{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:32:59Z","timestamp":1787149979990,"version":"build-2736575974"},"reference-count":82,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Population aging is driving a convergent rise in three disorders historically managed in isolation: cardiovascular disease, neurocognitive decline, and osteoporotic bone loss. Mechanistic data indicate that these systems are coupled through shared regulators of calcium trafficking, inflammation resolution, vascular integrity, and inflammaging. On this basis, a \u201cHeart\u2013Brain\u2013Bone\u201d axis has been proposed; it should be understood as an integrative conceptual framework that organizes evidence drawn from three separate studies, not as a validated physiological entity with agreed diagnostic criteria or demonstrated modifiability. Three lipid-soluble nutrients\u2014long-chain omega-3 polyunsaturated fatty acids (EPA\/DHA), vitamin D3 (cholecalciferol), and vitamin K2 (menaquinone-7 [MK-7])\u2014act on overlapping nodes of this network. Methods: We performed a structured narrative review. PubMed\/MEDLINE, Embase, the Cochrane Library, and Web of Science were searched from database inception to 25 June 2026 using predefined term blocks for each nutrient, each organ domain, and each candidate mechanism, and the search was updated on 7 August 2026. Records were screened against prespecified inclusion and exclusion criteria by two authors independently, with disagreements resolved by a third. The strength of evidence for each nutrient\u2013organ relationship was graded with an explicitly defined four-level scheme ((\u2212) to (+++)) applied separately to preclinical, observational, randomized and meta-analytic evidence. Results: Vitamin K2-dependent gamma-carboxylation of matrix Gla protein (MGP) and osteocalcin has been proposed to influence whether calcium is incorporated into the bone matrix or deposited in the arterial wall, offering a candidate mechanistic account of the \u201ccalcium paradox\u201d associated with isolated vitamin D3 supplementation; EPA\/DHA-derived specialized pro-resolving mediators may support resolution of endothelial and neuronal inflammation; and bone-, vascular- and brain-derived signals (osteocalcin, FGF23, the neurovascular unit) interconnect the three organs. These mechanisms are biologically plausible but remain insufficiently confirmed in humans. The clinical evidence is heterogeneous, formulation- and population-dependent, and comprises positive, neutral and null results: cardiovascular omega-3 trials are discordant (REDUCE-IT, which used icosapent ethyl [an EPA ethyl ester], positive; VITAL\/STRENGTH\/ASCEND null, predominantly in lower-risk or replete cohorts); cognitive trials are largely null or subgroup-dependent (MAPT, DO-HEALTH, VITAL); and MK-7 improves surrogate bone and calcification biomarkers and slowed coronary artery calcification in one recent randomized imaging trial (VitaK-CAC), whereas combined MK-7 plus vitamin D3 did not slow aortic valve or coronary calcification in AVADEC and MK-7 did not reduce bone loss in early menopausal women. Recognized safety signals include a dose-dependent increase in atrial fibrillation with high-dose omega-3, adverse skeletal effects of high-dose or bolus vitamin D, and clinically relevant interference of even low-dose MK-7 with vitamin K antagonist therapy. Conclusions: No adequately powered randomized trial has demonstrated that the combination of long-chain omega-3, vitamin D3 and MK-7 is superior to its individual components or to placebo for any clinical endpoint. The combined regimen is therefore mechanistically rational and hypothesis-generating rather than clinically established; benefit appears most plausible in individuals with elevated risk or demonstrable nutritional insufficiency, and least in replete, low-risk populations. Findings should be interpreted within a broader healthy-aging context that includes lifestyle and psychosocial factors. Adequately powered factorial randomized controlled trials stratified by baseline Omega-3 index, 25(OH)D and vitamin K status, with prespecified mechanistic biomarkers and hard endpoints, are required.<\/jats:p>","DOI":"10.3390\/nu18162711","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:07:34Z","timestamp":1787148454000},"page":"2711","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Bone Health: Exploring the \u201cHeart\u2013Brain\u2013Bone\u201d Axis Modulated by Lipid-Soluble Nutrients (Omega-3, Vitamin D3, and Vitamin K2)"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0655-6870","authenticated-orcid":false,"given":"Shih-Chin","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Neurology, Yonghe Cardinal Tien Hospital, New Taipei 234403, Taiwan"},{"name":"X-Source Clinic, Taipei 115, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Kai","family":"Huang","sequence":"additional","affiliation":[{"name":"Master Program in School of Dental Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Sheng Hou Clinic, Taipei 10674, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsieh-Tsung Ethan","family":"Shen","sequence":"additional","affiliation":[{"name":"YD Bio Limited, Taipei 115603, Taiwan"},{"name":"Division of Clinical Cariology and Endodontology, Department of Oral Rehabilitation, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo-Xiang Benjamin","family":"Zhang","sequence":"additional","affiliation":[{"name":"YD Bio Limited, Taipei 115603, Taiwan"},{"name":"Division of Clinical Cariology and Endodontology, Department of Oral Rehabilitation, School of Dentistry, Health Sciences University of Hokkaido, Tobetsu 061-0293, Japan"},{"name":"Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4840-7714","authenticated-orcid":false,"given":"Ting-Hsuan Collette","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, College of Letters and Science, University of California, Berkeley, CA 94720, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Che","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Taipei Medical University Hospital, Taipei 11031, Taiwan"},{"name":"Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrendo.2012.36","article-title":"Arterial calcification and bone physiology: Role of the bone-vascular axis","volume":"8","author":"Thompson","year":"2012","journal-title":"Nat. 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