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Review Open Access

Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review)

  • Authors:
    • Yangyi Cheng
    • Jingyuan Gao
    • Yuyang Yang
    • Lei Xing
    • Xiaoli Hou
    • Liu Zhang
    • Faming Tian
  • View Affiliations / Copyright

    Affiliations: Department of General Medicine, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P.R. China, Bone Metabolism Research Group, School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, P.R. China
    Copyright: © Cheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 84
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    Published online on: May 11, 2026
       https://doi.org/10.3892/br.2026.2157
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Abstract

Osteoporosis and diabetes typically occur together. The present review aimed to summarize the molecular mechanisms and intracellular signaling pathways that connect osteoporosis and diabetes. In diabetic conditions, persistent hyperglycemia triggers excessive oxidative stress, sustains low‑grade inflammation and perturbs insulin signaling pathways. In turn, bone metabolic abnormalities affect glucose regulation through the bone‑pancreas axis and osteoimmune signaling pathways, highlighting a bidirectional relationship between skeletal and metabolic health. Several antidiabetic agents (metformin, glucagon‑like peptide‑1 receptor agonists) protect against bone loss, while certain anti‑osteoporotic drugs (bisphosphonates, denosumab) exert favorable effects on glucose metabolism and diabetic complications. These dual benefits suggest overlapping molecular pathways and shared therapeutic targets. The present review aimed to summarize the inflammation‑insulin signaling axis, RANKL/OPG system, Wnt/β‑catenin pathway, AGE/RAGE signaling and bone‑derived endocrine factors as key mediators of interorgan communication. It also underscores the importance of systems biology and integrated cross‑tissue analyses in uncovering the mechanisms underlying diabetes‑associated bone disorder. Future research defining the molecular basis of intercellular and interorgan crosstalk may lead to precise, mechanism‑driven strategies for the integrated treatment of diabetes and osteoporosis.
View Figures

Figure 1

Inflammatory cytokine-mediated
signaling pathways involved in the interaction between glucose
metabolism and bone remodeling. (A) In skeletal muscle and
hepatocytes, inflammatory cytokines (TNF-α, IL-1β and IL-6) bind
cytokine receptors and activate the NF-κB, JNK and p38 signaling
pathways. These pathways are associated with the insulin signaling
cascade, including phosphorylation of IRS-1 and IRS-2 and
activation of the PI3K/AKT pathway. This process is associated with
GLUT4 vesicle translocation to the plasma membrane and glucose
uptake. Key signaling molecules such as FoxO1, SOCS3 and P65/P50
are expressed in the cytoplasm and, upon activation, translocate to
the nucleus to regulate the transcription of genes involved in
insulin resistance, inflammation and osteoblast differentiation.
(B) In osteoblasts, inflammatory cytokines activate multiple
intracellular signaling pathways via their receptors, including
NF-κB, JNK, p38 and FoxO1. These signaling events are associated
with transcriptional regulation in the nucleus, involving
osteogenic transcription factors such as Runx2 and osterix.
Molecules such as Bax are associated with apoptotic processes. (C)
In osteoclast precursor cells, RANKL binds to RANK on the cell
surface, recruiting signaling molecules and activating downstream
pathways, including JNK and NFATc1. NFATc1 is associated with gene
transcription in the nucleus. IRS, insulin receptor substrate;
GLUT, glucose transporter; NFATc1, nuclear factor of activated T
cells cytoplasmic 1; SOCS, suppressor of cytokine signaling; T2DM,
type 2 diabetes mellitus; OP, osteoporosis; OPG,
osteoprotegerin.

