Clinical Briefs: Vitamin A and Fracture Risk

With Comments from John La Puma, MD, FACP

Source: Michaelsson K et al. Serum retinol levels and the risk of fracture. N Engl J Med 2003;348:287-294.

Although studies in animals and epidemiologic studies have indicated that a high vitamin A intake is associated with increased bone fragility, no biologic marker of vitamin A status has thus far been used to assess the risk of fractures in humans.

A total of 2,322 men, 49-51 years of age, were enrolled in a population-based, longitudinal cohort study. Serum retinol and beta-carotene were analyzed in samples obtained at enrollment. Fractures were documented in 266 men during 30 years of follow-up. Cox regression analysis was used to determine the risk of fracture according to the serum retinol level.

The risk of fracture was highest among men with the highest levels of serum retinol. Multivariate analysis of the risk of fracture in the highest quintile for serum retinol (> 75.62 micrograms per deciliter [2.64 micromoles per liter]) as compared with the middle quintile (62.16-67.60 micrograms per deciliter [2.17-2.36 micromoles per liter]) showed that the rate ratio was 1.64 (95% confidence interval, 1.12-2.41) for any fracture and 2.47 (95% confidence interval, 1.15-5.28) for hip fracture. The risk of fracture was further increased within the highest quintile for serum retinol. Men with retinol levels in the 99th percentile (> 103.12 micrograms per deciliter [3.60 micromoles per liter]) had an overall risk of fracture that exceeded the risk among men with lower levels by a factor of seven (P < 0.001). The level of serum beta-carotene was not associated with the risk of fracture.

These findings, which are consistent with the results of studies in animals, as well as in vitro and epidemiologic dietary studies, suggest that current levels of vitamin A supplementation and food fortification in many Western countries may need to be reassessed.


In Sweden, hip fracture is more than twice as common among men than women. The authors postulate that serum retinol is a biological marker for fracture. Consuming more than 1.5 mg (4,500 IU) of vitamin A (retinyl palmitate) daily increased fracture risk.

What does vitamin A do? In premature and malnourished children it prevents some diseases of the eye, but in Western countries it appears to accelerate osteoporosis and promote bone fracture. The Harvard-based Nurses Health Study, of more than 70,000 nurses, found a similar association: Postmenopausal women whose daily intake of vitamin A exceeded 3,000 micrograms (about 10,000 IU) were 40% more likely to fracture a hip, compared with women whose daily intake was less than 1,250 micrograms (3,750 IU).

The therapeutic window of vitamin A is narrow and its serum levels increase with age. Editorialist Paul Lips writes, "One may conclude from such data that supplements containing vitamin A should not be routinely used by men or women and that fortification of cereals with vitamin A should be questioned."

Vitamin A is found in fatty fish, liver, kidney, and dairy products, and many are fortified with vitamin A, including milk and yogurt. Many processed cereals are augmented too. Beta-carotene and other carotenoids also are converted into vitamin A in the body, but these amounts are small relative to the direct intake and absorption of vitamin A.

How does fracture occur? Dietary vitamin A is converted to retinoic acid, which binds to specific receptors. In vitro, these receptors then curb osteoblast activity and encourage osteoclast formation. Osteoclasts take up old bone, and while this makes way for new bone, it also may cause susceptibility to fracture.

The Recommended Daily Intake for vitamin A is just 0.7 mg of vitamin A for women and 0.9 mg for men. Most multivitamins easily supply this—even twice this—on top of what people get from food.

What are the study’s limitations? It followed 2,322 middle-aged men over 30 years, but blood levels of vitamin A were taken once, at the beginning of the trial. Vitamin A is stored in fat cells, like the other fat-soluble vitamins (D, E, and K), but one time measurements are just that. A study of this duration and power is unlikely to be repeated prospectively.


Vitamin A toxicity has been well known for decades: Administration as a dietary supplement to adults should be avoided. For this vitamin, what patients get from food is enough. Advise your patients to take a multivitamin that derives all of its vitamin A from beta-carotene; patients also should avoid eating liver and reconsider fish oil supplements.

Dr. La Puma is Executive Editor of Alternative Medicine Alert and Director of Santa Barbara Institute for Medical Nutrition & Healthy Weight, Santa Barbara, CA.