AGE levels and cortical porosity; no significant improvement in biomechanical strength	[104]
FPS-ZM1 (RAGE small-molecule antagonist)	High-glucose-treated bone marrow mesenchymal stem cells (in vitro)	5 μM for 24 hours	Inflammatory markers (e.g., IL-6), osteogenic markers	Inhibited RAGE and TXNIP/NLRP3 inflammasome; reduced IL-1β and IL-6; upregulated ALP and osteogenic gene expression	[107]
Silybin (natural flavonolignan)	STZ-induced diabetic rats (in vivo); MC3T3-E1 cells (in vitro)	50 mg/kg/day intraperitoneal injection, 6 weeks; 100 μM in cells	BMD, bone strength; osteoblast apoptosis rate	Attenuated diabetic bone loss, increased BMD; inhibited AGE-induced apoptosis by downregulating RAGE and mitochondrial pathway	[111]
Resveratrol (natural polyphenol)	STZ-induced diabetic bone defect model (in vivo)	10 mg/kg/day oral gavage, 8 weeks	Bone regeneration (μCT), serum AGE levels	Promoted mineralized bone formation in defect site; reduced AGE deposition in bone; improved bone matrix quality	[112]

AGE: Advanced glycation end-product; T2DM: Type 2 diabetes mellitus; STZ: Streptozotocin; T1DM: Type 1 diabetes mellitus; MC3T3-E1: Mouse calvaria preosteoblast cell line; Cy/+: Heterozygous cyclophilin mutant (chronic kidney disease model); BMD: Bone mineral density; CT: Computed tomography; ALP: Alkaline phosphatase; BV/TV: Bone volume/total volume; IL-6: Interleukin-6; μCT: Micro-computed tomography; MGO: Methylglyoxal; RAGE: Receptor for advanced glycation end-products; TXNIP: Thioredoxin-interacting protein; NLRP3: NACHT, LRR and PYD domains-containing protein 3; IL-1β: Interleukin-1β.