A structured narrative review synthesizing evidence from PubMed, Embase, Cochrane, and Web of Science proposes a 'Heart-Brain-Bone' axis — a conceptual framework linking cardiovascular disease, neurocognitive decline, and osteoporosis through shared mechanisms: calcium trafficking, vascular integrity, inflammaging, and inflammation resolution. Three lipid-soluble nutrients — EPA/DHA, vitamin D3, and vitamin K2 (MK-7) — were evaluated across these domains using a four-level evidence grading scheme applied separately to preclinical, observational, RCT, and meta-analytic data. Key mechanistic proposals include vitamin K2-dependent gamma-carboxylation of matrix Gla protein (MGP) as a resolution to the 'calcium paradox,' and EPA/DHA-derived specialized pro-resolving mediators (SPMs) attenuating endothelial and neuronal inflammation.
The axis concept is intellectually appealing, particularly for an aging population where these three conditions converge, but the review's authors are admirably candid: the framework is not a validated physiological entity, and human confirmatory data remain heterogeneous and formulation-dependent. The notorious discordance between REDUCE-IT (icosapent ethyl, positive) and VITAL/STRENGTH/ASCEND (mixed-EPA/DHA, largely null) illustrates how mechanistic plausibility does not guarantee clinical translation. Narrative reviews, even structured ones, cannot establish causality, and the evidence grading — while systematic — still synthesizes heterogeneous trial populations. For practitioners, the takeaway is cautiously constructive: these three nutrients share biological logic, and their combined use in deficient older adults warrants formal co-supplementation RCTs rather than extrapolated clinical protocols.
