**6. Anticoagulation and vitamin K‐antagonist association with loss of bone mass**

The need of vitamin K for the activation of clotting factors is lower than for the activation of extrahepatic vitamin K‐dependent proteins. This is the plausible reason for deficient rebuilding of bone mass and increased calcification process in blood vessels. Long‐term use of anticoa‐ gulants, likes warfarin, may potentially lead to the loss of bone, and/or an increased incidence of osteopenia or osteoporosis with and without fractures. The crucial question then is: What time span for patients on warfarin medication will suffice for the detection of bone loss?

In an observational study conducted in Japan by Namba et al. 2015, the biomarkers during warfarin use in a 1‐year follow‐up on 42 patients treated for atrial fibrillation were described. Twenty‐four patients received warfarin (WF group) and 18 patients received non‐warfarin treatment (Non‐WF group). Results revealed an increased significant difference in ucOC in WF the group 10.3 ± 0.8 ng/ml, versus non‐WF group 3.4 ± 0.9 ng/ml, *P* < 0.01. In cytokines, RANKL in WF group 0.6 ± 0.1 ng/ml versus non‐WF group 0.4 ± 0.1 ng/ml, *P* < 0.01. After 1 year, DEXA scan showed no significant different between groups. It was concluded long‐term use of warfarin might be associated with high risk of osteoporosis but also risk of ectopic calcification in blood vessels. Further randomized studies are needed to evaluate these patients [58].

Twenty years ago, clinical observations and research demonstrated that women, taking warfarin during the first trimester of their pregnancy, gave birth to children with punctate calcifications in the axial skeleton, proximal femurs, and calcanei. The presumed reason has since long been that prenatal vitamin K deficiency, induced by warfarin, was the reason for these calcifications [59].

Large clinical studies on bone mass have given different results, and in early observation studies, the evaluation of duration of warfarin use and other patients receiving treatment for osteoporosis was not included. However, two newer studies showed no further risk on bone mass of warfarin use in elderly patients: In the first one published by Woo et al. in 2008, in a large cohort of elderly community‐dwelling men, no association was observed between current warfarin use and bone mass, bone loss or fracture risk. Although warfarin use was based upon a single assessment, the findings suggest that current warfarin use in older men does not appear to have clinically important effects on the skeleton [5, 60].

Because of the longer half‐life, bioavailability, and greater potency of the long‐chain MK‐7, they also measured the effect of low‐dose MK‐7 supplementation on bone health, as reflected by bone mineral density (BMD) of lumbar spine, total hip, and femoral neck. The assessment of vertebral fractures was performed using DXA. Furthermore, blood levels of ucOC and cOC were also analyzed, and the ucOC/cOC ratio functions as an indicator of vitamin K "health" status. All analyses were performed at baseline, and subsequent to 1, 2, and 3 years of sup‐ plementation, respectively. A carboxylation rate of >50% was achieved during the first year of

The main results obtained were as follows: MK‐7 ingestion significantly enhanced vitamin K status and decreased the age‐related reduction in bone mass, as well as both BMC and BMD at the level of lumbar spine and femoral neck. However, total hip BMC and BMD decline could not be "rescued." Bone strength also seemed to be favorably affected by MK‐7 ingestion, significantly decreasing the loss of vertebral height of the lower thoracic region at the mid‐site of the vertebrae**.** These results confirm the hypothesis that long term supplementation with MK‐7 beneficially affects bone health. Whether these results can be extrapolated to other

**6. Anticoagulation and vitamin K‐antagonist association with loss of**

The need of vitamin K for the activation of clotting factors is lower than for the activation of extrahepatic vitamin K‐dependent proteins. This is the plausible reason for deficient rebuilding of bone mass and increased calcification process in blood vessels. Long‐term use of anticoa‐ gulants, likes warfarin, may potentially lead to the loss of bone, and/or an increased incidence of osteopenia or osteoporosis with and without fractures. The crucial question then is: What time span for patients on warfarin medication will suffice for the detection of bone loss?

In an observational study conducted in Japan by Namba et al. 2015, the biomarkers during warfarin use in a 1‐year follow‐up on 42 patients treated for atrial fibrillation were described. Twenty‐four patients received warfarin (WF group) and 18 patients received non‐warfarin treatment (Non‐WF group). Results revealed an increased significant difference in ucOC in WF the group 10.3 ± 0.8 ng/ml, versus non‐WF group 3.4 ± 0.9 ng/ml, *P* < 0.01. In cytokines, RANKL in WF group 0.6 ± 0.1 ng/ml versus non‐WF group 0.4 ± 0.1 ng/ml, *P* < 0.01. After 1 year, DEXA scan showed no significant different between groups. It was concluded long‐term use of warfarin might be associated with high risk of osteoporosis but also risk of ectopic calcification in blood vessels. Further randomized studies are needed to evaluate these

Twenty years ago, clinical observations and research demonstrated that women, taking warfarin during the first trimester of their pregnancy, gave birth to children with punctate calcifications in the axial skeleton, proximal femurs, and calcanei. The presumed reason has since long been that prenatal vitamin K deficiency, induced by warfarin, was the reason for

treatment, and it was maintained throughout the study period.

populations with osteoporosis, needs further investigation [57].

**bone mass**

114 Vitamin K2 - Vital for Health and Wellbeing

patients [58].

these calcifications [59].

The second experience was summarized by Misra et al. in 2014, featuring long‐term treatment of incident atrial fibrillation without prior history of fractures. Long‐term warfarin use was defined in two ways: (1) warfarin use ≥1 year; (2) warfarin use ≥3 years. Event‐score on warfarin users and nonusers were created to evaluate the association between long‐term warfarin use and risk of hip, spine, and wrist fractures separately, as well as combined, using Cox‐propor‐ tional hazards regression models. Among more than 20,000 participants with incident atrial fibrillation, the hazard ratios (HR) for hip fracture with warfarin use ≥1 and ≥3 years, respec‐ tively, were 1.08 (95% CI 0.87, 1.35) and 1.13 (95% CI 0.84, 1.50).

The conclusion of the present trial was as follows: long‐term warfarin use among elders (i.e., >65 years of age) with atrial fibrillation was not associated with any increased risk of osteo‐ porotic fractures and therefore does not appear to necessitate additional surveillance or prophylaxis [61]. These observational studies have focused on clinical fractures as endpoints below follow‐up time at 5–10 years, but the thesis that warfarin‐induced clinical fractures was not confirmed. This may be due to the beneficial effect of MK‐7 on bone mass, which appears to stay unaffected by the impact of warfarin on vitamin K1, which again reinforces the notion that vitamin K2 status (measured as ucOC) per se is a good marker of bone homeostasis [58].
