For years, we've thought we understood osteoporosis: it's a disease in which the bones become more and more fragile as they lose density, usually due to aging, menopause, and other factors like lack of calcium and vitamin D in the diet.
But today, advances in research are shedding new light on osteoporosis, which is predicted to affect as many as half of all Americans over age 50 by the year 2020. From diagnosis to prevention to osteoporosis treatment, new research is turning our old understanding of osteoporosis upside down.
Fine-tuning Osteoporosis Risk
The "gold standard" test for diagnosing osteoporosis is the DEXA scan (dual energy X-ray absorptiometry), which measures bone density in the spine, hip, or wrist. These are the most common locations for bone fractures. But this test, as advanced as it is, has limitations.
"Many patients with normal bone density measurements on a DEXA scan still have fractures, and a substantial number of patients whose DEXA scan shows osteoporosis don't get fractures," says Sundeep Khosla, MD, a professor of medicine and osteoporosis researcher at the Mayo Clinic in Rochester, Minn. "The DEXA tells you how much bone is present, but not much about the internal structure of that bone." Obviously, doctors would like to be able to predict fracture risk much more accurately, to fine-tune who is at greatest risk of fracture and most in need of medication.
Khosla compares the human skeleton to a bridge made of metal. "You could have two bridges with the same amount of metal in them, but one could be more sturdy, just because of the way it's constructed," he says. "Similarly, because the microarchitecture of one person's bones is different from another's, their actual strength may be quite different."
Khosla and other osteoporosis researchers are studying new imaging and computer techniques that will allow them to look inside the bone, and see specific structural characteristics. This will help them to build models of bone strength that can help predict which patients are most likely to have fractures.
One such imaging technique is computed tomography (CT) scanning of the spine and hip. Researchers take the three-dimensional image of the bone that the CT scan creates, and use a computer modeling technique that breaks the image down into tiny pieces. "The density of each piece allows you to estimate the strength of each piece, and get the overall strength of the structure," says Khosla. "Depending on where a bone is weakest, it may be more or less prone to fracture."
That's taken to a higher level in a new instrument being used to study osteoporosis, called high-resolution peripheral quantitative tomography. Because it uses a higher level of radiation, it can't be used at the spine or near vital organs, but it can be used to image areas like wrist bones. "The resolution with peripheral scanners is good enough that you can see individual structural components, which give you much more information about the strength of the bone," Khosla says.
He predicts that the peripheral scanners, which may not be much more expensive than today's DEXA, may soon be approved for clinical use. Since CT scans are significantly more expensive, they may not be used as a stand-alone screening tool. However, when a patient has a CT scan for another reason, it's relatively easy to get bone information at the same time.
"We still need to accumulate more data about how these tools predict fracture risk, but initial results are promising," says Khosla.
Understanding Bone Remodeling
Bisphosphonate drugs were originally thought of as osteoporosis treatments that helped to build bone mass. But it soon became clear that something more was going on here. Many patients taking bisphosphonates may see only a modest increase in bone density -- as little as 1% -- and yet they have a much greater reduction in their risk of fractures, as much as 50%.
"Research has shown that there is no relationship between how much these drugs build bone mass and the reduction in fracture risk," says Robert Heaney, M.D., a professor of medicine at the Osteoporosis Research Center at Creighton University School of Medicine in Omaha, Neb.
Scientists realized that the drugs were also slowing down the rate of bone remodeling -- the process in which existing areas of bone is pared away, later to be replaced with new bone. In menopausal women, that rate of bone remodeling doubles -- and then it triples by a woman's early 60s.
"Imagine if you started remodeling your house: first you put an extension on one side, but before you finished that, you decided to tear out the garage, and before finishing that, you decided to put a deck on," says Heaney. "You'd have a pretty fragile house. That's what's happening with accelerated bone remodeling."
Now that they understand the importance of bone remodeling, osteoporosis experts are trying to use that knowledge to help predict osteoporosis risk factors. They're developing tools known as biomarkers, which are chemical measures of the rate of bone remodeling that can be found in secretions from blood or urine. There are already biomarkers for the rate of bone remodeling that work very well in large population studies, says Heaney, but they do not yet have markers that work well in the doctor's office, on an individual patient level. Once more accurate biomarkers are developed, these and advanced imaging techniques may enormously improve our understanding of who is at greatest risk from osteoporosis.
"This allows us to focus on where the problem really lies: the excess remodeling that's making bone fragile," Heaney says.
New Osteoporosis Treatments
A few years ago, Heaney saw an 18-year-old girl who'd been in a serious car accident. She'd escaped with only a few bruises, and X-rays revealed that she had unusually high bone density. It turned out that her mother, too, had bone density well above the average. Heaney and his colleagues at Creighton began studying the entire family -- over 150 people -- and eventually identified what they call the "high bone mass gene."
A particular mutation in this gene causes the body to make abnormally high amounts of a protein called LRP5 (low density lipoprotein receptor-related protein 5). LRP5 influences how much bone is formed and maintained. "None of the people with the high bone mass gene had ever broken anything, even if they'd fallen off the barn roof," says Heaney.
The identification of the high bone mass gene and the chemical signaling pathway it involves has opened up a wide range of new possibilities for osteoporosis treatment. "The prospect here is to build an osteoporosis drug or drugs that cause the body to act as if it has that mutation, building up more bone," says Heaney. He believes that drugs aimed at this pathway are already in human testing, but it may take some time before they can come to market. "Because this pathway acts on other areas of the body besides bone, you have to be sure that your drug isn't producing unintended results elsewhere."
Scientists are also investigating new compounds, called vitamin D analogs, as potential osteoporosis treatments. These drugs are, essentially, a supercharged version of vitamin D supplements -- molecules that have been altered, based on vitamin D's structure, to minimize bone loss and maximize bone formation.
One of these drugs, 2MD, has shown great promise in animal models of osteoporosis, and is now being studied in humans. "It dramatically stimulates bone formation, and if we are able to see anything that even vaguely approximates the same kind of results in humans, this is going to be huge," says Neil Binkley, MD, co-director of the Osteoporosis Clinical Center and Research Program at the University of Wisconsin-Madison. Another plus: because the drug is based on vitamin D, Binkley predicts that there may not be any unusual side effects, and it may even boost the immune system's function the way that natural vitamin D does.
One drug that is closer to approval is an experimental treatment called denosumab. This twice-yearly injection is now in Phase III clinical trials, and has been shown to improve bone density. Denosumab is aimed at an entirely new target for osteoporosis: a protein called RANK ligand. This protein plays a key role in the process by which cells called osteoclasts break down bone. And researchers hope the drug will help keep the process of bone loss in check with bone replacement. Denosumab could be on the market as soon as late 2008.
"Osteoporosis is a fairly young field," says Binkley. "When I was in medical school, you diagnosed osteoporosis only after someone broke a bone, just as we used to only diagnose heart disease after a heart attack. We know more now, and we're developing better tools to diagnose, treat, and prevent osteoporosis."