The Use of Vitamins and Minerals in Skeletal Health

American Association of Clinical Endocrinologists and the American College of Endocrinology Position Statement

Daniel L. Hurley, MD, FACE; Neil Binkley, MD, FACE; Pauline M. Camacho, MD, FACE; Dima L. Diab, MD, FACE, FACP, CCD; Kurt A. Kennel, MD, FACE; Alan Malabanan, MD, FACE, CCD; Vin Tangpricha, MD, PhD, FACE


Endocr Pract. 2018;24(10):915-924. 

In This Article

Other Vitamins

Vitamin A is known to influence bone content. Vitamin A is derived from retinol ingested as either retinyl esters (animal source foods) or carotenoids (fruits and vegetables) and metabolized to active compounds such as 11-cis-retinal, important for vision, and all-trans-retinoic acid, which is the primary mediator of the biologic actions of vitamin A. The role retinoids play in regulating osteoclastogenesis remains unclear. In a small cross-sectional study, vitamin A levels showed a negative correlation with BMD, but this association disappeared when a multivariate analysis was applied to include other anti-oxidants.[62] Plasma retinol levels and carotenoids tested in ambulatory women were found to be associated with lower hip BMD and consistently lower in those with osteoporosis.[63] Some studies suggest that moderate intakes of retinol[64] and increased circulating retinol levels[65] may increase fracture risk, whereas others have found no effect on hip BMD[66] or fractures.[67,68] In a randomized study of 998 adults, lower fracture risk was suggested with increasing plasma total carotenes after long-term supplementation, but no association was found between plasma retinol levels and fracture risk.[69]

Vitamin K is a cofactor of γ-carboxylase and essential for γ-carboxylation of osteocalcin, a major noncollagenous bone matrix protein important in bone mineralization. Undercarboxylated osteocalcin (ucOC) lacks structural integrity, and its ability to bind to hydroxyapatite is impaired.[70] Observational studies suggest diets low in vitamin K are associated with increased fracture risk in older adults.[71] However, a recent review of RCTs to assess the impact of fortified foods on bone outcomes assessed both before and after supplementation found only two studies of vitamin K and just one study with folate food fortification, with no effect from folate and inconsistent effects noted with vitamin K.[72] One RCT found no effect of vitamin K–fortified milk when compared to calcium, but the study was <4 months in duration and only assessed markers of bone turnover in young premenopausal women.[73] The second RCT included postmenopausal women consuming calcium and vitamin D–fortified dairy with or without vitamin K.[74] After 1 year, the vitamin K groups had significantly lower serum ucOC ratios and urine deoxypyridinoline bone turnover levels. Significant increases in total body BMD occurred in all treatment groups, with better increases in spine BMD observed only in the vitamin K groups after controlling for 25(OH)D levels and dietary calcium intake.

There are two naturally occurring vitamin K forms; phylloquinone (K1) is the major dietary form (especially in green leafy vegetables), whereas menaquinone-4 (K2) is the main tissue form, to include bone. Vitamin K2 is synthesized by gut bacteria but also present in some foods (fermented soy beans, cheese, and curds). A 2-year RCT with vitamin K1, vitamin D, and calcium or their combination was studied in postmenopausal women without osteoporosis. The group with combined vitamin K, vitamin D, and calcium had significant changes in serum vitamin K1 (+157%), ucOC (−51%), 25(OH)D (+17%), and PTH (−11%), with BMD improvement at the radius but no other skeletal sites.[75] A review of eight small RCTs (n = 63 to 241 subjects) of 1 to 2 years in duration showed that menatetrenone, a synthetic vitamin K2, decreased serum ucOC, increased spine BMD, and reduced the incidence of vertebral fractures.[70] Although vitamin K antagonists (VKAs) decrease serum bone turnover markers, their link with osteoporosis and fractures remains controversial. A meta-analysis of cross-sectional and longitudinal studies assessed patients treated with VKAs compared to healthy controls or those with a medical illness.[76] Compared with healthy controls, only a single study showed significantly lower spine BMD in the VKA group, and findings in the longitudinal studies were not significant. Currently, there is not enough evidence to recommend the use of vitamin K supplements for skeletal health.

There is conflicting evidence of the role of vitamin E on bone health. The most abundant vitamin E isomer present in food and most widely distributed in the body is α-tocopherol (αTF). Supplementation generally shows positive effects in various animal models of osteoporosis, but high-dose αTF may be detrimental to bone. Possible reasons αTF may be harmful to bone include interference with the effects of vitamin K on bone, blocking other vitamin E isomers beneficial to bone, and its role as a prooxidant. Observational studies to assess the skeletal effects of αTF have generally been positive.[77] However, several limitations are involved in the interpretation of these studies. The WHI Observational Study and Clinical Trial reported an association between the amount of vitamin E consumed, the αTF level, and BMD,[78] and neither serum vitamin E nor other anti-oxidant levels were associated with hip BMD. Due to the heterogeneity of these studies, no recommendation for vitamin E supplementation can be made for bone health.

Vitamin C is found naturally in fruits and vegetables, and it is a common fortification in cereals and juices due to its low toxicity. However, the prevalence of deficiency in the U.S. is reported as 6%.[79] Human studies generally showed a positive relationship between vitamin C and bone health, although some suggest that the relationship may be U-shaped, more prominent in certain subgroups and different between dietary and supplemental forms of ascorbic acid.[80,81] Many of these observational or cross-sectional studies used varied methods to assess vitamin C intake and differ in effect size and statistical significance. In contrast, the large WHI study found no association between dietary intake, total intake, or serum levels of vitamin C and BMD.[78] In addition, the National Health and Nutrition Examination Survey III found inconsistent outcomes between vitamin C status and BMD among 13,080 U.S. adults: positive among premenopausal women, nonlinear for men, and negative in postmenopausal women with no history of smoking or estrogen use.[82] Longitudinal study outcomes from the Framingham Osteoporosis Study, using dietary questionnaires to assess vitamin C intake, found mixed results for BMD outcomes over 4 years and no association with fracture risk, although significantly fewer hip and nonvertebral fractures occurred in the highest versus lowest tertile of intake.[83] Two small 6- and 12-month RCTs noted positive but different spine and hip BMD effects.[84,85] Taken together, the majority of studies have found either positive trends or significant effects of vitamin C on skeletal health. Vitamin C is known to play a role in collagen formation, bone matrix development, osteoblast differentiation, and in limiting bone resorption, but the exact effect that vitamin C may have on bone density is presently unknown.[78,80]