Vitamin E is one of the most important lipid-soluble antioxidants, and it has been reported to have beneficial effects on the cardiovascular system by reducing atherosclerotic plaques, coronary artery disease and acute myocardial infarction¹. A 2005 report from the Centers for Disease Control and Prevention found that one in nine adults takes more than 267 mg per day of vitamin E, even though the daily recommended dose is only 15 mg per day^{2, 3}. Although it is clear that vitamin D, another fat-soluble vitamin, when combined with calcium plays a major part in maintaining bone health and reducing the risk of fractures⁴, the effects of vitamin E on bone are unclear.

In vitro studies have shown that vitamin E can affect bone resorption by inhibiting the formation of bone-resorbing osteoclasts. Vitamin E may mediate this effect by decreasing receptor activator of NF-κB (RANK) ligand production by bone-producing osteoblasts and reducing c-fos expression in osteoclast precursors, as well as by decreasing osteoblast proliferation^{5, 6}. Antiosteoporotic effects of vitamin E have also been reported⁷. In a study of 533 nonsmoking females, use of vitamin E negatively correlated with bone resorption markers, suggesting that it inhibits bone resorption⁸. Similarly, in a study involving 1,000 subjects, there was an inverse relationship between vitamin E intake and the risk of fracture in current and former smokers but not in nonsmokers⁹. More recent studies have not shown an association between bone resorption markers and vitamin E concentrations in the serum, and a negative correlation between vitamin E levels and the expression of the bone formation marker bone-specific alkaline phosphatase in postmenopausal women has been reported, suggesting that vitamin E inhibits bone formation¹⁰. Together, these results suggest that vitamin E can have either beneficial or deleterious effects on bone remodeling.

In this issue of Nature Medicine, Fujita et al.¹¹ use mouse genetic models to define the role of vitamin E in bone remodeling. α-tocopherol is the predominant isoform of vitamin E, and α-tocopherol transfer protein (α-TTP) in the liver is required for the transfer of α-tocopherol into lipoproteins. The authors report that mice lacking α-TTP (Ttpa^−/− mice) developed increased bone mass in their vertebrae and long bones¹¹. The mice showed a decrease in the percentage of the bone undergoing bone resorption and in the expression of bone resorption markers but had normal bone formation, suggesting that lack of α-TTP specifically affects the bone resorption axis of bone remodeling.

Fujita et al.¹¹ then showed that dietary α-tocopherol supplementation rescued the abnormal bone phenotype in the Ttpa^−/− mice. Furthermore, osteoclast formation in bone marrow cell cultures from wild-type mice was inhibited by sera from Ttpa^−/− mice. In contrast, osteoclast precursors from Ttpa^−/− mice formed normal osteoclasts when cultured in wild-type sera. Addition of α-tocopherol to RANK ligand–treated bone marrow cultures increased osteoclast formation, osteoclast size and the number of nuclei per osteoclast. Notably, α-tocopherol affected only osteoclast formation during the maturation phase and did not affect the proliferative phase of osteoclast development. α-tocopherol also induced foreign-body giant cell formation by macrophages, demonstrating that it can induce macrophage fusion as well as osteoclast fusion. Interestingly, of all the vitamin E isoforms the authors tested, only α-tocopherol stimulated osteoclast precursor fusion. Other antioxidants had no effect on osteoclast fusion. These results suggest that the effects of α-tocopherol on osteoclast fusion are independent of its antioxidant effects.

The authors then analyzed osteoclast differentiation markers after α-tocopherol treatment and found that α-tocopherol increased the expression of a key molecule involved in osteoclast fusion, dendritic cell–specific transmembrane protein (DC-STAMP)¹², in osteoclast precursors¹¹. In addition, DC-STAMP expression was decreased in Ttpa^−/− mice. Using gain- and loss-of-function experiments for DC-STAMP, Fujita et al.¹¹ confirmed that this protein was responsible for mediating the effects of vitamin E on osteoclast precursor fusion. They also defined a pathway through which vitamin E increases DC-STAMP expression via p38 mitogen-activated protein kinase signaling to activate the transcriptional regulator microphthalmia-associated transcription factor, which binds the promoter of the gene encoding DC-STAMP. Finally, the authors found that rats or mice fed α-tocopherol for eight weeks at doses that are present in the vitamin E supplements used by many people showed a 20% decrease in bone mass and had increased bone resorption and osteoclast size¹¹. Together, these results show that the major effect of vitamin E on bone remodeling is to enhance osteoclast size, which results in increased bone resorption per osteoclast (Fig. 1).

Figure 1: Using mouse genetic models, Fujita et al.¹¹ show that the major vitamin E isoform, α-tocopherol, functions in the later differentiation stage of osteoclast (OC) formation to promote the fusion of osteoclast precursors.