Studies directed by Dr. Robert Recker, director of Creighton’s Osteoporosis Research Center, are leading the way to new treatments for fragile bones.
By Brian E. Clark
At least 10 million Americans are diagnosed annually with the debilitating, bone-thinning disease known as osteoporosis. Some 50,000 people – the majority of them women – will die this year from post-fracture complications.
And while current treatment is often able to stop additional bone loss, it doesn’t help the body build new bone.
But that could change, thanks to studies initiated by Dr. Robert Recker, director of Creighton University’s Osteoporosis Research Center, Dr. Mark L. Johnson, previously an associate professor of medicine at Creighton and other scientists.
Their work has already produced a number of patents for Creighton, but Recker and Johnson hope the research will lead to agents that build denser bones.
Recker, who also serves as president of the National Osteoporosis Foundation, did much of his research with Johnson, who is now at the University of Missouri Dental School in Kansas City. Recker recruited Johnson, a molecular geneticist, to work with him because he knew that osteoporosis is largely inherited. The two continue to collaborate on studies.
The pair teamed up in 1995, shortly before Recker began treating an 18-year-old who had been injured in a car accident.
The young woman hadn’t suffered any fractures. But X-rays showed that she had unusually dense bones, so she was referred to Recker by her orthopedist. The young woman’s bones were shaped normally, and when Recker put her on a densitometer, he found that her bones were about 50 percent more dense than normal.
“I’d never seen anything like it in 29 years of practicing medicine. It had to be exceedingly rare,” he says.
Next, after Recker tested the girl’s mother and found she had similarly dense bones, he knew he was really on to something.
“So after that, I asked her to bring other family members in,” says Recker, who found that none of the affected kin, ranging in age from four to 82, had ever had a broken bone.
“They had nature’s cure for osteoporosis,” he says.
Recker’s work with Johnson and other researchers led to the discovery that certain members of the patient’s family possessed a rare genetic mutation that made their bones unusually dense and resistant to fracture. Recker’s wife, Susan, played a key role in tracking down members of the young woman’s extended family.
“We had an important mutation to figure out… namely, how these bones get heavy and resistant to fracture while retaining their normal shape,” Recker says. “Over the years, we tracked down 250 members of this family and found 17 who were affected.”
Johnson sought funding, and eventually obtained a grant from Creighton’s Health Futures Foundation.
“That got us some money to pursue identification of the chromosomal region where the gene was located that was responsible for the high bone mass trait,” Johnson recalls.
Remarkably, that initial effort only took a month, says Johnson, who also worked with Dr. Bill Kimberling of Boys Town National Research Hospital attached to Creighton University Medical Center in Omaha.
At the time, little mapping of the human genome had been done.
“The tools we had then were pretty primitive compared to what we have now,” recalls Recker.
Johnson says Creighton purchased special reagents – little pieces of DNA – from a commercial vendor, and was one of the first to use them “off the shelf” in order to “identify a region which was consistently inherited in all the members of the family who had the high bone mass trait.”
Initially, they narrowed the gene down to chromosome 11, in a region called “q13.”
In collaboration with scientists from a Boston-based company then known as Genome Therapeutics, they subsequently identified the gene as the one responsible for coding a receptor molecule called “LRP5.”
Johnson said LRP5 was shown to be an important regulator of a signaling pathway called “Wnt/B-catenin pathway,” which, when properly activated, can tell the body to create more bone. At the time, no one knew it was connected to bone mass development. That breakthrough, he says, has significantly influenced bone mass research.
“The genetic part of finding LRP5 was relatively simple,” Johnson recalls, modestly. “The hard part was tracking down members of the family and getting blood draws. We were sort of flying by the seat of our pants to make it all happen.”
Other scientists have called the Creighton researchers’ discovery of the mutant gene one of the most important bone biology breakthroughs in recent decades. The entire direction of bone research changed with this discovery as labs around the world moved into the genetic age and specifically began to focus on this gene and the pathway it regulates as being crucial for the regulation of bone mass.
Six years after the young woman walked into the Creighton clinic, Recker and Johnson published their work on the mutation in American Journal of Human Genetics. Randall Little, then a senior research manager at Genome Therapeutics was the first author of the article, which laid out how they identified the specific gene mutation that stimulates high bone mass.
It was the first gene discovered that appeared to influence bone density directly. It also was special, Johnson recalls, because it was not related to any high bone mass genes associated with disease.
Recker, Johnson and other researchers believe bones have a thermostat-like control that regulates the rate at which bone is broken down – or built up. The mutation may function by controlling the way the skeletal system sets the thermostat-like control at a higher or lower bone density.
In the case of the Nebraska teen and her family, their "thermostats" seemed to be set higher so they build bone at a much higher rate than it breaks down.
The first patent resulting from their work was filed in 1997 and was one of the initial collaborations with Creighton Intellectual Resources Management, then known as the Office of Technology Transfer.
Genome Therapeutics, now Oscient Pharmaceuticals, later sublicensed the discovery to a major pharmaceutical company for drug development. This world-renowned company is using the research begun at Creighton University to develop treatments for osteoporosis and other bone diseases.
IRM continues to monitor progress of the development, and the license fees collected have risen to approximately $2 million that is being shared with the researchers and being used by the university to further research.
Johnson figures those drugs are between five and 10 years from reaching the market.
Recker says he has long believed “that if we could develop a drug that would do what the mutation did, we’d have the answer to osteoporosis. That is still my hope.”