Does Vitamin A cause Osteoporosis? – Editorial
A recent epidemiological study published in the Journal of the American Medical Association concluded that long-term intake of a diet high in vitamin A may promote the development of osteoporotic hip fractures in postmenopausal women. That conclusion was based on data from the Nurses’ Health Study, a prospective cohort study of 72,337 postmenopausal women. (1) In 1980, information on diet and use of nutritional supplements was obtained from each participant, and this information was updated periodically in subsequent years. During 18 years of follow-up, 603 hip fractures resulting from low or moderate trauma (i.e., fractures presumably due to osteoporosis) were documented.
After controlling for confounding factors, women in the highest quintile of retinol intake (i.e., preformed vitamin A from food and supplements, excluding beta-carotene) had an 89% higher risk of hip fracture, compared with women in the lowest quintile (p for trend < 0.001). Women in the highest quintile of retinol intake were consuming 2,000 mcg (6,667 IU) or more of vitamin A per day, whereas those in the lowest quintile were consuming less than 500 mcg (1,667 IU) per day. Among women not taking vitamin A supplements, retinol from food was also significantly associated with hip-fracture risk; women in the highest quintile (1,000 mcg [3,333 IU] or more per day) had a 69% higher risk, compared with those in the lowest quintile (less than 400 mcg [1,333 IU] per day).
Women currently taking a specific vitamin A supplement had a 40% increase in the risk of hip fracture compared with those not taking a vitamin A supplement, but this difference was not statistically significant. Beta-carotene intake was also associated with a 22% increase in risk, comparing the highest and lowest quintiles of intake, but again the difference was not statistically significant.
If the results of this study are to be taken at face value, then vitamin A can cause adverse effects on bone health at a level well below that which is typically associated with vitamin A toxicity. Even 10,000 TU of supplemental vitamin A (an amount found in many multiple-vitamin preparations) would be above the safety threshold, and as little as 5,000 IU per day of supplemental vitamin A would be bordering on too much.
However, there are a number of reasons to question the assertion that relatively small amounts of vitamin A might lead to osteoporosis. First, that conclusion is not consistent with the known biological effects of retinol. While vitamin A toxicity is known to have adverse effects on bone, the amounts required to produce such effects are extremely large. For example, in a study in rats, supplementation with vitamin A at a dose equivalent to 70 million IU per 70 kg of body weight twice a week for 5 weeks inhibited the healing of experimental fractures and resulted in the formation of fragile bones. However, half that dose (equivalent to a human dose of approximately 10 million IU per day for 5 weeks) actually accelerated fracture healing. (2) Well-known effects of chronic vitamin A toxicity in humans include hair loss, neurological problems, headaches, liver damage, visual impairment, and dry skin. However, although vitamin A excess can result in bone pain (which usually disappears within weeks to months after supplementation is discontinued), chronic vitamin A overdose has not previously been reported to be associated with osteoporosis. Since chronic vitamin A toxicity (which requires long-term intake of at least 33,300 IU per day) has not previously been reported to cause osteoporosis, it is difficult to believe that intakes more than 80% lower than that would lead to bone loss.
A more likely explanation for the findings in the recent JAMA report is that vitamin A intake is merely a marker for certain dietary patterns that are associated with osteoporosis. The main food sources of vitamin A in the American diet, aside from liver, are fortified skim and low-fat milk (5,000 IU per liter), fortified breakfast cereals (up to 1,250 IU per serving), and fortified margarine (approximately 500 IU per tablespoon). A daily diet that includes 2 cups of fortified milk plus either 1 serving of fortified breakfast cereal or 2 tablespoons of margarine would put a person in the top quintile of vitamin A intake.
There is circumstantial evidence that some or all of the foods that are high in vitamin A can promote the development of osteoporosis, for reasons unrelated to their vitamin A content. For example, fortified breakfast cereals often contain large amounts of added sugar. A high intake of refined sugar has been shown to increase urinary calcium excretion in humans (3) and to cause bone loss in experimental animals. (4) Most brands of margarine contain substantial quantities of compounds known as trans-fatty acids, (5) which are produced during the manufacturing process. Ingestion of these trans-fatty acids can promote a deficiency of essential fatty acids, nutrients that are essential for normal bone health. (6) Fortified milk, another significant dietary source of vitamin A, may also be a less-than-perfect food for the bones, despite its high calcium content. Milk is one of the major sources of dietary phosphorus, a mineral that is often present in excessive amounts in the American diet. Consumption of too much phosphorus can impair bone health, particularly in older women. (7) In addition, dairy products are the only significant dietary source of naturally occurring transfatty acids. (8) Studies examining the relationship between milk consumption and bone health have yielded conflicting results, (9) and one study (using data from the same Nurses’ Health Study described above) showed an increased risk of fractures in women who consumed two or more glasses of milk per day, as compared with women consuming one glass or less per week. (10)
Liver, the other major dietary source of vitamin A, accumulates various environmental toxins, including lead and cadmium, (11) both of which can cause osteoporosis. In addition, some environmental chemicals that might concentrate in the liver could promote bone loss through their capacity to inhibit androgen activity. (12)
Based on these considerations, it seems unlikely that the reported association between vitamin A and hip fractures represents a cause-effect relationship. Perhaps the real culprits are refined sugar, transfatty acids, milk, and environmental toxins.
Alan R. Gaby, MD
(1.) Feskanich D, et al. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287:47-54.
(2.) Udupa KN, et al. Role of vitamin A in the repair of fracture. Indian J Med Res 1966;54:1l22-1130.
(3.) Lemann J Jr, et al. Possible role of carboydrate-induced calciuria in calcium oxalate kidney-stone formation. N Engl J Med 1969;280:232.237.
(4.) Saffar JL, et al. Osteoporotic effect of a high-carbohydrate diet (Keyes 2000) in golden hamsters. Arch Oral Biol 1981;26:393-397.
(5.) Holman RT, et al. Effects of trans fatty acid isomers upon essential fatty acid deficiency in rats. Proc Soc Exp Bio Med 1956;93:l75-179.
(6.) Odutuga AA. Effects of low-zinc status and essential fatty acid deficiency on bone development and mineralization. Comp Biochem Physiol 1982;71A:383-388.
(7.) Calvo MS, et al. changing phosphorus content of the U.S. diet: potential for adverse effects on bone. J Nutr 1996;126:1168S-1180S.
(8.) Oomen CM, et al. Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study. Lancet 2001;357:746-751.
(9.) Weinsier RL, et al. Dairy foods and bone health: examination of the evidence. Am J Clin Nutr 2000;72:681-689.
(10.) Feskanich D, et al. Milk, dietary calcium, and bone fractures in women: a 12-year prospective study. Am J Public Health 1997;87:992-997.
(11.) Boyer KW, et al. Trace element levels in tissues from cattle fed a sewage sludge-amended diet. J Toxicol Environ Health 1981;8:281-295.
(12.) Sohoni P, et al. Several environmental oestrogens are also anti-androgens. J Endocrinol 1998;158:327-339.
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