Aug 2026· International Journal of Molecular Medicine· Vol 58· 0 citations· 200 references
Medicine
TL;DR
It is demonstrated that abnormal glucose metabolism is a key pathogenic mechanism in osteoporosis and that targeting insulin signaling may represent a fundamental strategy for correcting glucose metabolic abnormalities across diverse etiologies.
Abstract
Osteoporosis is a systemic skeletal disease characterized by progressive bone loss and an increased risk of fracture, and it represents a major public health challenge worldwide. Osteoporosis has multiple pathogenic determinants, including age, endocrine disorders and medication. Current therapeutic approaches primarily aim to promote osteogenesis directly or inhibit osteoclast activity; however, these strategies may limit therapeutic efficacy and increase the risk of adverse effects. The present review provided an integrated perspective on the pathogenesis of osteoporosis from the standpoint of glucose metabolism. Glucose oxidation generates ATP and metabolic intermediates that are key to bone homeostasis. During early differentiation, mesenchymal stem cells rely predominantly on glycolysis during commitment toward pre-osteoblasts, whereas maturation into functional osteoblasts depends more notably on oxidative phosphorylation. The fusion and differentiation of osteoclasts require robust mitochondrial oxidation. Lactate derived from anaerobic metabolism has a dual role in bone metabolism. High-risk populations for osteoporosis include postmenopausal women, patients with type 2 diabetes mellitus and individuals with obesity. Estrogen exerts anti-inflammatory and antioxidant effects through receptor activation. Excessive production of advanced glycation end-products disrupts the bone matrix, whereas hyperlipidemia promotes inflammatory factor-induced bone resorption. These pathological changes disrupt the insulin receptor substrate/PI3K/AKT signaling pathway, compromise glucose transporter-mediated cellular glucose uptake and thus, contribute to relative insulin resistance and insufficiency compared with physiological states. In conclusion, the present review demonstrated that abnormal glucose metabolism is a key pathogenic mechanism in osteoporosis and that targeting insulin signaling may represent a fundamental strategy for correcting glucose metabolic abnormalities across diverse etiologies.
Osteoporosis is the most prevalent chronic metabolic bone disease, affecting approximately 200 million individuals worldwide. With the rapid acceleration of global aging, osteoporosis has emerged as a major global health challenge, significantly increasing the occurrence rate of fractures and the associated medical burden. In recent years, considerable progress has been made in understanding the molecular mechanisms underlying osteoporosis, including bone remodeling, osteoblast-osteoclast communication, and signaling pathways such as RANKL/RANK/OPG and Wnt/β-catenin. These mechanistic studies have been translated into clinical applications. Emerging therapies, including targeted biologics and precision medicine approaches, offer novel strategies and methods for future prevention and treatment. This review summarizes recent advances in research, with a particular focus on therapeutic agents and mechanistic studies of osteoporosis. Following the mainline of “mechanism–target–translation,” this review proposes new research perspectives and approaches, and provides an outlook on future research directions for the disease, aiming to promote the development of more effective diagnostic and therapeutic strategies.
Ping Xie, Jie Cai, Zheng-Jie Yu et al.· Frontiers in Endocrinology· 0 citations
A practical clinical framework is proposed that integrates endocrine phenotype, vertebral imaging, trabecular bone score, and biochemical assessment into fracture-risk stratification and therapeutic decision-making, enabling improved identification of high- and very-high-risk patients and facilitating the appropriate use of anabolic and antiresorptive therapies.
