Yonsei Med J.  2006 Apr;47(2):157-166. 10.3349/ymj.2006.47.2.157.

Effects of Vitamin K2 on the Development of Osteopenia in Rats as the Models of Osteoporosis

• Iwamoto J
• Takeda T
• Sato Y

• KMID: 1110737
• DOI: http://doi.org/10.3349/ymj.2006.47.2.157

Abstract

Vitamin K2 is widely used for the treatment of osteoporosis in Japan. To understand the effects of vitamin K2 on bone mass and bone metabolism, we reviewed its effects on the development of osteopenia in rats, which characterizes models of osteoporosis. Vitamin K2 was found to attenuate the increase in bone resorption and/or maintain bone formation, reduce bone loss, protect against the loss of trabecular bone mass and its connectivity, and prevent the decrease in strength of the long bone in ovariectomized rats. However, combined treatment of bisphosphonates and vitamin K2 had an additive effect in preventing the deterioration of the trabecular bone architecture in ovariectomized rats, while the combined treatment of raloxifene and vitamin K2 improved the bone strength of the femoral neck. The use of vitamin K2 alone suppressed the increase in trabecular bone turnover and endocortical bone resorption, which attenuated the development of cancellous and cortical osteopenia in orchidectomized rats. In addition, vitamin K2 inhibited the decrease in bone formation in prednisolone-treated rats, thereby preventing cancellous and cortical osteopenia. In sciatic neurectomized rats, vitamin K2 suppressed endocortical bone resorption and stimulated bone formation, delaying the reduction of the trabecular thickness and retarding the development of cortical osteopenia. Vitamin K2 also prevented the acceleration of bone resorption and the reduction in bone formation in tail-suspended rats, which counteracted cancellous bone loss. Concomitant use of vitamin K2 with a bisphosphonate ameliorated the suppression of bone formation and more effectively prevented cancellous bone loss in tail-suspended rats. Vitamin K2 stimulated renal calcium reabsorption, retarded the increase in serum parathyroid hormone levels, and attenuated cortical bone loss primarily by suppressing bone resorption in calcium-deficient rats while maintaining the strength of the long bone in rats with magnesium deficiency. These findings suggest that vitamin K2 may not only stimulate bone formation, but may also suppress bone resorption. Thus, vitamin K2 could regulate bone metabolism in rats, which represented the various models of osteoporosis. However, the effects of vitamin K2 on bone mass and bone metabolism seem to be modest.

Keyword

Vitamin K2; bone formation; bone resorption; rat; osteopenia

MeSH Terms

Vitamin K 2/chemistry/metabolism/*pharmacology
Tomography, X-Ray Computed
Tibia/pathology
Rats
Osteoporosis/*drug therapy/*prevention & control
Male
Magnesium Deficiency/diagnosis
Magnesium/metabolism
Homeostasis
Female
*Disease Models, Animal
Diphosphonates
Calcium/metabolism
Bone and Bones/*drug effects/metabolism
Bone Resorption
Bone Diseases, Metabolic/*metabolism
Animals

Figure

• 

  Fig. 1 Three-dimensional µCT images of the proximal tibial metaphysis in rats [Adopted from the reference 31]. The upper row shows the whole bone and the lower row shows the same specimens after the removal of the cortex. Vitamin K2 prevented OVX-induced cancellous bone loss. OVX, ovariectomy; Sham, sham-operation; MK-4, menaquinone-4 (menatetrenone: vitamin K2).

• 

  Fig. 2 Light micrographs of the proximal tibial metaphysis in rats (magnification × 10) [Adopted from the reference 36]. A. sham, B. OVX (ovariectomy), C. OVX + vitamin K2 supplementation, D. OVX + vitamin D supplementation, and E: OVX + vitamin K2 and vitamin D supplementation. Vitamin K2 supplementation did not significantly affect the OVX-induced cancellous bone loss, while vitamin D supplementation ameliorated it. Combined supplementation of vitamin K2 and vitamin D prevented OVX-induced cancellous bone loss.

• 

  Fig. 3 Effects of raloxifene and vitamin K2 individually and in combination on bone strength [Adopted from the reference 39]. K. OVX + vitamin K2 administration, Ral: OVX + raloxifene administration. Load-to-failure analyses were conducted on the femoral neck and L-5 vertebra. Ultimate loads (N) are plotted as mean ± SEM with significant differences with respect to Sham and OVX indicated by "s", and "o", respectively (p < 0.05, Fishers PLSD). No significant beneficial effect of either raloxifene or vitamin K2 was observed on the femoral neck bone strength; however, vitamin K2 plus raloxifene had greater femoral neck bone strength than sham-operated controls. Raloxifene and vitamin K2 had complementary effects on bone resorption and formation activities, respectively, resulting in a significant improvement of the femoral neck bone strength. OVX, ovariectomy.

• 

  Fig. 4 Three-dimensional µCT images of the proximal tibial metaphysis in rats [Adopted from the reference 46]. The lower row shows the whole bone and the upper row shows the same specimens after the removal of the cortex. Vitamin K2 administration prevented cancellous bone loss that was induced by 3 and 30 mg/kg Pred-treatment. Pred, prednisolone.

• 

  Fig. 5 Micrographs of the cross-sections of the cortical bone of the tibial diaphysis in rats (magnification × 400) [Adopted from the reference 46]. The tibial diaphysis was fixed with 70% alcohol and embedded in methylmethacrylate after Villanueva bone staining. It was sectioned transversely (10 µm thickness) at a point 2.78 mm from the tibiofibular junction. Images were scanned by fluorescence laser microscope. The red lines indicate the cortical periosteal surface, the green lines indicate calcein that was taken into the bone formation area, and the distance between the double green lines indicates bone formation width during the 7 day period. Vitamin K2 administration prevented the decrease in periosteal bone formation that was induced by 3 and 30 mg/kg Pred-treatment. Pred: prednisolone.

• 

  Fig. 6 Two-dimensional CT images of the femoral distal metaphysis in rats [Adopted from the reference 55]. NS, non-tail-suspension (control); S, tail-suspension; K, tail suspension + vitamin K2 administration; B, tail-suspension + bisphosphonate (incadronate) administration; BK, tail-suspension + bisphosphonate (incadronate) and vitamin K2 administration. Vitamin K2 administration attenuated the tail-suspension-induced cancellous bone loss, whereas bisphosphoante prevented tail-suspension-induced cancellous bone loss. The combined administration of bisphosphonate and vitamin K2 was more effective than the single administration of bisphophonate in increasing cancellous bone mass.

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