Molecular mechanisms and preclinical evidence of natural products in diabetic osteoporosis: a review

Diabetic osteoporosis (DOP) is a prevalent and severe skeletal complication of diabetes, characterized by reduced bone mass, impaired bone microarchitecture, and elevated fracture risk. Its pathogenesis involves multiple interconnected mechanisms, including hyperglycemia-induced accumulation of advanced glycation end products (AGEs), oxidative stress, chronic inflammation, immune dysregulation, and programmed cell death of bone-related cells. Conventional therapies targeting single pathways often yield limited benefits, underscoring the need for alternative approaches. Traditional natural products and herbal formulations have long been used as complementary strategies for DOP prevention and treatment, exhibiting multifaceted protective effects. Experimental studies have demonstrated that bioactive compounds derived from these products can attenuate AGEs toxicity, reduce oxidative stress, modulate inflammation within the bone microenvironment, and regulate osteoblast and osteoclast apoptosis, autophagy, ferroptosis, and pyroptosis, thereby restoring the balance between bone formation and resorption. Some compounds also influence epigenetic regulation and cellular senescence and indirectly contribute to bone remodeling through modulation of gut microbiota, bone angiogenesis, and endocrine signaling. Stimulus-responsive delivery systems have been investigated to enhance bioavailability and bone-targeting efficiency. This review provides a comprehensive and updated overview of natural products and their active constituents in DOP management, highlighting underlying molecular mechanisms and potential therapeutic targets to support rational application and drug development.