Review of research into how cells and proteins repair fractured bones

A review of research into how cells and proteins repair fractured bones published in the November 2008 issue of The Journal of the American Academy of Orthopaedic Surgeons demonstrates that understanding the biology behind this healing process may lead to improved and less invasive treatments for fractures.

"The healing of a fracture takes place at the injury site and at other points in the body further away. It is one of the few human biological processes that are capable of regenerating exactly the same tissue," says study co-author Mitchell B. Harris, MD, associate professor at Harvard Medical School and chief of the orthopaedic trauma service at Brigham and Women's Hospital in Boston.

Recent research has explained more about how the body naturally repairs broken bones, and this data has allowed trauma surgeons to combine conventional treatments such as putting a cast on a fracture with "biological treatments" that mimic or exaggerate some of the regenerative processes involved in bone repair. However, there is still much to learn to improve fracture repair, especially fractures that are difficult to treat.

By understanding the processes that fail when fractures do not heal, scientists can pursue new methods of treatment. Study co-author Francois N. K. Kwong, MD, says, "We know which clinical factors impair fracture healing, but we do not always understand how they affect the cells and proteins involved in fracture repair." Dr. Kwong was a research fellow, supervised by Dr. Christopher Evans, director of the Center for Molecular Orthopaedics at the Brigham and Women's Hospital, Harvard Medical School, when the research was conducted.

Several factors are known to interfere with the healing of a fracture:

• Compromised blood supply
• Not stabilizing the broken bone enough during healing
• Non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen
• Tobacco or drug use
• Older age
• Damage to the surrounding tissues or blood vessels
• Bones in several fragments or large gap between the bones.

Broken bones need three components to heal:

• Cells
• Proteins that signal cells to provide new building material
• Support structures in the bones that act as scaffolding for the cells
• Trauma surgeons have used a combination of these three building blocks as novel treatment of fractures.

One area of interest is bone morphogenetic proteins or (BMP). These proteins, which exist in human bones, appear to have a significant affect on cells and tissues during the repair process. Several studies have demonstrated a positive effect when BMPs are applied to fractures. However, these proteins cannot make up for the lack of factors needed for a bone to heal. There are two FDA-approved proteins, (BMP-2 and BMP-7), currently in use.

The authors state that research into the balance between BMPs and their inhibitors will probably prove to be a critical factor in determining how a fracture will heal. BMPs can be less effective when several other proteins, or "inhibitors," bind to them and interfere with their ability to work. Recent evidence suggests that blocking the inhibitors may increase the rate of bone regeneration. This discovery may lead to new treatment strategies in the repair of broken bones.

Another potential biologic treatment involves stem cells. Research has demonstrated that stem cells find a route from different areas of the body directly to a fracture site. Therefore, it may be possible to inject stem cells into the circulation to promote fracture repair. Stem cells have been used by trauma surgeons working on difficult to treat fractures by transplanting cells from different regions of the body to the fracture site.

Despite these promising areas of research, there are still challenges with the hard to heal fractures that require several months of treatment. Significant research is focused on how to accelerate this repair process.

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither Dr. Kwong or Dr. Harris, nor a member of their immediate families, has received anything of value from, or owns stock in, a commercial company or institution related directly or indirectly to the subject of this article.