I. Cincione, Robert A. Marcantonio, Marcellino Monda et al.· Frontiers in Endocrinology· 0 citations
Purpose of review This review aims to summarize recent advances in the mechanistic understanding of senile osteoporosis, with particular focus on the interconnected roles of cellular senescence, metabolic dysfunction, and systemic homeostatic imbalance in age-related skeletal degeneration. Recent findings Emerging evidence indicates that senile osteoporosis is not driven solely by age-related hormonal decline, but by a complex network of biological processes involving senescence of bone marrow mesenchymal stem cells, accumulation of the senescence-associated secretory phenotype, mitochondrial dysfunction, oxidative stress, chronic low-grade inflammation, and disturbances in glucose and lipid metabolism. These alterations disrupt bone remodeling through key signaling pathways, including RANKL/OPG, Wnt/β-catenin, AMPK/SIRT1, NF-κB, and PI3K/Akt/mTOR. Together, these mechanisms impair osteogenesis, enhance osteoclastogenesis, deteriorate bone microarchitecture, and increase skeletal fragility. This broader pathophysiological framework may explain why conventional antiresorptive therapies, although effective in reducing bone resorption, often fail to fully restore the structural and functional deficits of the aging skeleton. Summary Senile osteoporosis should be viewed as a systemic aging-related disorder involving both deterioration of the local bone microenvironment and whole-body metabolic dysregulation. Current evidence-based pharmacological treatments, including bisphosphonates, denosumab, teriparatide, abaloparatide, and romosozumab, remain central to fracture prevention and bone mass preservation. However, these interventions do not fully reverse the biological processes of skeletal aging. Emerging strategies targeting cellular senescence, the senescence-associated secretory phenotype, mitochondrial dysfunction, oxidative stress, nutrient-sensing pathways, and gut microbiota are under active investigation and may complement established therapies in the future. A clearer distinction between approved anti-osteoporotic drugs and experimental geroscience-based interventions is essential for translating mechanistic insights into clinically meaningful treatment strategies.
Ruifeng Bai, Zi-Shuai Huang, Xuan Tian et al.· Frontiers in Aging· 0 citations
Bone metabolism-related disorders represent a significant global health burden, due to their high prevalence and substantial socioeconomic costs, particularly osteoporosis. Conventional antiresorptive and anabolic agents have well-established clinical utility, such as bisphosphonates, denosumab, teriparatide, and romosozumab. Nevertheless, their long-term clinical use remains limited by safety concerns and inadequate efficacy in a subset of patients. In this review, we highlight recent chemical innovations designed to mechanistically reprogram the skeletal microenvironment and overcome those longstanding barriers. We also analyze how the metabolic coupling signals govern bone bioenergetics, particularly within the Wnt and RANKL axes. We place specific focus on three emerging and transformative strategies: proteolysis-targeting chimeras (PROTACs), bone-targeted senolytics, and direct metabolic modulators. Ultimately, we provide a multidisciplinary roadmap for the development of next-generation therapeutics to achieve durable skeletal restoration in patients with bone metabolic disorders.
Yeqiong Song, Rui-Xin Zhang, Xin-Yu Zhang et al.· Frontiers in Chemistry· 0 citations
Results indicate that radiofrequency echographic multispectrometry provides BMD and fracture risk assessment comparable to DXA in patients on peritoneal dialysis, while also highlighting the impact of vascular calcifications on the diagnostic accuracy of lumbar spine DXA measurements.
O. I. Nishkumay, O. B. Iaremenko, V. Kondratiuk et al.· International Journal of End...· 0 citations
Osteoporosis is a systemic skeletal disease characterized by low bone mass, deterioration of bone microarchitecture, and increased fracture risk, which imposes a heavy burden on global public health, especially in postmenopausal women and the elderly. The gut-bone axis, a bidirectional regulatory network between the gut microbiota and bone metabolism, has emerged as a novel therapeutic target for osteoporosis. Indole derivatives, a class of bioactive compounds derived from tryptophan metabolism by gut microbiota or plant secondary metabolism, have attracted increasing attention due to their extensive biological activities, including anti-inflammatory, antioxidant, and metabolic regulatory effects. Accumulating evidence indicates that indole derivatives can regulate bone homeostasis through the gut-bone axis, providing a new strategy for the prevention and treatment of osteoporosis. This review systematically summarizes the types of indole derivative, elaborates their molecular mechanisms in the treatment of osteoporosis via the gut-bone axis (including regulating gut microbiota composition, maintaining intestinal barrier integrity, modulating immune-inflammatory responses, and mediating key signaling pathways), and discusses the current translational progress, existing challenges, and future prospects. This review aims to provide a comprehensive theoretical basis for the clinical application of indole derivatives in osteoporosis treatment and the development of novel targeted drugs.
Wen-Dong Wang· Frontiers in Cellular and In...· 0 citations
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