**7. Chronic kidney disease and loss of bone mass (CKD‐MBD)**

The link between increased calcification of vessels and bone complications changes the definition of CKD‐MBD to better describe the complexity of the syndrome [62]. The link between osteoporosis and cardiovascular morbidity is well described in postmenopausal women with intact renal function [63]. In chronic hemodialysis patients, a lower bone volume is associated with higher coronary calcification scores measured by multislice computed tomography, reflecting a higher risk of cardiovascular events [64]. This association between vascular calcification, arterial stiffness and bone mineral density in chronic kidney disease was also described in 2008 by Toussaint et al. [65]. Furthermore, the mortality of hemodialysis patients was evaluated in 2003 by Taal et al. among 88 hemodialysis patients over a 3.5 years follow‐up period. Here, it appeared that mortality was associated with age, Ca‐P product, lack of transplantation and a low bone mineral density measured at the hip. The leading cause of death (42.5%) appeared to be related to cardiovascular events [66].

The therapeutic options are few, since many women on renal replacement treatment did not accept reinstigation of hormone replacement therapy. However, the efficacy of hormone replacement was confirmed in a randomized trial in women on continuous dialysis, receiving hormone therapy (estradiol and cyclic norethisterone) for 1 year. At the end of the study, the active group showed an increase in bone mineral density at the lumbar spine. This difference between the active and control group (receiving cinacalcet) was significant at all measure‐ ment sites [67]. Active vitamin D analogs, calcimimetics administration and phosphate‐binders are widely used to suppress iPTH and thus bone specific alkaline phosphatase, as a marker of enhanced bone turnover.

**8. Conclusion**

**Author details**

**References**

195.

1245.

presenting with low bone mass (osteopenia).

Niels Erik Frandsen1\* and Jan Oxholm Gordeladze2

\*Address all correspondence to: nef@dadlnet.dk

Science, University of Oslo, Oslo, Norway

Vitam Horm, 1985. 42: 65–108.

In the near future, the dose, bioavailability and potency of the vitamin K2 subfamily member menaquinone MK‐7, will most probably make it possible to improve on the bone building process, yielding enhanced bone strength and resilience in several bone‐losing patient categories, such as those suffering from osteoporosis of different etiologies, and patients

Vitamin K2 and Bone Health http://dx.doi.org/10.5772/64876 117

1 Department of Nephrology, University Hospital Roskilde, Roskilde, Denmark

[3] International‐Osteoporosis Foundation. *Facts and Statistics.* 2013.

*Calcium to Prevent Fractures: Preventive Medication*. 2014.

*and femoral neck.* Bone, 1991. 12: 387–389.

2 Section for Biochemistry, Department of Molecular Medicine, Institute of Basic Medical

[1] Shearer MJ, Fu X, Booth LS. *Vitamin K nutrition, metabolism, and requirements: current concepts and future research 2012 American Society for Nutrition.* Adv. Nutr., 2012. 3: 182–

[2] Price PA. *Vitamin K‐dependent formation of bone Gla protein (Osteocalcin ) and its function.*

[4] USA Preventive Services Task Force (USPSTF). Clinical summary: *Vitamin D and*

[5] Hart JP, Catteral A, Dodds RA, Klenerman L, Shearer MJ, Bitensky L, Chayen J. *Circulating vitamin K1 levels in fractured neck of femur.* Lancet, 1984. 324: 283.

[6] Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD. *Circulating levels of vitamin K1and K2 decreased in elderly women with hip fracture.* J Bone Miner Res, 1993. 8: 1241–

[7] Hodges SJ, Pilkington MJ, Stamp TC, Catterall A, Shearer MJ, Bitensky L, Chayen J. *Depressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine*

Kohlmeier et al. were the first to show an independent association between serum concentra‐ tion of phylloquinone <1.2 nmol/l or less (poor vitamin K status) and an increased risk of bone fracture in patients with end‐stage renal disease [68]. This observation was confirmed by Fusaro et al. [69] in 2013, showing that hemodialysis patients treated by warfarin for longer than 1 year had an increased risk of vertebral fractures, compared with patients not on warfarin. McCabe et al. enrolling 172, stage 3–5 CKD patients without dialysis treatment, showed that intake of vitamin K was insufficient in more than 50–60% of individuals on a given diet, if measures of ucOC were conducted (>20% ucOC), and 97% if evaluation was done by the prothrombin induced by vitamin K absence‐II (PIVKA‐II) assessment (>2 nmol/l) [70, 71]. After establishment of dialysis as a therapeutic intervention, Cranenburg et al. showed in a study of 40 chronic hemodialysis patients from 2012 that the dietary intake of vitamin K1 and K2, in general, was insufficient. This was reflected by analyses of plasma levels of desphospho‐ undercarboxylated (dp‐uc) MGP (matrix‐GLA protein), which was increased over the normal range by some 82.5% with elevated PIVKA‐II values 3.81.4–12.4 ng/ml, reference value <2 ng/ ml. [72]. Elevated dp‐ucMGP levels suggest insufficient vitamin K2 levels on the vascular site, while high ucOC reflects insufficient vitamin K2 on bone or osseous sites.

A 6 weeks randomized controlled trial on hemodialysis patients evaluated the response of biomarkers of vitamin K status (dp‐ucMGP, PIVKA‐II and ucOC) to the ingestion of 45, 135, 360 μg/day of MK‐7. The study confirmed that most patients displayed a functional deficiency at baseline, and that MK‐7 supplementation decreased dp‐ucMGP and PIVKA‐II. However, only the highest doses brought about a significant decrease in ucOC [73].

In osteoporosis, the main treatment aims at inhibiting osteoclastic bone resorption. The osteoclast and osteoblast are functionally tightly coupled, and the mechanism of this reciprocal link is now very well known. By the discovery of MK‐7, which is able to play a role in the prevention of bone loss from most sites of the skeleton, there is hope for efficient treatment. MK‐7 has been shown to stimulate osteoblastic bone formation, as well as suppressing osteoclastic bone resorption *in vitro* and in humans, as showed by Knapen et al. [57]. MK‐7 suppresses the activation of NF‐κB signaling pathways in both osteoblasts and osteoclasts. These treatments have not yet been enrolled side by side with vitamin D analogs in CKD patients. Unfortunately, vitamin K2 is rare in Western diets, but in CKD patients, vitamin K2 levels are very low due to recommended restriction of potassium and phosphate in the diet.

New trials enrolling CKD and chronic dialysis patients treated with MK‐7 supplementation are presently being conducted to fully evaluate the effect of MK‐7 on atherosclerosis and bone mineral density.
