As reported by Science Magazine, June 10, 2005.

Bone Quality Fills Holes in Fracture Risk

By Erik Stokstad

Osteoporosis isn't the only factor behind broken bones. A better understanding of bone quality, coming from biochemical markers and refined imaging techniques, will help predict who is most at risk of debilitating fractures.

When a woman is tested for osteoporosis, technicians shoot low-dose x-rays through her hip to get a picture of the bone and a measure of its density. The less bone, the higher the overall risk of breaks, including debilitating hip fractures. But over the last decade, researchers have come to a greater awareness that it's not just quantity that matters: Bone quality counts for a lot.

The importance of bone quality--a term covering aspects such as the organization of the tiny struts that make up the inner tissue--became obvious during clinical trials of drugs for osteoporosis. These drugs prevent the loss of bone, but it turned out that, statistically, bone mineral density (BMD) couldn't explain all of the reduction in fracture risk. That fit with observations by clinicians: Some women with osteoporotic bones don't suffer breaks, whereas many women with apparently healthy bones still end up with fractures.

Identifying women at risk before they fracture is "the most challenging public health question" facing osteoporosis researchers, says Ego Seeman of Austin Hospital in Melbourne, Australia. And it's not just an issue for women. Osteoporosis is becoming more common in men, and more commonly diagnosed, especially as they live longer.

Researchers are trying to get a better handle on bone quality in several ways. They're searching for new and better biochemical markers of bone change, to add to the handful already used in the clinic to assess the effects of drugs. Higher resolution imaging with computed tomography (CT) and magnetic resonance imaging (MRI) is beginning to probe the inner architecture of bones without the need for direct sampling.

The hope is that these advances may one day better identify patients in need of treatment, as well as provide a way to chart their progress on drugs, but the newer imaging techniques are still being developed and won't be widely available for several years. In the meantime, some researchers are trying to integrate proven risk factors to predict a woman's chance of fracture.

Strong bones
Osteoporosis is a factor in more than 1.5 million fractures each year in the United States alone. Costs have been estimated at more than $17 billion a year, particularly from hip fractures, more than 75% of them in women. Part of the reason is that women who are not in nursing homes are twice as likely as men to fall, perhaps because they lose muscle strength faster with age. But another major factor is that their bones tend to become much weaker with age than men's do.

Strength comes from two features of bones. The outer shell of dense material, called cortical bone, is like the metal tubing of a bicycle that makes a strong, light frame. Inside this cortex is a porous network of tiny support struts and rods, called trabeculae. Trabecular bone makes up just 20% of bone mass but most of its surface area.

Sex differences appear relatively early in life. Growing girls tend to add more mass to the inner side of the bone cortex, beefing up the trabeculae to create a storehouse of calcium for pregnancy and lactation. Boys, in contrast, tend to add more material to the outside of the cortex. The greater the diameter, the stronger the bone. The effect, as seen in cross-sectional studies, is "absolutely huge," says Heather McKay of the University of British Columbia in Vancouver. In addition, girls tend to be less active than boys, she says, so many don't get the bone-building benefits of exercise.

The big kicker comes at menopause. Estrogen is a key regulating signal for the cells that are constantly remodeling bone, thus repairing damage and allowing bones to bulk up to the loads placed on them. When estrogen levels decline during menopause, the bone-building cells known as osteoblasts slacken their activity. But the bone-resorbing osteoclasts continue to remove bone mineral and break down collagen. That means women typically lose 1% to 2% of their bone per year around menopause, more of it from trabecular bone.

Several risk factors influence the likelihood that a woman will lose more bone than normal and eventually suffer a fracture. A previous fracture ups the odds substantially, as does a family history of fracture, although genetic factors remain fairly murky. Race matters, too. The incidence of hip fractures is 25% lower in Asian than in white women, for example, even for women with similar bone densities. Behaviors--poor diet and lack of exercise, especially in youth--are also negative influences on bone health, as discussed in a massive report from the Surgeon General last year.*

These risk factors are fairly weak predictors of an individual's absolute risk, however. Up until the 1980s, clinicians basically waited until a fracture occurred before treating patients for osteoporosis. Diagnosis--and research--got a considerable boost in the 1990s with the advent of dual x-ray absorptiometry (DXA). "It just revolutionized the field," says B. Lawrence Riggs of the Mayo Clinic in Rochester, Minnesota. DXA enabled clinicians and researchers to follow patients over a long time and assess their responses to medications, helping bring the current crop of drugs to market, Riggs says (Science, 3 September 2004, p. 1420). In the United States, the National Osteoporosis Foundation recommends that women over the age of 65, or younger women who have one or more risk factors, be tested with DXA for osteoporosis.

