Effects of hyperglycemia on the bone microenvironment in diabetic osteoporosis

Table 1 The impact of different hypoglycemic drugs on bone metabolism

Hypoglycemic/bone-targeted class	Main mechanism of action	Effects on bone metabolism	Clinical trial/clinical evidence	Clinical note (relevance to diabetic osteoporosis)
Metformin	Activates AMPK; improves insulin sensitivity; reduces hepatic glucose output	Bone formation: May support osteogenic differentiation and bone formation	Observational studies and some clinical evidence suggest potential fracture-risk reduction or neutral-to-beneficial effects, though results are heterogeneous across cohorts/trials	Widely used as first-line therapy; bone-protective potential makes it relevant for diabetic osteoporosis management
Thiazolidinediones e.g., pioglitazone, rosiglitazone	Activate PPARγ, improving insulin sensitivity but shifting marrow fate toward adipogenesis	Bone resorption: May increase osteoclastogenic signaling	Multiple clinical studies consistently show increased fracture risk, particularly in women and at specific fracture sites (e.g., distal extremities)	Effective glycemic control comes with clear skeletal risks; limits suitability in high-risk bone disease populations
Sclerostin inhibitors (e.g., romosozumab)	Block sclerostin activate Wnt/β-catenin signaling enhance osteoblast function	Bone formation: Strong stimulation of bone formation	Phase 3 trials (e.g., FRAME/ARCH/BRIDGE) show significant increases in bone mineral density and reductions in vertebral and non-vertebral fractures. FDA-approved for osteoporosis in patients at high fracture risk	Potentially attractive for diabetic osteoporosis because of potent anabolic effects; cardiovascular risk stratification is important
GLP-1 receptor agonists	Activate GLP-1 receptor; glucose-dependent insulin secretion; reduce glucagon; slow gastric emptying	Bone formation: May enhance osteogenic signaling in some contexts	Clinical data remain more limited than for osteoporosis drugs; available evidence does not clearly indicate increased fracture risk, and some studies suggest possible bone benefits	Often chosen in diabetes patients with weight and cardiometabolic benefits; bone outcomes are still an active evidence area
SGLT2 inhibitors	Inhibit renal SGLT2 increase urinary glucose excretion	Bone formation: Net effects remain complex/uncertain	Earlier concerns (e.g., canagliflozin) suggested possible fracture risk; later evidence is more mixed and does not consistently show major harm. Further studies are needed	Strong cardio-renal advantages; bone-related outcomes require ongoing clarification in diabetic osteoporosis
		Bone resorption/mineral metabolism: Altered urinary calcium handling may affect bone remodeling, long-term effects are debated
Emerging therapies	Examples: RANKL/OPG-axis modulation, other osteoanabolic/anti-resorptive targets (e.g., novel pathway inhibitors)	Intended to restore the disequilibrium between bone formation and resorption	Mostly preclinical or early-phase clinical studies; evidence is still evolving	May broaden future treatment options once robust clinical outcome data become available

GLP-1: Glucagon-like peptide 1; SGLT2: Sodium-dependent glucose transporters 2; AMPK: Adenosine 5’-monophosphate-activated protein kinase; PPAR: Peroxisome proliferators-activated receptor; RANKL: Receptor activator of nuclear factor-kappa B ligand; OPG: Osteoprotegerin; FDA: Food and Drug Administration.