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.

Table 2 Molecular pathway effects on osteoblasts/osteoclasts

Molecular pathway/axis	Upstream trigger in hyperglycemia (DOP context)	Effects on osteoblasts/osteogenic lineage	Effects on osteoclasts/resorption	Potential therapeutic targets (examples)
AGEs-RAGE axis	Non-enzymatic glycation of bone ECM proteins (especially type I collagen) AGEs accumulation; AGEs binding to RAGE	Impairs proliferation, differentiation, mineralization; promotes apoptosis/senescence through stress signaling	Enhances pro-resorptive inflammatory milieu that favors osteoclast activity; may indirectly upregulate osteoclastogenesis	AGE formation inhibitors; RAGE antagonists or soluble RAGE; agents reducing AGE-protein crosslinking; downstream anti-inflammatory modulation
NF-κB driven inflammatory signaling	ROS/AGEs stimulate inflammatory cascades in bone microenvironment	Inhibits osteoblast differentiation and function; accelerates apoptosis via inflammatory signals	Promotes osteoclastogenesis and survival via inflammatory cytokines	NF-κB pathway inhibitors; cytokine/immune modulators (e.g., TNF-α/IL-1β/IL-6 axis)
Oxidative stress/ROS mitochondria dysfunction (general)	High glucose mitochondrial ETC dysfunction + autoxidation excess ROS; reduced endogenous antioxidant defenses	Cellular damage leads to impaired anabolic programs and energy depletion; increases susceptibility to ROS and apoptosis	ROS supports osteoclast differentiation/function (osteoclast activity rises under oxidative/inflammatory conditions)	Antioxidants; Nrf2 activators; mitochondrial protective strategies; ROS scavengers
FOXO-Nrf2 intrinsic stress-defense network	Sustained oxidative damage under hyperglycemia weakens stress-response programs	Reduced FOXO activity (decrease) autophagic clearance; impaired Nrf2 (decrease) antioxidant enzyme synthesis (e.g., SOD) osteoblast/osteocyte vulnerability	Indirectly supports a higher-resorption phenotype by maintaining high oxidative/inflammatory stress	Activate FOXO/Nrf2 pathways; enhance antioxidant enzyme capacity; autophagy-restoring interventions
Wnt/β-catenin pathway	Oxidative stress/AGEs induce endogenous antagonists (e.g., Dkk1, sclerostin) β-catenin phosphorylation/degradation	Inhibits nuclear translocation of β-catenin downregulation of osteogenic targets (e.g., Runx2); suppresses osteoblast activity and mineralization	Reduced osteogenic signaling may exacerbate remodeling imbalance; osteoclast activity can be indirectly favored	Sclerostin inhibition (e.g., romosozumab); Wnt pathway agonism; block Wnt antagonists (e.g., Dkk1-related strategies)
RANKL/OPG axis	Hyperglycemia alters osteoblast/osteocyte secretion: RANKL (increase), OPG (decrease) elevated RANKL/OPG ratio	Osteogenesis impaired in parallel with inflammatory/oxidative stress, disrupting coupling	Directly promotes osteoclast recruitment, fusion, and activation through RANK receptor signaling	RANKL/RANK blockade strategies; restore OPG-like decoy function; pathway modulation to normalize RANKL/OPG balance
BMP/Smad pathway	High glucose interferes with BMP ligand–receptor binding; disrupts phosphorylation and nuclear translocation of Smad1/5/8	Blocks directed differentiation of osteoprogenitors; prevents activation of osteogenic transcription factors (e.g., Osterix)	Indirectly contributes to altered remodeling balance (weaker bone formation coupled with persistent resorption)	Restore BMP signaling efficiency; target upstream regulators interfering with BMP receptor/Smad activation; osteoanabolic BMP-pathway modulation
Mitochondrial dysfunction and metabolic rewiring (OXPHOS glycolysis)	High glucose damages mitochondrial ETC ATP production inefficiency; energy stress	ATP deficiency compromises energy-dependent anabolic processes; metabolic shift to glycolysis reduces efficiency and promotes lactate/acidification	Metabolic/inflammatory changes in niche favor pro-resorptive remodeling environment	Mitochondria/energy-restoration therapies; metabolic modulators improving OXPHOS efficiency; microenvironment pH/energy-supportive strategies
Osteoimmunology-coupled inflammation (cytokine-driven remodeling)	Hyperglycemia-evoked oxidative stress/AGEs activate immune and non-immune cells in marrow	Inflammatory milieu inhibits osteoblast proliferation/differentiation and promotes apoptosis	Cytokine-driven signaling strongly promotes osteoclastogenesis via RANKL-related mechanisms	Immune modulation; cytokine targeting; integrated multi-pathway anti-inflammatory regimens
Senescence/autophagy apoptosis imbalance	High glucose suppresses autophagy and accelerates apoptosis/senescence in bone cells	Loss of survival/repair capacity; impaired regenerative signaling and osteogenic competence	Osteoclastogenic remodeling environment worsens as niche health declines	Senolytics; autophagy-enhancing agents; anti-apoptotic/repair-supportive approaches
Type H vessels/angiogenesis-osteogenesis coupling (endothelial metabolic dysregulation)	Hyperglycemia-induced endothelial metabolic dysregulation damages angiogenesis	Reduced vessel support weakens nutrient/oxygen delivery and osteogenic signaling in the niche	Indirectly promotes remodeling imbalance by impairing microvascular supply supporting coupling	Target endothelial metabolic dysfunction; promote H-type vessel formation; restore vessel–bone coupling

DOP: Diabetic osteoporosis; AGEs: Advanced glycation end products; RAGE: Receptor for advanced glycation end products; NF-κB: Nuclear factor kappa-B; ROS: Reactive oxygen species; BMPs: Bone morphogenetic protein; RANKL: Receptor activator of nuclear factor-kappa B ligand; OPG: Osteoprotegerin; OXPHOS: Oxidative phosphorylation; ETC: Electron transport chain; ATP: Adenosine triphosphate; ECM: Extracellular matrix; Dkk1: Dickkopf-related protein 1; SOD: Superoxide dismutase; RANK: Receptor activator of nuclear factor-kappa B; TNF: Tumor necrosis factor; IL: Interleukin; pH: Potential of hydrogen.