But DXA's usefulness for making predictions is limited. "The number one clinical goal is to be able to sit down with a patient and give a numerical indicator of fracture risk," says Lawrence Raisz of the University of Connecticut Health Center in Farmington. DXA doesn't do that well, although many researchers point out that it's a better predictor than is cholesterol level for heart disease. By factoring in bone quality as well, researchers and doctors eventually hope to do better.

Sharpening the picture
One of the main approaches to gleaning details about the quality of bones is to measure the activity of osteoclasts and osteoblasts, the cells that remodel bone and thus influence its structural properties. The first cell activity marker approved by the U.S. Food and Drug Administration, in 1995, measures the products of bone breakdown and can pick out women with extremely high rates of bone loss. In general, however, markers are not currently useful for diagnosis of osteoporosis, because levels overlap between those who have and don't have the disorder. Researchers are trying to explain the variability and investigating new markers that might be more specific.

The main clinical use of markers at the moment is to help chart how patients respond to drugs. That kind of information may also encourage patients to keep taking their medicine, as Pierre Delmas of Claude Bernard University in Lyon, France, explained last month at a meeting on bone quality run by the National Institutes of Health and the American Society of Bone and Mineral Research in Bethesda, Maryland. His unpublished data showed that providing patients with progress reports from biomarkers could increase the numbers who stay on their medications by 20%. Biochemical markers may also help refine the assessment of fracture risk, but the results of large studies so far have been inconsistent.

Another way of getting new information about bone quality is by looking at bone architecture directly. A time-tested research method is to study actual bone from biopsies, cadavers, or hip replacement operations. CT and electron microscopy can resolve individual rods and struts, the crucial support elements inside trabecular bone. But direct sampling is too invasive and expensive to be used to track individual patients' health.

Researchers have been trying to get similar and more clinically useful information using imaging tools. One benchmark in the field is a 2001 paper in the Journal of Bone and Mineral Research (JBMR) by Felix Wehrli's group at the University of Pennsylvania, Philadelphia. The researchers showed in a study of 79 women with various bone densities and vertebral deformities that a souped-up MRI machine can reveal microscopic bone structure noninvasively. In April, a group led by Charles Chesnut of the University of Washington, Seattle, published online in JBMR the first such longitudinal study of bone microarchitecture with MRI.

The other main imaging techniques use quantitative CT, mainly to study peripheral bones, such as the forearm. Aspects of bone quality are then extrapolated to hip and spine. Given the small size of studies so far, CT and MRI haven't been used to assess fracture risk. Researchers say those results should come in the next few years: Larger trials are incorporating CT and MRI in subsets of patients.

One attempt to get at fracture risk is already under way. Tony Keaveny, a biomechanical engineer at the University of California, Berkeley, is using a technique called finite element analysis. Keaveny and colleagues take CT images of human vertebrae, including information about the trabecular architecture, and model how they respond to stress. In a paper published in Bone in 2003, he and his former student R. Paul Crawford showed that their analysis of CT images of cadaver bones predicted 85% of the variation in bone strength in experiments with actual loadings of the bones--"better than BMD did," he says. Ultimately, Keaveny says, the method should be able to provide a personalized fracture risk assessment for patients, adjusted for their height and weight and other factors. Clinicians say the approach is exciting but might be prohibitively expensive for screening patients.

In the meantime, clinicians and researchers say much can be done to get more women checked for osteoporosis and give patients a better idea of their fracture risk. In one high-profile effort, a center at the University of Sheffield, U.K., sponsored by the World Health Organization has been designing a method to express a person's absolute risk of fracture during the next 10 years. "This will allow us to have a standard of care," comments Ethel Siris of Columbia University College of Physicians and Surgeons. "It will give us a better threshold for determining treatment."

* Bone Health and Osteoporosis: A Report of the Surgeon General (2004), HHS. www.surgeongeneral.gov/library/bonehealth/content.html.