NATIONAL INSTITUTES OF HEALTH National Institute of Arthritis and Musculoskeletal and Skin Diseases
January 19, 1994 Contact: Elia Ben-Arii 
Office of Scientific and 
Health Communications 
(301) 496-8188

Researchers have found a gene that may help to identify, early in life, individuals at high risk for osteoporosis. This gene strongly influences bone density, an important determinant of the risk of osteoporosis. Osteoporosis (porous, weak bone) affects more than 25 million people in the U.S.; it is the major underlying cause of bone fractures in postmenopausal women and the elderly. Osteoporosis usually results from two factors: the peak bone strength (density) attained in early life, and how rapidly a person loses bone in later life. "The prospect of having a genetic marker of bone density that would permit early intervention to prevent osteoporosis is extremely exciting," says Dr. Lawrence E. Shulman, Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, which funded the study.

Although heredity has long been suspected of playing a role in bone density, until now genes responsible for this trait have not been identified. As reported in the January 20th issue of the scientific journal Nature, Dr. John A. Eisman and colleagues at the Garvan Institute of Medical Research in Sydney, Australia, have now found that a single gene can account for up to 75 percent of the total genetic effect on bone density. This gene codes for the vitamin D receptor (VDR), a protein that enables vitamin D to exert its actions on bone and on calcium metabolism. Non-genetic factors such as hormones, calcium intake, and exercise also influence the density of bone.

Eisman and his colleagues measured bone densities in 70 pairs of identical twins and 55 nonidentical twins. The researchers found that identical twins, who share 100 percent of their genes, had more similar bone densities than did nonidentical twins, who do not share all genes. The researchers also found that there are two forms (alleles) of the VDR gene, one called "B" and the other called "b." Normal people have one copy of the VDR gene from each parent, and thus may have either the BB, Bb, or bb combination. The researchers then looked at the effect of the two forms of the VDR gene on bone density. They found a strong link between the "B" version of the VDR gene and low bone density in the spine and femur (thigh bone at the hip). Bone density was lowest in those with the BB combination, intermediate in those with Bb, and highest in those with bb. Nonidentical twins that had the same alleles of the VDR gene were similar to identical twins in this regard, thus strengthening the importance of these receptor genes to bone density. It is not yet clear how the difference between the two forms of the VDR gene could affect bone density.

The researchers also examined 311 unrelated healthy women from the Sydney area. In this second population, the vitamin D receptor gene was also found to be a strong predictor of bone density, and again the "B" allele was associated with lower bone density. Eisman and colleagues predict that women with BB, having low bone density in early life, will, when they start to lose bone as they age, reach the "fracture threshold" of low bone density in the spine 11 years earlier, and in the hip 8 years earlier, than those with bb. The latter translates to a four-fold increase in the risk of hip fracture for BB individuals as compared to those with bb.

These findings need to be extended to other and larger populations in the United States and elsewhere. They may provide an important explanation for the wide variation in bone density, not only among individuals, but also among various ethnic groups. African-American women in the United States, for example, develop approximately 10 percent greater peak bone mass by age 35 than do Caucasian women.

Research is also needed to uncover the precise role of the vitamin D receptor in regulating bone density. These investigations open new frontiers in research on the underlying causes of osteoporosis, and in particular the critical role of vitamin D in bone formation and metabolism. They could also pave the way for developing new targeted approaches to the prevention and treatment of this common and debilitating disease, a major public health problem in the United States.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health, leads and coordinates the Federal research effort in osteoporosis and related bone disorders by supporting research projects, research training, clinical trials, and epidemiological studies, and by disseminating information on research results.

# # #

Reference: Nigel A. Morrison et al. Nature 367: 284-287. January 20, 1994. 

Last Reviewed: