Xtranet-ISA

The GEFOS project has detected dozens of genes that contribute to the risk of developing osteoporosis. These insights are helping elucidate the biological mechanisms that shape this condition and generate leads for the development of new drugs, such as bone-building medication. They could, eventually, also feed into the production of risk assessment and diagnostic tools that could help pre-empt the onset of the illness.

“Osteoporosis is a silent disease,” says André Uitterlinden of Erasmus Medical Center in the Netherlands, who coordinated this EU-funded project. “You will only notice it once a bone actually breaks, unless a doctor happens to spot it before.”

At this advanced stage, the condition will already have done a lot of damage. “We want to be able to predict the risk at an early stage so that better preventive measure can be taken,” Uitterlinden explains.

Factors of fracture

The genetics of osteoporosis don’t involve just one gene, but a combination of variations in a large number of genes. Taken in isolation, these variants add very little to the risk of low bone density or fractures, but their effects add up.

GEFOS is a consortium of research organisations striving to identify the exact genetic signature that spells out a predisposition to osteoporosis. The collaborative approach holds the key to their success, says Uitterlinden.

The subtle effects of the underlying variations can only be detected in very large groups of people. Previous attempts to find them in the small samples that individual research groups can hope to muster have produced limited effects, Uitterlinden explains.

The GEFOS partners have thus pooled their genetic resources. Together, they have created a repository of material that already covers 150 000 individuals, along with harmonised methodology to put this bounty to good use.

Recognising the risk

GEFOS was set up in 2008 with financial backing from the EU. It applied new high-throughput technology for the comparison of DNA volunteered by healthy individuals and patients. By the end of the funding period, the partners had compiled a list of more than 80 genetic variants implicated in the disease.

These variants only explain a fraction of the genetic risk, he concedes, but the approach holds great promise. “They are just the tip of the iceberg,” Uitterlinden notes. “With bigger samples, we could pick up far more risk factors.”

The GEFOS team is keen to do so. While the project as such has ended, the collaboration continues under the same name, says Fernando Rivadeneira, also of Erasmus Medical Center, who now leads this joint effort.

“From a molecular perspective, osteoporosis is not a single disease, but a conglomerate of different diseases,” Rivadeneira explains. Eventually, the partners’ findings could help not only to identify persons at risk, but also to pinpoint which particular type of condition they are likely to develop and which drugs would work best for them.

The partners are also flagging new avenues for treatment, says Rivadeneira. “Until very recently, most of the medication in use has focused on stopping bone resorption,” he explains. GEFOS has identified targets that could generate leads for new drugs designed to stimulate the growth of fresh bone tissue.

As part of the collaboration, the partners intend to produce a microarray of genetic material — a so-called “gene chip” — for use in genetic investigations. This “bone chip” will incorporate thousands of variants in the gene regions known to be related with common and rare musculoskeletal conditions, Rivadeneira notes. It will be very valuable for further research, he explains, and would also enable doctors to screen patients for such conditions. 

GEFOS has meanwhile switched to next-generation sequencing technology. While this is still applied on a small scale, it has already produced promising results, soon to be published in the prestigious journal Nature in 2015, Rivadeneira reports. The new technology will help the partners to cover far more ground in their quest to find where the bones are buried in our genome.