Exercise Modulates the Osteoimmune Axis: Myokine-Mediated Mechanisms in Diabetic Bone Disease

Patients with type 2 diabetes mellitus (T2DM) often present with normal or even elevated bone mineral density (BMD), yet exhibit a significantly increased fracture risk-a phenomenon referred to as the 'diabetic bone paradox'. This discrepancy underscores the inadequacy of conventional BMD-centred assessment systems in fully elucidating the mechanisms underlying bone fragility in T2DM. Current evidence suggests that T2DM-related skeletal fragility is multifactorial, involving alterations in bone quality, advanced glycation end-product (AGE) accumulation, low bone turnover, microarchitectural deterioration, diabetic complications, increased fall risk and chronic inflammation. Recent advances in osteoimmunology have revealed that immune cell polarization driven by chronic low-grade inflammation, along with an imbalanced receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) axis, may contribute to the dysregulation of bone remodelling in T2DM. As a cornerstone intervention in T2DM management, exercise not only acts directly on bone tissue via mechanical loading but also may exert systemic immunomodulatory effects through myokines secreted by skeletal muscle. Exercise-induced myokines, such as interleukin-6 (IL-6), irisin, β-aminoisobutyric acid (BAIBA) and interleukin-15 (IL-15), may modulate the osteoimmune microenvironment and restore the dynamic equilibrium between bone resorption and formation by modulating macrophage polarization, restoring the Th17/Treg balance, bone marrow adipose tissue metabolism, and chronic inflammatory signalling pathways. Moreover, exercise may further promote bone metabolic homoeostasis by suppressing negative regulatory signals, such as myostatin. Therefore, this narrative review summarises the aberrant features of the osteoimmune axis in T2DM, with a focus on the potential mechanisms by which exercise and its induced myokines may modulate the osteoimmune microenvironment to ameliorate diabetic bone disease, thereby providing a framework for understanding exercise as a potential non-pharmacological intervention and identifying areas requiring further translational investigation.