Research finding new clues about bone loss

Monday, September 11th 2000, 12:00 am
By: News On 6

Data could aid osteoporosis, ease space travel

By Emily Sohn / The Dallas Morning News

Bone today, gone tomorrow.
People are living longer than ever before. But bones weaken with age, and brittle-bone diseases like osteoporosis are already widespread.

Scientific scrutiny is rapidly revealing what makes young bones strong and old bones weak, however. New research is identifying genes involved in bone loss. Other studies are finding what makes bones grow. Some of the most promising leads have popped up in unexpected places – in a hormone famous for its role in body weight, for one, and in the spongy structure of sea coral.

A biological understanding of bone growth and repair may open up new ways to prevent and treat osteoporosis and other bone disorders. The knowledge may also help future generations withstand long-distance space travel by fighting the toll that weightlessness takes on bone strength.

Bones – tissues made mostly of mineralized proteins – are constantly re-creating themselves. In fact, scientists estimate that the human skeleton completely replaces itself every seven to 10 years.

In most healthy, young bones, destruction and reconstruction occur in balance. Broken bones can usually heal fairly quickly. But as people get older, bones often deteriorate faster than they can repair themselves. The result can be crippling.

Osteoporosis affects an estimated 10 million Americans, with post-menopausal women hit the hardest. More than one in three women over age 50 will experience a bone fracture due to osteoporosis, says the Centers for Disease Control and Prevention. One in eight men over age 50 will have an osteoporosis-related fracture in their lifetimes, the Washington, D.C.-based National Osteoporosis Foundation estimates.

As the population matures, so too have approaches to protecting and repairing aging bones.

Decades of research have given scientists a general understanding of the cycle of bone loss and growth known as remodeling. Two kinds of cells are responsible: One type ruthlessly chews up bone. The other meticulously puts it back.

So far, most approaches to preventing and treating osteoporosis have focused on disabling the bone-destroyers, called osteoclasts. Supplemental estrogen is the most commonly used example. When women reach menopause, their estrogen levels drop, and osteoclast numbers rise. Taking estrogen helps keep the bone-destroyers from forming. But many are wary of hormone therapy, because some studies have linked it with increased risk of breast and other kinds of cancer.

Recent advances in genetics have armed scientists with a new arsenal of information for fighting osteoclasts, though. By disabling certain genes in mice, researchers have been able to pinpoint genes that control the production and action of bone-wrecking cells. Scientists hope to use the information to stop the wreckers at the source.

"Once we understand the molecules and genes important in regulating osteoclasts, we can design drugs that will target these genes directly," said Dr. Steven Teitelbaum, of Washington University School of Medicine in St. Louis. "That's what this is all about."

So far, the Food and Drug Administration has approved three such drugs, said Dr. Gideon Rodan, of Merck Research Laboratories in West Point, Pa. Merck and Co. Inc. makes a drug called Fosamax, widely used to treat osteoporosis since it hit the U.S. market in 1995.

As part of a nationwide study of 6,000 women, scientists from the University of California, San Francisco, reported in 1998 that the drug, also known as alendronate, reduced the risk of hip fractures by 56 percent and spine fractures by 49 percent in women who had never suffered a spinal fracture.

Last month, a study in the New England Journal of Medicine showed that the drug worked just as well in men.

"That's already history, in a way," Dr. Rodan said. Even more effective treatments may be in the works, he said. "What we are trying to do is show how an understanding of osteoclasts can lead us to additional ways of blocking this activity."

Dr. Teitelbaum has been working with protein molecules called integrins, which help osteoclasts bind to bones and make cavities in the tissue. From his work with mice, Dr. Teitelbaum has found that integrins send messages to osteoclasts when a bone is underfoot, so the cells can change shape and dissolve bone tissues. More work may help scientists devise drugs to intercept those messages, he wrote in February in The Journal of Clinical Investigation.

Other osteoclast-controlling molecules are also in various stages of study, and some have made it as far as clinical trials, Dr. Teitelbaum said.

But fighting the wrecking action of osteoclasts only slows bone damage. "All of the successes we've had to date have enabled us to prevent further bone loss," Dr. Teitelbaum said. "You get a person with osteoporosis, we're pretty good at preventing them from getting worse. You can't take a person with osteoporosis and make them a person without osteoporosis."

To do that, most scientists agree that they need a better understanding of how the builder cells, called osteoblasts, work. Bones are like the foundation of a house, which needs repair after disaster strikes, said Dr. Gerard Karsenty, of Baylor College of Medicine in Houston.

