MASLD and MASH increase fracture risk in humans and mice by arresting new bone formation

Early data suggest metabolic dysfunction-associated steatotic liver disease (MASLD) associates with increased fractures. However, absolute risk, subpopulations at greatest risk, and risk basis are unknown. We use a two-pronged approach to address these gaps: we investigated fracture risk among humans with MASLD and mechanisms among diet-induced animal model of NAFLD (DIAMOND™) mice. We interrogated the TriNetX US collaborative database, propensity-matching people with MASLD 10-fold with people with metabolic dysfunction alone. All-fracture and pathological-fracture risks are elevated among people > 51 years of age with MASLD. DIAMOND mice with MASLD lost bone thickness, strength, and bone formation and gained increased bone resorption. MASLD associated with differential expression of key indicators of bone loss: decreased hepatic igf1 and cyp2r1 , increased hepatic fgf21, ctgf , and anxa2 , decreased skeletal bglap, runx2 , and postn , and increased skeletal pparg . These expression changes are supported by increased serum FGF21, reported in literature to impair bone anabolism. Herein, we establish MASLD as a risk factor for fracture and propose putative mechanisms driving bone loss.