Hotline Archive - Why the Bones Break
February 1994
Osteoporosis is a major global public health problem. About 25 million people, most of them women, have osteoporosis in the United States. Osteoporotic fractures can be catastrophic. There are 1.7 million hip fractures per year worldwide. About 25 percent of the people who suffer hip fractures die in six months, and many require permanent institutional care. Humpback posturing in women is a visible sign of osteoporosis and signifies the crush of life's passage.
Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Bone density depends on complex interactions between the osteoclast and osteoblast. It is controlled by multiple systemic hormones, local cytokines, and growth regulation factors. It has previously been shown that osteoporotic fracture as a result of low bone density is under strong genetic control. It has been known for 20 years that bone density varies less in monozygotic twins than in dizygotic twins.
In the Jan. 20, 1994, issue of Nature (367, 284-287, 1994), Nigel A. Morrison et al from the Garvan Institute of Medical Research in Sydney, Australia, reported on the prediction of bone density from vitamin D receptor alleles. They showed that common allelic variants in the gene encoding for the vitamin D receptor can predict the bone mineral density and account for up to 75 percent of the total genetic effect on bone density in healthy individuals.
There are two versions of the specific gene that direct construction of the receptor, called B and b. The B allele predicts the weaker skeleton apparently because a mutation of the receptor gene encodes a dysfunctional receptor. Each parent contributes a copy, producing bb, Bb, or BB genotypes.
Morrison et al, in studying 311 women, found the genotype associated with lower bone density was over-represented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The BB genotype was the most severe threat with osteoporosis appearing at age 65 years, Bb genotype at age 69 years, and bb genotype at age 76 years. The vitamin D receptor acts as a director after vitamin D locks on to the receptor, switching on and off other genes that control calcium absorption.
It is possible, if the work is confirmed, that a simple gene blood screening test could be developed that could alert vulnerable young people of this new risk for osteoporosis. This information can offer assurance or concern, but the BB genotype need not doom one to a severe osteoporosis. Bone density is generally thought to be 75 percent hereditary and 25 percent environmental. An early prevention program could be instituted promoting appropriate calcium intake, increased exercise with weights, avoidance of cigarettes and alcohol, increased vitamin D, and estrogen replacement therapy after menopause. New drugs that stimulate bone are likely to be available in the foreseeable future.
This study is exciting, but it should be regarded cautiously until confirmed and expanded. A restricted population of Caucasian Anglo-Irish descent in Australia was examined. The population needs to be extended to ethnic groups with different bone mass such as Afro-American, Hispanic-American, and Orientals. We need to know the effect on bone parameters of administering vitamin D to individuals with unfavorable alleles compared with the effect on individuals with different alleles.
Richard S. Panush, MD, and Robert Thoburn, MD
Editors, Hotline
2-1-94
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