Role of vitamins beyond vitamin D3 in bone health and osteoporosis (Review)

Abstract

The objective of the present review was to summarize the molecular mechanisms associated with the effects of the vitamins A, C, E and K, and group B vitamins on bone and their potential roles in the development of osteoporosis. Epidemiological findings have demonstrated an association between vitamin deficiency and a higher risk of developing osteoporosis; vitamins are positively related to bone health upon their intake at the physiological range. Excessive vitamin intake can also adversely affect bone formation, as clearly demonstrated for vitamin A. Vitamins E (tocopherols and tocotrienols), K2 (menaquinones 4 and 7) and C have also been shown to promote osteoblast development through bone morphogenetic protein (BMP)/Smad and Wnt/β‑catenin signaling, as well as the TGFβ/Smad pathway (α‑tocopherol). Vitamin A metabolite (all‑trans retinoic acid) exerts both inhibitory and stimulatory effects on BMP‑ and Wnt/β‑catenin‑mediated osteogenesis at the nanomolar and micromolar range, respectively. Certain vitamins significantly reduce receptor activator of nuclear factor kappa‑B ligand (RANKL) production and RANKL/RANK signaling, while increasing the level of osteoprotegerin (OPG), thus reducing the RANKL/OPG ratio and exerting anti‑osteoclastogenic effects. Ascorbic acid can both promote and inhibit RANKL signaling, being essential for osteoclastogenesis. Vitamin K2 has also been shown to prevent vascular calcification by activating matrix Gla protein through its carboxylation. Therefore, the maintenance of a physiological intake of vitamins should be considered as a nutritional strategy for the prevention of osteoporosis.

Keywords: menaquinone; osteogenesis; osteoporosis; tocopherol; vitamins.

Figure 1

Role of the PI3K/Akt/mTOR pathway in the osteogenic effects of vitamin E. Tocopherol increases PI3K, Akt and mTOR phosphorylation, as well as TGF1β gene expression. Similarly, tocotrienol upregulates PI3K/Akt signaling.

Figure 2

Role of VK2 in the prevention of vascular calcification via carboxylation of MGP. Briefly, VK2 has been used as a cofactor for γ-glutamyl carboxylase, which converts glutamate residues of dephosphorylated, dp-ucMGP, to γ-carboxyglutamic residues, resulting in the formation of dp-cMGP. Further phosphorylation induces the formation of active MGP, which inhibits BMP2-induced osteogenic signaling in vascular cells, and binds Ca²⁺ cations, in turn, preventing hydroxyapatite formation. KH2, vitamin K hydroquinone; KO, vitamin K epoxide; MGP, matrix Gla protein; dp-ucMGP, uncarboxylated MGP; dp-cMGP, dephosphorylated carboxylated MGP.

Figure 3

The proposed mechanisms underlying the osteoblastogenic effects of vitamins. Vitamins E, K2 and C promote osteogenesis through the upregulation of BMP/Smad and Wnt/β-catenin signaling. In addition, vitamin E in the form of tocopherol stimulates TGFβ signaling through Smad2. In turn, vitamin A exerts both inhibitory and stimulatory effect on BMP- and Wnt/β-catenin-mediated osteogenesis, and the effect appears to be dependent on the exposure dose. BMP, bone morphogenetic protein; DKK, Dickkopf-related protein; APC, adenomatous polyposis coli; LRP, low density lipoprotein receptor-related protein.

Figure 4

Regulatory effect of vitamins on osteoclastogenesis through the modulation of the RANKL/OPG ratio. Vitamins E, K2, A, B1, B6, B12 and folic acid inhibit osteoclastogenesis through the downregulation of RANKL production and subsequent RANK signaling. In addition, vitamins E, K2, A and C significantly increase the production of OPG that antagonizes RANKL/RANK signaling. In turn, vitamin B5 and particularly, ascorbic acid (VC) stimulate and inhibit RANKL-mediated osteoclastogenesis dependent on the dose. The inhibition of osteoclastogenesis due to a reduced RANKL/OPG ratio results in inhibition of osteoclast formation with subsequent decrease in bone resorption. The dotted line is indicative of indirect effect, the 'T' line indicates inhibition, and the black arrow line indicates stimulation. RANKL, receptor activator of nuclear factor kappa-B ligand; OPG, osteoprotegerin.