Figure 2

RANKL/RANK/OPG signaling in bone
remodeling and pancreatic β cell-associated signaling. (A) In bone
tissue, osteoblasts produce RANKL and OPG. RANKL binds RANK on
osteoclast precursor cells, leading to recruitment of TRAF6 and
activation of downstream signaling pathways, including NF-κB and
MAPK. These signaling events are associated with activation of
transcription factors such as c-Fos and NFATc1 and the expression
of osteoclast-associated genes. (B) In pancreatic β cells, RANKL
interacts with RANK on the cell membrane and activates downstream
signaling involving TRAF3, NIK and IKKα. This signaling cascade is
associated with processing of NF-κB2 (p100) to p52 and formation of
the p52-RelB complex. The complex is involved in transcriptional
regulation in the nucleus. OPG, osteoprotegerin; TRAF, TNF
receptor-associated factor; NFATc1, nuclear factor of activated T
cells cytoplasmic 1; NIK, NF-κB-inducing kinase; RelB, v-rel
reticuloendotheliosis viral oncogene homolog B (a member of the
NF-κB family); COL, collagen (e.g., type I collagen, COL1); Bim,
Bcl-2 interacting mediator of cell death.

Figure 3

Wnt/β-catenin signaling in the
regulation of BMSC differentiation and metabolic homeostasis. Wnt
binds the Frizzled receptor and co-receptor LRP5/6 on the cell
membrane, associated with regulation of GSK-3β activity and
stabilization of β-catenin. β-catenin translocates into the
nucleus, where it is associated with transcriptional regulation
involving osteogenic factors such as Runx2 and osterix. BMSCs
differentiate into adipocytes and osteoblasts. During adipogenic
differentiation, BMSC-derived adipocytes secrete TNF-α. This
cytokine suppresses osteoblast activity and bone formation,
promotes osteoclastogenesis and bone resorption, and impairs
insulin signaling, thereby contributing to insulin resistance.
Pancreatic β cells secrete insulin to control blood glucose levels
and their function is impaired under insulin-resistant conditions.
Osteoclasts resorb bone, whereas osteoblasts form bone, and the
balance between these two cell types determines net bone mass.
BMSC, bone marrow mesenchymal stem/stromal cell; LRP, low-density
lipoprotein receptor-related protein; GSK, glycogen synthase
kinase.
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Copy and paste a formatted citation
Spandidos Publications style
Cheng Y, Gao J, Yang Y, Xing L, Hou X, Zhang L and Tian F: Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review). Biomed Rep 25: 84, 2026.
APA
Cheng, Y., Gao, J., Yang, Y., Xing, L., Hou, X., Zhang, L., & Tian, F. (2026). Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review). Biomedical Reports, 25, 84. https://doi.org/10.3892/br.2026.2157
MLA
Cheng, Y., Gao, J., Yang, Y., Xing, L., Hou, X., Zhang, L., Tian, F."Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review)". Biomedical Reports 25.1 (2026): 84.
Chicago
Cheng, Y., Gao, J., Yang, Y., Xing, L., Hou, X., Zhang, L., Tian, F."Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review)". Biomedical Reports 25, no. 1 (2026): 84. https://doi.org/10.3892/br.2026.2157
Copy and paste a formatted citation
x
Spandidos Publications style
Cheng Y, Gao J, Yang Y, Xing L, Hou X, Zhang L and Tian F: Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review). Biomed Rep 25: 84, 2026.
APA
Cheng, Y., Gao, J., Yang, Y., Xing, L., Hou, X., Zhang, L., & Tian, F. (2026). Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review). Biomedical Reports, 25, 84. https://doi.org/10.3892/br.2026.2157
MLA
Cheng, Y., Gao, J., Yang, Y., Xing, L., Hou, X., Zhang, L., Tian, F."Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review)". Biomedical Reports 25.1 (2026): 84.
Chicago
Cheng, Y., Gao, J., Yang, Y., Xing, L., Hou, X., Zhang, L., Tian, F."Cellular signaling crosstalk between osteoporosis and diabetes: Common mechanisms and therapeutic targets (Review)". Biomedical Reports 25, no. 1 (2026): 84. https://doi.org/10.3892/br.2026.2157
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