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The Genetic Component of Osteoporosis
(Released Fall 1997)

  by Frederic A. Spangler, Janet L. Padgett & Wilma S. Ek  
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Osteoporosis is a significant and growing public health problem among the elderly. In the U.S. alone, it affects over 25 million people, mostly older women. Osteoporosis has been defined in a variety of ways. However, every definition has two mandatory parts: a decrease in bone mass and a concomitant increase in the propensity for bone fractures.

There are numerous risk factors for osteoporosis. While many of these factors are non-genetic in nature, there is a definite genetic component as well.

This mini-review will briefly look at: WHAT osteoporosis is, WHO is susceptible based on risk factors and epidemiology, and HOW genetic determinants factor into the picture.

What is Osteoporosis?

Osteoporosis is a reduction in skeletal mass with associated bone microarchitectural deterioration that results in an increased risk of fractures. It can be a debilitating disease with devastating health and economic consequences.

Who is Most Susceptible?
Epidemiology and Related Statistics

Osteoporosis is most often considered a bone disorder of postmenopausal women, but men and younger women can also be affected. Overall, women are five times more likely than men to develop osteoporosis, but 4-5 million men in the U.S. have or are at risk for the disorder. However, where the spinal bones are concerned, women are eight times more prone than men to vertebral osteoporosis.

As the life expectancy of women increases, there is an increase in the proportion of females living beyond menopause. In the western world, 17% of all women are now
over 50 years of age. A woman today can expect to live 1/3 of her life after menopause.

The bones of an osteoporotic postmenopausal woman are often described as brittle and fracture-prone. Although one frequently hears about problems concerning hip, wrist, and vertebral bones, all bones are at increased risk of fracture in the osteoporotic person.

The lifetime risk of bone fracture for a 50-year-old Caucasian-American woman is almost 40%, which is double the risk for an African-American woman. In general, Caucasian- and Asian-Americans are more susceptible to osteoporosis, but African- and Hispanic-Americans are at significant risk as well.

There are over 1.5 million osteoporosis-associated bone fractures per year in the U.S. of which 300,000 are hip fractures, 200,000 are wrist fractures, and 500,000 are vertebral (spinal) fractures.

Osteoporotic hip fracture usually requires hospitalization and surgery and may result in lengthy or permanent disability or even death. Within the first year after injury, a patient with a hip fracture has a 10-15% greater chance of dying than others of the same age. Men, though suffering fewer hip fractures than women, are 25% more likely than women to die within one year of the injury.

About one in every five patients who was living independently before fracturing a hip still remains confined in a long-term health care facility one year later. The treatment of osteoporosis and osteoporosis-related fractures costs over $10 billion annually.

Who is Most Susceptible?
Risk Factors

Non-genetic risk factors contributing to the development of osteoporosis have been categor-ized in a number of ways. We will simply list them here ungrouped:

* Gender
* Age
* Early menopause in women
* Amenorrhea
* Low testosterone levels in men
* Low calcium intake
* Race and ethnicity
* Small or thin body frame
* Excessive alcohol use
* Smoking
* Inadequate physical exercise
* Certain endocrine disorders
* Chronic diseases of the lungs, kidneys, stomach, and intestines
* Prolonged use of medicines like steroids, antacids, anticonvulsants

The Contribution of Heredity

The etimology of osteoporosis is clearly multifactorial in nature. While many of the non-genetic factors contributing to the risk for the disorder have been widely investigated in recent decades, the search for genetic determinants is relatively new, albeit very intense.

From family histories, twin studies, and molecular genetics, it is quite evident now that some of the predisposition for osteoporosis can be inherited. Genetic control of osteoporosis is polygenic; the specific genes involved are beginning to be enumerated.

Both structural and regulatory genes have been implicated in the propensity toward osteoporosis. Variance or mutation in genes that control bone mass (and its mineral content) and/or bone turnover are obvious candidate genes. Estimation of the genetic component to the variance found in bone mineral density (BMD), for example, ranges from 60% to 90%.

We will look at four of the primary areas where researchers have begun to forge the link between genetics and osteoporosis.

1. In a variety of population groups, there exists a natural variation (polymorphism) in the vitamin D receptor (VDR) gene. There is an association between VDR gene allelic variation and BMD. Low BMD suggests an increased tendency toward osteoporotic fractures. However, other studies have shown no effect on BMD due to polymorphism of the VDR gene.

2. Since estrogen levels play a major role in pre- and postmenopausal women, mutation of the estrogen receptor (ER) gene may be implicated in some cases of osteoporosis. In fact, in some populations, polymorphism of the ER gene has been correlated with BMD. Other studies have not found this effect.

3. The COLIA1 and COLIA2 genes encode type I collagen, a key bone protein, and, therefore, may play a role in the genetic control of bone mass. Mutations in coding regions of the two genes lead to the formation of abnormal collagen and, accordingly, abnormal bone strength and architecture.

These dysfunctional mutations result in severe forms of osteoporosis but do not account for the much more prevalent milder forms of the disorder. It was once thought that similar, but less severe mutations at these loci would be identified. These mutations, if they exist, have not been found.

4. Identification of BMD-related polymorphism of the regulatory region of the COLIA1 gene has proven to be a more productive route to follow. S.F.A. Grant et al. have just published (Nature Genetics, 14(2), Oct. 1996) a potentially seminal paper on the topic entitled "Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene."

They report a novel G-->T polymorphism in a regulatory region of the COLIA1 gene at a transcription factor Sp1 recognition site. They correlate the polymorphism of this regulatory region with low bone mass and osteoporotic fracture. The work has been confirmed in three independent populations.

The Overall Picture

As with many medical conditions, genetic and non-genetic factors interact with each other to exacerbate or ameliorate the problem. There simply is not enough information at this point to speculate on the relative weighting genetic and non-genetic factors contribute to the sequelae of events that result in overt osteoporosis.

However, with more and more molecular information concerning the genetic aspects of osteoporosis becoming available almost on a daily basis, there is an ever-increasing hope and likelihood for the design of new drugs to treat, reverse, or prevent the devastating effects of osteoporosis and also for new tests for identifying those at risk for the disorder.



Frederic A. Spangler, Ph.D.

  • CSA Senior Science and Internet Editor

  • Ph.D. (Physiology and Biophysics; thesis research area: Biochemical Endocrinology; minor fields of study: Neurobiology, Pharmacology), The Georgetown University Medical Center

  • B.S. (Biology; minor concentrations in Mathematics, Biophysics, and Earth Sciences), Pennsylvania State University

Janet L. Padgett, Ph.D.

  • CSA Senior Life Science Editor

  • Ph.D. (Biophysics), The Johns Hopkins University

  • M.Ac. (Master of Acupuncture), Traditional Acupuncture

  • B.S. (Physics), University of Virginia

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Wilma S. Ek, M.S.

  • CSA Senior Life Science Editor

  • M.S. (Microbiology and Biochemistry), University of Bombay

  • M.S. (Genetics), Pennsylvania State University

  • B.S., University of Bombay

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