Table 1: Summary of clinical trials of combined vitamin D and K supplementation on bone health.

Author, yearCountryParticipantsTreatmentStudy durationOutcomeResults for the highest versus the lowest quartiles

Iwamoto et al., 2000 [46]Japan osteoporotic women ≥ 5 years after menopause, mean age 64 years(i) Calcium (calcium lactate, 2 g/day)
(ii) Vitamin D3 0.75 μg/day
(iii) Vitamin K2 45 mg/day
(iv) Vitamin D3 plus vitamin K2
2 yearsBone mineral density % changeCombined vitamins D and K increased BMD
Ushiroyama et al., 2002 [45]Japan postmenopausal women with osteopenia and osteoporosis, mean age 53 years(i) Diet
(ii) Vitamin K2 45 mg/day MK-4
(iii) 1-α hydroxylcholecalciferol 1 μg/day
(iv) Vitamin K2 + 1-α hydroxylcholecalciferol
2 yearsBone mineral density % changeK + D group increased BMD % change at 2 years
Braam et al., 2003 [48]Netherlands postmenopausal women between 50 and 60 years(i) Placebo
(ii) Mineral + vitamin D (8 μg/day)
(iii) Mineral + vitamin D + vitamin K1 1 mg
3 yearsBone lossMineral + vitamin D + vitamin K showed reduced bone loss of the femoral neck
Yonemura et al., 2004 [55]Japan patients with chronic glomerulonephritis, mean age 32 years, 53% female(i) Control
(ii) Vitamin D (alfacalcidol 0.5 mg)
(iii) Vitamin K2 MK-4 45 mg/d
(iv) Vitamins D plus K
8 weeksBone mineral densityThe preventive effect in groups K and D + K was similar to D
Sato et al., 2005 [51]Japan older women with Alzheimer’s disease, mean age 78 years(i) Placebo
(ii) 45 mg menatetrenone, 1000 IU ergocalciferol, and 600 mg calcium
2 yearsBone mineral density and fracturesBMD increased in vitamin D + K group
Odds ratio nonvertebral fractures 7.5 (95% CI 5.6, 10.1)
Bolton-Smith et al., 2007 [47]UK healthy women, mean age 68 years  (i) Placebo
(ii) 200 mg/d vitamin K1
(iii) 400 IU vitamin D3 + 1000 mg calcium
(iv) Vitamins K1 and D3 plus calcium
2 yearsBone mineral contentCombined vitamin K with vitamin D plus calcium associated with an increase in bone mineral content at the ultradistal radius
Booth et al. 2008 [19]US healthy men and women, mean age 69, 59% female(i) Multivitamin + 10 μg vitamin D and 600 mg calcium
(ii) Multivitamin + vitamin D + calcium + 500 μg vitamin K1
3 yearsBone mineral densityNo differences in change in BMD
Vitamin D + K group lower uncarboxylated osteocalcin concentrations
Cheung et al., 2008 [54]Canada postmenopausal women with osteopenia, mean age 59 years(i) 1500 mg calcium + 800 IU vitamin D
(ii) 5 mg of vitamin K1 + calcium and vitamin D
2–4 yearsBone mineral densityNo effect on BMD
Binkley et al., 2009 [53]US postmenopausal women, mean age 62 years(i) Calcium 315 mg + vitamin D3 200 IU
(ii) Phylloquinone 1 mg + calcium and vitamin D3
(iii) MK-4 (45 mg day) + calcium and vitamin D3
1 yearBone mineral densityNo effect on BMD
Je et al., 2011 [49]South Korea Korean postmenopausal women, mean age 68 years(i) Vitamin D 400 IU + calcium (630 mg)
(ii) Vitamin D + calcium +45 mg of vitamin K2
6 monthsBone mineral densityBMD increased significantly in the vitamin D + K group
O’Connor et al., 2014 [52]Ireland adults with Crohn’s disease, mean age 45 years(i) Placebo
(ii) Phylloquinone 1 mg, vitamin D 10 μg, and calcium 500 mg/d
1 yearBone mineral densitySmall effect on BMD of the total radius for vitamin D + K group
Mazzanti et al., 2015 [50]Italy60 healthy postmenopausal women, mean age 55 years(i) Extra virgin olive oil
(ii) Extra virgin olive oil enriched with vitamins D3, K1, and B6
1 yearBone mineral densityVitaminized oil D, K, and B6 increased the T-score of BMD

BMD: bone mineral density; MK-4: menaquinone-4.