"When you have a fire in your house, you have to stop the fire," he said, "and you have to rebuild."

Less is known about the rebuilding, though.

"It's always more difficult to build than to destroy," Dr. Rodan said. "You put a monkey wrench in something and you stop it. To build something, it's a very fine, complicated process." Stimulating growth in a body tissue also risks creating tumors, he said.

No one has figured out yet how to get bones to pump themselves up. "We don't have a single drug application in use which stimulates bone formation or increases osteoblast number," Dr. Rodan said. "The biggest pharmaceutical challenge in the immediate future will be to identify some agents that assume bone formation."

Scientists may be getting closer to that goal.

Recently, Dr. Karsenty found a clue in a hormone called leptin. In both people and mice, leptin helps regulate body weight and reproductive organs – ovaries in women, testes in men. Scientists have also long known that obesity keeps bones strong. On the other hand, menopause, or ovary shut-down, makes bones weaker. Dr. Karsenty set out to see whether these observations might be related.

Mice genetically engineered so they can't produce or recognize leptin are obese and sterile. Surprisingly, Dr. Karsenty found, the animals also had denser bones than normal. Mice with leptin regulation that was impaired but not fully disabled weren't obese, but their bones were still more dense than normal. The results, published this year in the journal Cell, strongly suggest that leptin plays a major role in building bones in mice, Dr. Karsenty said. The same may be true for people, although scientists haven't yet studied that link.

Elsewhere, researchers are trying to grow bones in petri dishes. Figuring out which genes and molecules are most important in the process may help scientists prod bone to bulk up in the body. The prospect is still "a pie in the sky," said Michael Long, of the University of Michigan Medical Center in Ann Arbor. But he recently took one of the first steps.

Dr. Long and his research group were able to grow a three-dimensional lump of bone cells out of stem cells – generalized cells that have not yet picked a specialty, such as a nerve cell or a blood cell. In the September issue of the journal Nature Biotechnology, the group reports that the key to its success was one type of molecule known as a growth factor.

The study "points out things that are really important as far as what it takes for bone to grow," said Dr. Laura Niklason, of Duke University in Durham, N.C. Identifying the growth factor was especially exciting, she said. "It's something we can bottle," she said, "meaning it's a chemical that we can synthesize in the lab, that we can characterize and understand. It doesn't tell us how to give it to patients with osteoporosis to make patients better. But the fact that he's figured out how it's important – that helps us."

Other work with stem cells may be closer to actually helping people. Scientists from France were recently able to grow bone cells from stem cells inside scaffolding made of coral. Implanting the framework into sheep repaired bones that had been damaged, the scientists report in the September issue of Nature Biotechnology. Coral-based scaffolds may repair bones more effectively than previous attempts to use plastic and other materials, because coral's sponginess is similar to bone structure, the scientists say.

The scientists want to test the technique in people next, Dr. Long said. Coral scaffolds may eventually help treat bone fractures that are especially severe or that occur in people whose bones are too weak to heal themselves, scientists say.

Together, different kinds of bone growth studies "point out the importance of working on more than one level of a complex problem," Dr. Niklason said.

Bone research in particular has the potential to affect people in many different situations, she said. Even though osteoporosis is the most common bone disorder, "There are lots of different bony diseases," she said. "It's not one approach fits all."

Outside the laboratory, a wide variety of strategies have shown themselves capable of strengthening bones. Many studies show that taking calcium and vitamin D can help fortify bones, for example. Other studies point to the benefits of soy products, which may act like estrogen in the body. And weight-bearing exercises have been found to strengthen bones.

Even NASA has jumped into the game, Dr. Teitelbaum said. Weightlessness weakens astronauts' bones. Understanding bone remodeling might eventually help people stand tall, even after months in outer space.

"There is no line of [bone] research that is unnecessary," Dr. Karsenty said. "Everything is useful, and time will tell which ones develop" into the most promising therapies.

Keeping your bones healthy

Nationwide, costs for treating osteoporosis-related fractures total an estimated $13.8 billion a year, or about $38 million each day.

Building strong bones early in life is essential, because women build 98 percent of their skeletal mass by age 20. The National Osteoporosis Foundation recommends the following strategies to people of all ages to ward off the brittle-bone disease:

A balanced diet rich in calcium and vitamin D

Weight-bearing exercise

A healthy lifestyle with no smoking or excessive alcohol intake

Regular bone density tests, when appropriate

Medication, including estrogen supplements, when appropriate