High doses of vitamin A and beta-carotene do not seem to increase bone fracture risk

Long-term supplementation with high doses of vitamin A (retinol) and/or beta-carotene are not associated with an elevated risk for bone fracture, suggests a new Australian study.

The researchers analyzed data of an intervention study originally investigating cancer prevention in a very high-risk population of asbestos-exposed workers (1). The new analysis focused on cases of bone fractures documented among 2,322 participants with a mean age of 55 years, who received supplements of 7.5 mg retinol equivalents (RE) per day for up to 16 years and/or 30mg beta-carotene per day for up to 7 years (2). The study results showed that cumulative dose of vitamin A is not associated to the risk for any type of bone fracture, including osteoporotic fracture. Among men, the cumulative dose of beta-carotene was associated with a slightly reduced risk of bone fracture, including osteoporotic fracture.

The scientists noted that it was not possible to utilize the design of a randomized controlled trial in their analysis. The primary purpose of the original study (1) and nature of the exposure (beta-carotene and retinol are nutrients found in many foods) negated the use of a placebo. In Australia, the recommended dietary intake for vitamin A is 700 μg RE/day for women who are not pregnant and 900 μg RE/day for men (3). The daily dose of 7.5 mg RE administered in this study is equivalent to eight to ten times greater than these recommended amounts. Furthermore, the administered dose of beta-carotene (30mg/day) exceeds the recommended by many times.

Observational studies examining vitamin A supplement used in relation to fracture risk have shown mixed results. In one study, which followed up over 34,000 post-menopausal women for an average of 9.5 years, a slightly increased risk for self-reported hip fracture was suggested among vitamin A supplement users, but not for all types of fracture (4). However, no relationship between dose and response was demonstrated, and hip fracture was not associated with dietary or total retinol intake. A large cohort study reported associations between increased dietary retinol intake and higher fracture risk (5). More recent cohort studies have not observed associations between dietary or supplementary retinol intake and fracture risk (6,7).

It has been hypothesized that carotenoids may reduce fracture risk by counteracting oxidative stress, which can adversely affect bone mineral density (8,9). The Australian researchers commented that the new fin-dings of a decreased fracture risk with longer duration of beta-carotene supplementation, albeit in men only (possibly because of the small number of women in the study), would be in line with these observations.

1. De Klerk, N. H. et al. Vitamin A and cancer prevention II: comparison of the effects of retinol and beta-carotene. Int J Cancer. 1998; 75:362–367.
2. Ambrosini, G. L. et al. No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene. Osteoporosis International. Published online September 2012.
3. Commonwealth Department of Health and Ageing, Australia, the National Health and Medical Research Council, Australia and the Ministry of Health, New Zealand (2006) Nutrient reference values for Australia and New Zealand. ISBN 1864962372.
4. Lim, L. S. et al. Vitamin A intake and the risk of hip fracture in postmenopausal women: the Iowa Women’s Health Study. Osteopor Int. 2004; 15:552–559.
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9. Zhang, J. et al. Antioxidant intake and risk of osteoporotic hip fracture in Utah: an effect modified by smoking status. Am J Epidemiol. 2006; 163:9–17.