LONDON – A meta-analysis of several genomewide association studies has identified variants in 56 genetic loci related to bone mineral density, 14 of which increase the risk of bone fracture.

The study pinpointed 32 previously unknown genetic loci associated with bone mineral density, which should encourage researchers to explore new biological pathways in order to understand what role those have in determining risk of fracture, as well as confirming many genes that are already targets for new therapies for osteoporosis.

Karol Estrada, scientific researcher at Erasmus Medical Center in Rotterdam, the Netherlands, told BioWorld International: "These findings have important potential for future applications, as they will complement or even improve current therapeutic applications. Most strategies are directed to interfere with the process of bone resorption, but it might be beneficial to build up new bone and increase bone mineral density, or even reduce fracture risk by mechanisms independent of bone remodeling. These results, therefore, provide new leads for those working in drug discovery to follow up over the next few years."

Estrada and his colleagues at the Erasmus Medical Institute have led an international consortium of investigators from more than 50 studies originating in Europe, North America, East Asia and Australia. The study is part of the GEnetic Factors of OSteoporosis (GEFOS) project, which is sponsored by the European Commission.

An account of the findings is published in the April 15, 2012, issue of Nature Genetics, in a paper, titled "Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture." Estrada is the first author.

The consortium studied more than 80,000 individuals with dual energy X-ray absorptiometry (DXA) scans, which measured their bone mineral density. The scientists looked for loci that were associated with different levels of bone mineral density, and then tested those loci for association with fracture in more than 130,000 cases and controls. The study is the largest genetic study of osteoporosis performed to date.

Even though bone mineral density has an imperfect relationship with risk of fracture, in that about 50 percent of individuals without osteoporosis (as diagnosed by DXA scanning) still suffer fractures, the researchers said they believe their study allows an "unprecedented leap" in the understanding of human skeletal biology.

"Our results provide the 'big picture' for us," said Fernando Rivadeneira, assistant professor at Erasmus Medical Center and lead senior author of the study. "We have found clustering of important genes that will allow us to focus on pathways rather than just on individual genes. This will allow us to prioritize our future efforts more effectively," he told BioWorld International.

Several factors lie clustered in pathways already known to play an important part in bone mineral density, Estrada said. Those include the Wnt signaling pathway, the RANK-RANKL-OPG pathway and the mesenchymal stem cell differentiation pathway.

Rivadeneira said the work has "allowed us to pinpoint many factors in critical molecular pathways, which are candidates for therapeutic applications." A "striking feature" of the results, he added, is that the study did not always find an association between fractures and some genes known to play a critical role in bone biology.

One of the genes identified encodes a protein that is already the target for a new therapy called denosumab – a human monoclonal antibody against RANKL, a protein that mediates the activation of bone resorption. Denosumab is marketed as Prolia for osteoporosis by Thousand Oaks, Calif.-based Amgen Inc. In addition, the gene SOST was also identified; SOST encodes a protein also targeted with monoclonal antibodies that are now undergoing Phase II trials. "These two factors are good examples of what is probably the tip of the iceberg for the potential therapeutic applications of our discoveries," Rivadeneira added.

Estrada said one of the most striking surprises in the results was the identification of a novel gene that was associated with fracture risk but has never been associated with a role in determining bone mineral density before.

"This gene, which was named only last month, is called FAM210A. We know nothing about it – this discovery leads us to completely new biology," he said.

"As researchers we are completely overwhelmed with the challenge we are confronted with, to determine the biology that lies behind the genetic information we have obtained," Rivadeneira noted. "We expect more collaborations to evolve now with colleagues working in basic sciences, who have the means to study these genes and proteins at the molecular, cellular and organism level, to underpin the effects they have on bone biology."