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Diane Feskanich, ScD; Vishwa Singh, PhD; Walter C. Willett, MD,DrPH; Graham A. Colditz, MD,DrPH

JAMA. 2002;287:47-54.

Context  Ingestion of toxic amounts of vitamin A affects bone remodeling and can have adverse skeletal effects in animals. The possibility has been raised that long-term high vitamin A intake could contribute to fracture risk in humans.

Objective  To assess the relationship between high vitamin A intake from foods and supplements and risk of hip fracture among postmenopausal women.

Design  Prospective analysis begun in 1980 with 18 years of follow-up within the Nurses' Health Study.

Setting  General community of registered nurses within 11 US states.

Participants  A total of 72 337 postmenopausal women aged 34 to 77 years.

Main Outcome Measures  Incident hip fractures resulting from low or moderate trauma, analyzed by quintiles of vitamin A intake and by use of multivitamins and vitamin A supplements, assessed at baseline and updated during follow-up.

Results  From 1980 to 1998, 603 incident hip fractures resulting from low or moderate trauma were identified. After controlling for confounding factors, women in the highest quintile of total vitamin A intake (3000 µg/d of retinol equivalents [RE]) had a significantly elevated relative risk (RR) of hip fracture (RR, 1.48; 95% confidence interval [CI], 1.05-2.07; P for trend = .003) compared with women in the lowest quintile of intake (<1250 µg/d of RE). This increased risk was attributable primarily to retinol (RR, 1.89; 95% CI, 1.33-2.68; P for trend <.001 comparing 2000 µg/d vs <500 µg/d). The association of high retinol intake with hip fracture was attenuated among women using postmenopausal estrogens. Beta carotene did not contribute significantly to fracture risk (RR, 1.22; 95% CI, 0.90-1.66; P for trend = .10 comparing 6300 µg/d vs <2550 µg/d). Women currently taking a specific vitamin A supplement had a nonsignificant 40% increased risk of hip fracture (RR, 1.40; 95% CI, 0.99-1.99) compared with those not taking that supplement, and, among women not taking supplemental vitamin A, retinol from food was significantly associated with fracture risk (RR, 1.69; 95% CI, 1.05-2.74; P for trend = .05 comparing 1000 µg/d vs <400 µg/d).

Conclusions  Long-term intake of a diet high in retinol may promote the development of osteoporotic hip fractures in women. The amounts of retinol in fortified foods and vitamin supplements may need to be reassessed.

Author Affiliations: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (Drs Feskanich, Willett, and Colditz), and Departments of Nutrition (Dr Willett) and Epidemiology (Drs Willett and Colditz), Harvard School of Public Health, Boston, Mass; and Roche Vitamins Inc, Human Nutrition Research, Parsipanny, NJ (Dr Singh).

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