Proteins linked to osteoporosis a step towards new drugs

Claes Ohlsson has analyzed the genes of people with brittle bones – osteoporosis. He has discovered genetic changes that increase the risk of fractures. As a Wallenberg Clinical Scholar, he wants to use this new knowledge to develop better diagnostic methods and drugs.

Claes Ohlsson

Senior Physician and Professor of Hormonal Regulation of Bone Metabolism and Growth

Wallenberg Clinical Scholar 2016

Institution:
University of Gothenburg

Research field:
Osteoporosis

Many of us suffer from osteoporosis as we grow older. Bone density declines, leading to a greater risk of fractures. Around half of women and a quarter of men suffer fractures caused by brittle bones.

The condition is diagnosed with the help of X-ray examinations, which reveal bone density. Osteoporosis is diagnosed if bone mass has fallen below a certain level in the hips or lumbar spine. This is one of several factors increasing the risk of fractures.

“The people with osteoporosis who run the greatest risk of broken bones are also those who benefit most from treatment. We now have a fairly good method of identifying them – a model known as FRAX. Researchers in Gothenburg were involved in developing the model, which is used throughout the world. Various risk factors are weighed up, including bone density, history of fractures, and smoking. But the model could be made more accurate,” Ohlsson says.

He is a professor at the University of Gothenburg and senior physician at Sahlgrenska University Hospital. He is researching into the impact of environmental factors and genetic changes on the risk of developing osteoporosis. His findings may result in more accurate diagnoses and more effective therapies.

Current drugs not effective in preventing all fractures

Our skeleton is in a constant state of rebuilding: cells called osteoblasts build up bone mass; osteoclasts break it down. Today’s osteoporosis patients are usually given biphosphonate drugs, which slow the rate at which osteoclasts break down bone mass. The treatment works well in reducing the risk of fractured vertebrae. But it is not as effective in lowering the risk of other fractures, e.g. in the forearm or hip.

Fractured vertebrae are painful and can greatly reduce the patient’s quality of life. But a broken hip can be much more dangerous. Surgery is required, which, for the elderly, poses a risk of death from complications. There is an urgent need for better medicines to reduce the risk of falls and fractures.

With the help of genetic analyses of a large number of subjects, Ohlsson has found a new path towards more reliable diagnoses and new drugs. His hypothesis was that different kinds of fracture had different causes, and should be treated differently. So he studied different parts of bone using advanced X-ray technology, and analyzed the DNA of patients with fractures of various kinds. The results were compared with healthy individuals to see whether they had anything in common in genetic terms. Ohlsson’s research team found a handful of altered genes that differed between the different types of fracture and changes in bone.

Gene variants inspiring new drugs

The genetic changes alter the quantity or the activity of one of the proteins in question, which regulate the risk of fractures. Ohlsson explains that this may happen in two ways: either they affect bone strength, or they influence the risk of falling – perhaps by improving balance or strengthening muscles.

In the case of one protein, known as WNT16, he knows the answer. Studies in mice and cell cultures have shown how WNT16 increases the quantity of compact bone. Ohlsson’s team is now studying another protein that appears to inhibit WNT16 activity. If a drug can be developed to prevent that protein from acting, the patient will gain the full benefit of their WNT16, which might compensate for the abnormally low concentration.

Ohlsson and his colleagues are convinced that different fractures in osteoporosis patients are based on different mechanisms in the body. This requires diagnostic methods capable of distinguishing between the variants, along with targeted drugs.

“In the future I think we’ll know much more about the risk that you as an individual will suffer a particular type of fracture, and how we should treat you,” he says.

“Being chosen as a Wallenberg Clinical Scholar is a great honor, which gives the whole research team a little more security. We can commit to more adventurous and long-term projects.”

Ohlsson devotes 70 percent of his time to research and 30 percent to his work as a clinical pharmacologist at Sahlgrenska University Hospital. His job enables him to assess the drugs that work best, and are most cost-effective. He is also involved in work on formulating guidelines on how various diseases should be investigated and treated.

“I do find research in itself highly stimulating, but I also realize that my clinical work is critical to the success of my research. You have to be involved in health care to see what’s happening, the therapies that have been developed, and the needs that exist. After a session at the clinic I often go straight back to the lab with a new idea. It enriches my research enormously. My clinical work helps me to identify relevant research topics.”

Text Lisa Kirsebom
Translation Maxwell Arding
Photo Magnus Bergström