Serum retinol levels and the risk of fracture

N Engl J Med. 2003 Jan 23;348(4):287-94. doi: 10.1056/NEJMoa021171.


Background: 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.

Methods: We enrolled 2322 men, 49 to 51 years of age, 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.

Results: 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 microg per deciliter [2.64 micromol per liter]) as compared with the middle quintile (62.16 to 67.60 microg per deciliter [2.17 to 2.36 micromol per liter]) showed that the rate ratio was 1.64 (95 percent confidence interval, 1.12 to 2.41) for any fracture and 2.47 (95 percent confidence interval, 1.15 to 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 microg per deciliter [3.60 micromol 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.

Conclusions: Our 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Mass Index
  • Dose-Response Relationship, Drug
  • Fractures, Bone / epidemiology*
  • Fractures, Bone / etiology
  • Hip Fractures / etiology
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Osteoporosis / chemically induced
  • Proportional Hazards Models
  • Risk Factors
  • Vitamin A / administration & dosage
  • Vitamin A / adverse effects
  • Vitamin A / blood*
  • beta Carotene / blood


  • beta Carotene
  • Vitamin A