An American woman over 50 years of age has a 50-50 chance of breaking at least one bone in her lifetime. That is, a bone weakened by osteoporosis. For men, the odds of such a fracture are only 1-in-8.

The risk of osteoporosis is highest in postmenopausal women. This is due to a hormonal switch at menopause, which triggers bone resorption. It happens in men, too around 65 to 70 years of age.

The cost to society of osteoporosis in the U.S. has been estimated as high as $14 billion annually, with 1.5 million osteoporotic fractures every year.

Five years ago, two osteoporosis researchers at Creighton University in Omaha, Neb., discovered a large family that had extremely high bone mass and located the initial linkage of that trait the opposite of osteoporosis’ low bone density to the long arm of human chromosome 11. The researchers are Mark Johnson and Robert Recker at Creighton’s Osteoporosis Research Center.

Johnson recounted to BioWorld Today how they pinpointed this contrarian gene in one extended family, but nowhere else.

“In November 1995,” he said, “a young woman, about 18 years old, was referred into our Osteoporosis Research Center by a clinical orthopedist here at Creighton. He had seen the woman for chronic back pain, which she blamed on an automobile accident a couple of years earlier. She hadn’t broken any bones in the accident, so it wasn’t clear why she still suffered this residual pain.

“Dr. Recker, director of our Osteoporosis Clinic, looked at her X-rays and thought her bones seemed much denser than normal. There are a number of diseases of high bone density in humans,” Johnson continued, “that ultimately involve pinching the nerves, so one gets pain. Recker performed a bone density scan on the young woman, and found her bone density 50 percent higher than normal. That was remarkable because one hardly ever sees a patient with a bone density that high in an osteoporosis clinic. Osteoporosis is the opposite condition low density.”

Male Family Members Lack Density Gene

“The young woman’s mother agreed to have her bone density measured as well. Her readout was essentially the same, which suggested that this high bone mass was an inherited trait. (Ultimately, her daughter’s back pain proved to be just a muscle involvement.)

“So we began exploring her family,” Johnson went on. “We tested the father and brother, neither of whom had the phenotype. Eventually, among the extended kindred, we identified several hundred people, of whom 37 were useful in our analysis for determining where the high bone mass mutant gene might be located. Through linkage analysis we did a whole genome scan and identified a position on chromosome 11’s long arm, where the phenotypic genetic trait linked.

“At that time,” Johnson recalled, “I presented our results to a Bone and Mineral Research meeting. A number of interested people came to my poster. One of them was a vice president at Genome Therapeutics Corp., in Waltham, Mass. So ultimately we partnered with GTC, and together went after identifying the gene, and the rest is history.”

Johnson and Recker are co-senior authors of a paper in the January 2002 American Journal of Human Genetics, which updates this account. Its title: “A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.” Its lead author is human geneticist Randall Little, who directs Genome Therapeutics’ department of human genetics.

“Working with Creighton,” Little told BioWorld Today, “we found a relatively rare mutation in the LRP5 gene, resulting in autosomal dominant high bone mass in that particular family. Our company’s role was to map the region on chromosome 11, clone it, sequence it and identify all mutations in a critical genomic interval. This resulted in a single mutated gene, present only in that one family.

“Our initial studies relied heavily on these families that had this autosomal dominant trait,” Little went on. “We looked for mutations present only in affected people. Once we found this unique mutation, we extended our search to two different, larger populations: one, a cohort of men and women with normal bone density; two, a random collection of people to make up a total of 1,000. Part of the samples Creighton transferred to us. We added other populations that included ethnically diverse panels. We developed an allele-specific assay, which allowed us to quickly monitor the presence of this particular mutation in a large number of people, in DNA isolated from their blood samples. And we did not find that mutation in anybody except the affected members of Creighton’s index family. It was all done here at GTC.”

Mutant A Natural For Osteoporosis Drug

“We didn’t know,” Johnson observed, “that this mutant LRP5 gene we identified is the first human gene that may be involved in the regulation of bone density. And certainly we have a pathway that we never suspected before, which is the WNT signaling pathway. It’s known to be involved in the embryonic development of the skeleton. We never knew it was also involved in regulating the adult skeleton as well. So that’s very exciting in terms of what it may lead us to.

“GTC and Creighton have partnered with Wyeth-Ayerst,” Johnson said, “and obviously the great hope is that we can build a pharmaceutical agent that will mimic the action of our mutation. So we can take a patient who has an osteoporotic skeleton, administer the pharmaceutical and build a perfectly normally shaped skeleton, but much stronger. It will increase the person’s bone density with this really good anabolic agent for building more bone mass, by mimicking the action of our mutation.

“As with any pharmaceutical development,” Johnson allowed, “that’s a big unknown. If everything goes smoothly and we make progress, it could be in the clinic within five to 10 years. Meanwhile, we’ve introduced this mutation into a transgenic mouse. They got high bone density just like our humans do, and don’t seem to have any negative consequences.”

GTC’s Little made the point: “Current osteoporosis therapies are targeted to inhibit bone degradation, whereas our pathway is targeted to accelerate bone deposition.”