Natural bioactive compounds in estrogen deficiency-induced osteoporosis: Classification and an integrated gut microbiota-metabolite-immune-bone framework

Abstract

Postmenopausal osteoporosis is primarily driven by estrogen deficiency, while gut dysbiosis, inflammation, microbial metabolites, and immune reprogramming may modify bone loss, although current evidence remains largely preclinical or associative. Natural bioactive compounds, probiotics, fermented foods, and medicinal-food resources have emerged as potential interventions, but existing research is fragmented and rarely distinguishes direct skeletal effects from microbiota-dependent actions. This review proposes a hypothesis-generating microbiota-dependent classification, rather than a validated clinical system, comprising phytoestrogens; polyphenols, flavonoids, and terpenoids; polysaccharides and dietary fibers; probiotics and postbiotics; fermented foods and dietary-pattern interventions; and complex traditional herbal formulations. These interventions may act directly on bone cells or indirectly through microbial biotransformation, intestinal barrier-mmune signaling, endocrine and estrobolome pathways, and epigenetic regulation. We additionally propose a microbiota-etabolite-xtracellular vesicle microRNA-one marrow cell fate axis as an unvalidated regulatory model. Preclinical evidence is strongest for short-chain fatty acid-related and gut barrier-mmune mechanisms, whereas the skeletal roles of bile acids, tryptophan-derived metabolites, microbiota-associated vitamins, and extracellular vesicle microRNAs remain uncertain, particularly in humans. Future studies should prioritize causal validation and microbiota-stratified clinical investigations.

Keywords: Natural bioactive compounds; Postmenopausal osteoporosis; Gut microbiota; Phytoestrogens; Short-chain fatty acids; Th17/Treg; Microrna; Extracellular vesicles; Gut-bone axis

Core Tip: This minireview introduces a microbiota-dependent classification of natural bioactive compounds for estrogen deficiency-induced osteoporosis and proposes an integrated gut-metabolite-immune-bone framework. Rather than acting solely on bone cells, these interventions may reshape microbial metabolites, intestinal barrier function, estrogen availability, immune balance, and post-transcriptional regulation. This framework highlights priorities for causal multi-omics studies, microbiota-stratified trials, and the clinical evaluation of individualized nutrition-based interventions as potential adjunctive strategies.