Protocol
Vitamin D3 2,000–4,000 IU + K2 MK-7 100 mcg
No trial has tested vitamin D3 2,000 to 4,000 IU together with MK-7 100 mcg; the name is the common retail pairing, and the evidence below is for other doses and for each component alone.
Grade C: human trials exist, but they are small, mixed or not yet repeated. This is not a finding that it does not work. How to read a grade →
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How this letter has changedLatest: October 2026 · Corrected.
The protocol is named for the common retail pairing, which no trial has tested; the nearest combination trial, AVADEC (Diederichsen et al., Circulation, 2022; PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 35465686), used MK-7 720 mcg with D3 1,000 IU and was null on its primary endpoint The one outcome a trial names in advance as its main test. Results on other outcomes carry less weight.. Decided: keep the name readers search for and open the record with the statement that these doses are untested, rather than rename to doses no reader buys. The citation_incomplete review is closed on that basis; the letter stays C. Decided October 2026 by editor adjudication (Arnold Sandlow, D.C.).PMID 35465686
The D3 2,000 to 4,000 IU plus MK-7 100 mcg protocol held a B on one MK-7-alone trial at 180 mcg (Knapen et al., Osteoporos Int 2013; PMID 23525894) measuring bone density, a surrogate. No trial has tested the combination at these doses. The largest combination trial, AVADEC (Diederichsen et al., Circulation 2022; PMID 35465686; 720 mcg MK-7 plus 1,000 IU D3), missed its primary endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score., and vitamin D alone did not prevent fractures in VITAL (LeBoff et al., N Engl J Med 2022; PMID 35939577) or D-Health (Waterhouse et al., Lancet Diabetes Endocrinol 2023; PMID 37011645). C, with the name's doses flagged as untested. Editor adjudication, October 2026.PMID 23525894 PMID 35465686 PMID 35939577 PMID 37011645
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This protocol pairs vitamin D3 at 2,000 to 4,000 units with vitamin K2 at 100 micrograms. No study has tested this exact pair. In one study, vitamin K2 alone at a higher dose slowed bone loss in women after menopause, but that is a scan result, not fewer broken bones. In another, a high dose with vitamin D did not slow calcium buildup in a heart valve.
No trial has tested vitamin D3 2,000 to 4,000 IU together with MK-7 100 mcg; the name is the common retail pairing, and the evidence below is for other doses and for each component alone. Three-year MK-7 alone at 180 mcg/day reduced bone loss in postmenopausal women, a surrogate. Vitamin D alone did not prevent fractures in large trials of adults not selected for deficiency. 25-OH-D is tested first. No optimal concentration is established: no randomized trial sets one.
Why this gradeGrade C, small or unreplicated trials. The reasoning, and what the grade does not cover.
Grade C, on surrogate bone evidence for one component. No trial has tested vitamin D3 2,000 to 4,000 IU together with MK-7 100 mcg. MK-7 alone at 180 mcg/day for 3 years reduced bone loss in 244 postmenopausal women (Knapen et al., 2013; PMID 23525894), a surrogate. In AVADEC, MK-7 720 mcg with vitamin D3 did not change aortic valve calcification (Diederichsen et al., 2022; PMID 35465686). Vitamin D alone did not reduce fractures in VITAL (LeBoff et al., 2022; PMID 35939577) or D-Health (Waterhouse et al., 2023; PMID 37011645).
WHAT THIS GRADE DOES NOT COVERfracture prevention, vascular calcification, or the combination at these doses, none of which a cited trial supports. No optimal 25-OH-D concentration is set by any randomized trial.
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The evidence, in fullSix papers, each linked to its PubMed record.
Knapen et al. (Osteoporos Int, 2013; PMID 23525894): MK-7 alone, 180 mcg/day for 3 years, 244 postmenopausal women; bone loss reduced (bone density is a surrogate). Diederichsen et al. (Circulation, 2022; PMID 35465686): AVADEC, 365 men with aortic valve calcification, MK-7 720 mcg with vitamin D3 1,000 IU/day for 2 years; no effect on valve calcification, the primary endpoint. LeBoff et al. (N Engl J Med, 2022; PMID 35939577): VITAL fracture study, 25,871 adults, vitamin D3 2,000 IU/day; no reduction in fractures. Waterhouse et al. (Lancet Diabetes Endocrinol, 2023; PMID 37011645): D-Health, monthly 60,000 IU in older Australians; no reduction in fractures. Chapuy et al. (N Engl J Med, 1992; PMID 1331788): vitamin D3 with calcium in institutionalized elderly women; it tested the combination with calcium, not vitamin D3 alone. Chen et al. (J Gerontol A Biol Sci Med Sci, 2019; PMID 30256915): vitamin D3 and an epigenetic clock A test that estimates biological age from chemical marks on DNA (DNA methylation)., a surrogate, in overweight African Americans; context only.
Measured outcome: serum 25-OH-D at baseline and at 12 weeks, and bone mineral density in the cited trials. No target concentration is established, so the reading is a change from a known baseline rather than a number to reach. Concentrations above 100 ng/mL are associated with toxicity.
Evidence notes: randomized trial
Endpoint graded: Bone loss in postmenopausal women, measured for the MK-7 component alone (surrogate)
Last reviewed: July 2026
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(menaquinone[tiab] OR "vitamin K2"[tiab] OR MK-7[tiab]) AND ("vitamin D"[tiab] OR cholecalciferol[tiab]) AND randomized controlled trial[pt]Grades move when new trials publish. A free monthly email lists every grade EBL moved, with the reason and the trial behind it: the sign-up is on the Evidence Log →