IOF LogoIOF World Congress on Osteoporosis 2004, May 14-18, 2004, Rio de Janeiro, Brazil
IOF Website  |  IOF World Congress 2006
Your Account: Log in or Register
Congress Homepage
Scientific Committee
Scientific Program
Press releases
Exhibitors / Sponsors
Version Española
Versão Portuguêsa

Download this press release: PDF / Word

BASIC SCIENCE IDENTIFIES NEW AVENUES FOR OSTEOPOROSIS RESEARCH

Genetic variation linked to bone development in boys and adult men, estrogen-related genes and protein modifications may provide new diagnostic tools

RIO DE JANEIRO, Brazil
May 19, 2004

Basic science is the launch pad for clinical research. While much of the IOF World Congress on Osteoporosis was devoted to clinically relevant studies, important basic discoveries, which may lead to new treatments or diagnostic tools for osteoporosis, were also presented. These findings included subtle genetic variations that influence bone mineral density; novel genes that are activated by estrogen, a powerful promoter of bone formation; and changes in protein structure that weaken bone.

Small genetic changes linked to osteoporosis in men...

Dr. Serge Ferrari and colleagues from the Geneva University Hospital, Switzerland and the Lariboisière Hospital, Paris, France, reported that genetic differences in the gene for a protein called LDL receptor-related protein 5, or LRP5, are associated with an increased risk for low bone mineral density (conference abstract OC37). People with osteoporosis have low bone mineral density and are at increased risk for fractures.

Mutations in LRP5 have previously been shown to be responsible for extremely strong bones in a US family. Other mutations are associated with severe osteoporosis, already in infancy. Ferrari and colleagues wondered if different LRP5 gene variations could be associated with osteoporotic fractures. To test this, they examined LRP5 DNA from 67 European-Caucasian men with osteoporosis.

The results showed that two DNA changes were strongly linked to low bone strength. Sixty one percent of men with one of the changes had osteoporosis, and these patients had over a two-fold greater risk for fracture than those without the mutation.

LRP5 is known to be involved in activation of osteoblasts, cells that are responsible for laying down the matrix that gives bone its inherent strength. "These results are compelling with regard to the ongoing development of agents that may stimulate bone formation and bone mass through the LRP5 protein," said Ferrari. Small molecules that activate LRP5 may be potential drugs for osteoporosis.

...and boys

In a separate presentation, Ferrari and colleagues reported that genetic variations in another receptor, this one for the weight control hormone leptin, may also influence bone mineral content in pre-pubertal boys (conference abstract OC29).

"Leptin has recently been shown to control bone mass in mice," said Ferrari, "but the question remains whether the leptin system may also contribute to bone mass in humans."

Ferrari and colleagues tested for two known genetic variations in 235 healthy, pre-pubertal European-Caucasian boys. They found that one of the mutations, in the part of the gene that codes for protein, was significantly associated with bone mineral content of the hip, spine, femur and radius. Boys with the change in both copies of the LEPR gene had bone mineral densities 8-12% lower than in boys with two normal copies.

"Genetic markers such as LRP5 and leptin polymorphisms might help identify subjects, particularly males, at increased risk for osteoporosis. Accordingly they might help [researchers] implement targeted prevention strategies against osteoporosis," said Ferrari.

In women, identification of estrogen-regulated genes could lead to diagnostic test

Postmenopausal women are particularly susceptible to osteoporosis and much research has focussed on the effects of estrogen loss following menopause. The hormone has wide-ranging effects, modulating the switching on and off of genes in many different cell types. Finding out which of these genes are crucial for regulating bone formation and destruction will help researchers understand some of the causes of osteoporosis at the most basic level.

Dr. Zsolt Nagy and colleagues from Semmelweis University, Budapest and the Hungarian Academy of Sciences, Szeged, reported that in mouse bone they have found novel genes that are controlled by estrogen (conference abstract OC 38). Given the similarities between the mouse and human genomes, these findings could yield important clues to the regulation of human bone metabolism by this hormone.

Nagy and colleagues used a gene profiling technology to test the activity of over 3,000 genes in female mice that lack ovaries and which therefore produce almost no estrogen. These animals are commonly used as a model for postmenopause.

Forty six genes were found to be regulated by addition of estrogen, exactly half being activated and half deactivated. Some of these had been previously identified as being sensitive to estrogen, thus validating the technique. But significantly, several novel genes previously unknown to be sensitive to estrogen, were also identified, as were some genes that had not previously been connected to bone biology.

"The next step is human studies," said Nagy. "Though these results are not immediately applicable to the clinic," Nagy added, "a diagnostic DNA chip (microarray) could be developed in the near future."

Microarrays are small glass slides that are loaded with samples of different DNA strands, or genes. They can be used to simultaneously measures subtle changes in the regulation of thousands of genes and have revolutionary diagnostic potential.

Protein modifications can weaken bone

In the clinic, bone strength is usually estimated by measuring the density of bone minerals. Patients with osteoporosis have bone mineral densities that are considerably lower than that in the general population. But in addition to these minerals, bone also is also strengthened by organic molecules, such as proteins. Dr. Patrick Garnero and colleagues from INSERM and Synarc, both in Lyon, France, and from the Center for Clinical Bone Research and NordicBioscience, both in Copenhagen, Denmark, reported that chemical changes to one of these proteins, collagen, can weaken bone without affecting the bone mineral density (conference abstract OC28). The data suggests that monitoring protein modification may provide an additional test to help identify those at risk for fracture.

Garnero measured changes that take place in fetal bovine bones as they age. He found that the collagen molecules, which are laid down in the bone as long strands, gradually become connected by chemical cross-links when the bones are cultured. When Garnero measured bone strength by subjecting the aged bones to mechanical stress, he found that the bones were weaker, even though the mineral density remained the same.

"Collagen is the most important protein in the bone. It accounts for 90% of the protein and 30% of the weight of bone," said Prof. Pierre Delmas, IOF president and co-investigator on the study. The cross-links are probably very important for the structure.

Delmas suggested that the way to study cross-linking in humans will be to find biological markers that would reflect the cross-linking.

ENDS

The International Osteoporosis Foundation (IOF) is a worldwide organization dedicated to the fight against osteoporosis. It brings together scientists, physicians, patient societies and corporate partners. Working with its 165 member societies in more than 85 locations, and other healthcare-related organizations around the world, IOF encourages awareness and prevention, early detection and improved treatment of osteoporosis.

Osteoporosis, in which the bones become porous and break easily, is one of the world's most common and debilitating diseases. The result: pain, loss of movement, inability to perform daily chores, and in many cases, death. One out of three women over 50 will experience osteoporotic fractures, as will one out of eight men(1). Unfortunately, screening for people at risk is far from being a standard practice. Osteoporosis can, to a certain extent, be prevented, it can be easily diagnosed and effective treatments are available.

1 Melton U, Chrischilles EA, Cooper C et al. How many women have osteoporosis? Journal of Bone Mineral Research, 1992; 7:1005-10

For more information on the IOF World Congress on Osteoporosis, including access to all the abstracts and press releases, please refer to: www.osteofound.org

Find out if you are at risk, take the IOF One Minute Risk Test at: www.osteofound.org

For further information, please contact
Paul Spencer Sochaczewski, Head of Communications,
International Osteoporosis Foundation:

Tel. +41 22 994 0100
Fax. +41 22 994 0101
E-mail: psochaczewski@osteofound.org

Back to:
Press Releases

Page Top

© 2004 International Osteoporosis Foundation Web design and programming by Zephir Software Design