Intermuscular adipose tissue drives bone loss in postmenopausal osteoporosis via fibro-adipogenic progenitors-mediated osteoclastogenesis.

BACKGROUND

To determine whether intermuscular adipose tissue (IMAT) shows region-specific associations with bone mineral density (BMD) in postmenopausal osteoporosis (PMOP) and to define a muscle-resident stromal mechanism linking IMAT expansion to osteoclast activation.

METHODS

In a clinical cohort 120 postmenopausal women were included in the primary analyses. IMAT and muscle cross-sectional areas in the thigh, calf, and paraspinal muscles were quantified by computed tomography and analyzed for associations with BMD using correlation and prespecified multivariable regression models. An ovariectomized (OVX) mouse model was used to assess IMAT accumulation, trabecular microarchitecture by micro-CT, and osteoclast activity by histology. Fibro-adipogenic progenitors (FAPs) were isolated for bulk RNA sequencing, and conditioned media from adipogenically induced FAPs were applied to bone marrow-derived macrophages to evaluate osteoclast differentiation, cytoskeletal maturation, and marker expression.

RESULTS

Higher IMAT-to-muscle ratios in thigh, calf, and paraspinal muscles were independently associated with lower BMD at the femur and lumbar spine. OVX mice exhibited increased IMAT infiltration, trabecular deterioration, and elevated osteoclast indices, with IMAT strongly correlating with bone microstructural loss and osteoclast parameters. FAPs showed transcriptional reprogramming enriched for adipogenic, inflammatory, and osteoclastogenic pathways in OVX mice. Conditioned media from adipogenically differentiated FAPs increased osteoclast number, resorptive structures, and expression of Ctsk, Mmp9, and Nfatc1, compared with day-0 conditioned media.

CONCLUSION

IMAT is associated with lower BMD in PMOP, and adipogenic and inflammatory reprogramming of IMAT-derived FAPs provides a plausible paracrine route by which muscle adiposity may potentiate osteoclastogenesis and bone loss.