Marrow fatty acids in osteoporosis: metabolic insights, emerging therapeutic targets

This review examines the role of marrow adipose tissue fatty acid composition in skeletal homeostasis, focusing on osteoporosis. To avoid conceptual confusion, we define evidence tiers: human studies assessing endogenous marrow lipid profiles; mechanistic studies applying exogenous fatty acids in vitro and in vivo; indirect MRI-based surrogates of marrow fat quantity; and direct ex vivo measurements of fatty acid composition via GC-MS, LC-MS, and lipidomics. We also clarify the distinction between marrow fat quantity and fatty acid quality.

Human data reveal disease-, age-, and site-related alterations in marrow lipid saturation and unsaturation; however, findings vary by skeletal site, marrow compartment, fracture status, analytical platform, and study population. Experimental evidence demonstrates that saturated fatty acids (e.g., palmitic acid) induce lipotoxicity and osteoblast dysfunction, whereas unsaturated fatty acids (e.g., oleic acid and n-3 polyunsaturated fatty acids) exert protective effects via modulation of mesenchymal stem cell differentiation, osteoclastogenesis, ferroptosis, autophagy, and mitochondrial metabolism. Collectively, current evidence supports an association between marrow fatty acid biology and osteoporotic bone loss.

Causal, diagnostic, and therapeutic implications remain preliminary. This review's main contribution is a fatty-acid-centered framework that integrates evidence tiers, molecular categories, and skeletal-site heterogeneity, guiding future research.