30-year study links vitamin A to risk of fracture in humans

Graham McKerrow, HIV i-Base

Swedish researchers have concluded from a 30-year study of 2,322 men that current levels of vitamin A supplementation and food fortification in many western countries may need to be reassessed.

The findings of their study are consistent with the results of animal studies, but no biologic marker of vitamin A status had been used to assess the risk of fractures in humans.

From 1970 to 1973 the researchers from University Hospital, Uppsala, enrolled the men, born between 1920 and 1924 in a population-based, longitudinal, cohort study. The base-line evaluation included a medical and lifestyle questionnaire and interview, tests of serum samples and anthropometric measurements. At 60 years of age, 1,860 men (80% of the total cohort) took part in a second evaluation, and at 70 years, 1,221 men (53%) took part in a third evaluation. Fractures were documented in 266 men in the 30 years of follow-up.

Karl Michaelsson and colleagues report that 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 µg per decilitre [2.64 µmol per litre]) as compared with the middle quintile (62.16 to 67.60 µg per decilitre [2.17 to 2.36 µmol per litre]) 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 µg per decilitre [3.60 µmol per litre]) 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.

The researchers write: “Our findings are consistent with the results of two previous prospective epidemiologic investigations that examined dietary retinol intake and the risk of hip fracture in women. Our study, in which retinol was used as a biologic marker together with the overall risk of fracture, corroborates the detrimental effect of excess retinol on human bone. Serum retinol has been positively associated with both dietary vitamin A intake and use of supplemental vitamin A in most studies but not all. As in the two previous epidemiologic dietary studies, we compared the risk of fracture among subjects who had an estimated dietary vitamin A intake of more than 1.5 mg per day with the risk among those whose intake was less than 0.5 mg per day. All three studies showed that the risk was increased by a factor of approximately two among subjects in the highest category of vitamin A intake.”


Karl Michaelsson, Hans Lithell, Bengt Vessby et al. Serum retinol Levels and the Risk of Fracture. New England Journal of Medicine, Volume 348:287-294, January 23, 2003, Number 4.

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