Frontiers in Endocrinology · Oct 30, 2026
Endocrine aging shapes immune-skeletal vulnerability in osteoporosis: an evidence-weighted framework
By Dongyu Shang, Xiaodong Li, Zhi Chen et al.
Skeletal deterioration in later life reflects endocrine transitions alongside changes in immune activity, hematopoiesis and the bone marrow environment. These processes are often considered together, although the evidence linking them to human fracture outcomes is uneven. We critically examine sex-steroid decline, vitamin D signaling, exogenous glucocorticoids and metabolic hormones in relation to immune-cell remodeling, marrow niche dysfunction and bone remodeling. Evidence was appraised qualitatively at the level of specific claims, distinguishing established human skeletal effects from observational associations, experimental mechanisms and early hypotheses. The clearest clinical evidence concerns postmenopausal estrogen deficiency, glucocorticoid-induced bone loss and receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclastogenesis. By contrast, the contribution of particular T-cell cytokine routes, vitamin D-mediated immune polarization, NOD-like receptor family pyrin domain-containing 3 (NLRP3), cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) and senescence-associated secretory programs to common human osteoporosis remains difficult to establish. Randomized trial findings also challenge straightforward translation of plausible pathways: vitamin D supplementation did not reduce fractures in an unselected population, and an exploratory senolytic intervention did not improve its prespecified bone resorption endpoint overall. Bone marrow adiposity and inflammatory biomarkers add further complexity because their meaning varies with tissue location, comorbidity and time. We discuss five overlapping research profiles and the prospective evidence needed to determine whether endocrine–immune measurements improve skeletal prediction or treatment selection beyond established clinical assessment.