Metabolic Syndrome and Bone Fragility: Molecular Mechanisms of Metabolic Reprogramming and Their Consequence on Alterations in Bone Quality

Abstract

Metabolic syndrome (MS) is associated with an increased risk of skeletal fragility fractures that occur independently of bone mineral density (BMD), suggesting a dissociation between bone quantity and quality, with deterioration of microarchitecture and biomechanical properties predominating over quantitative bone mass loss. The purpose of this review is to analyze and integrate recent experimental and clinical evidence on the molecular mechanisms that mediate the impact of MS on bone tissue homeostasis. The review of preclinical models identifies four interconnected pathophysiological nodes: 1) chronic low-grade inflammation, characterized by an increase in proinflammatory cytokines (TNF-α, IL-1β) and a senescence-associated secretory phenotype (SASP) that favors osteoclastogenesis; 2) lipotoxicity and accumulation of advanced glycation end products (AGEs), which induce an adipogenic bias in the bone marrow microenvironment at the expense of osteoblast formation; 3) mitochondrial dysfunction, with a critical reduction in PGC-1α that generates a bioenergetic crisis in both osteoprogenitor cells and skeletal muscle; and 4) epigenetic convergence, where excess systemic lipids and intestinal dysbiosis silence the osteogenic and mitochondrial biogenesis programs. The emergence of the osteosarcopenic obesity phenotype as an integrated vulnerability requiring multifaceted therapeutic approaches is highlighted. Taken together, these findings indicate that metabolic syndrome induces molecular reprogramming of bone tissue, the magnitude of which is underestimated by conventional densitometric methods, and that the combined intervention of physical exercise, antioxidant agents, and insulin-sensitizing drugs represents the most promising strategy for reversing the structural and metabolic bone damage.