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Proliferation of fragility fractures requires a managed approach

Stem cells show potential for fragility fracture healing.

Issue: December 2003

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BRIMINGHAM, England — While new fragility fracture treatments may be in the works — including advances in stem cell research — the issue takes on greater urgency as a rapidly aging population requires immediate, practical interventions.

David R. Marsh, MD, of Belfast, addressed both issues in presenting the prestigious Robert Jones Lecture here at the British Orthopaedic Association (BOA) Annual Congress.

Orthopedic and trauma units in the United Kingdom are already struggling to treat a large number of osteoporotic fractures. Health officials conservatively estimate that the rate of fragility fractures will double to about 200,000 annually by the year 2050 as the senior population increases, Marsh said.

To combat this problem, the BOA produced a “blue book” titled, The Care of Fragility Fracture Patients, which outlines methods for handling the epidemiological trend. Distributed to attendees during the BOA congress, the 30-page booklet includes proposed guidelines and recommendations for fracture treatment units, rehabilitation, prevention, surgery and data collection and sharing.

Marsh detailed the main points of the blue book, including the need for a multidisciplinary approach to treating fragility fractures, which are complex due to the comorbidities associated with elderly patients. He said such cases require attention from an adequate number of experienced doctors.

“These are some of the most complicated medical patients in the hospital, and it’s ridiculous that junior surgeons should be responsible for managing this complex medical situation,” Marsh said.

The fragility fracture blue book calls for treatment units to include geriatricians and osteoporosis specialists in addition to orthopedic surgeons because so many fracture patients have multiple health problems.

Marsh said each treatment unit should include three sections: an orthopedic team, a bone service and a falls service. The orthopedic team would be responsible for treating the fracture, and the bone service would subsequently test for the presence of osteoporosis. The falls service would offer safety measures like hip protectors to prevent future falls and fractures.

The comprehensive system is aimed at providing “secondary prevention,” according to Marsh, who said the best indicator of a fragility fracture is an initial fracture.

The fracture liaison nurse

A key element of an effective fracture treatment unit is employment of a fracture liaison nurse, who would make sure that patients most at risk for a second fracture are referred to the proper specialist, Marsh said.

“We must campaign for the resources for every fracture unit to have a fracture liaison nurse. It’s our responsibility, along with our colleagues [in geriatrics] in the fracture unit, to look after the patients completely and then to refer on so further fractures can be prevented as much as possible.”

Rehabilitation is important in order to maximize the results of surgery and minimize future surgeries by preventing additional fractures, he said. “This is something that isn’t being raised enough, and it’s our job to raise it because this is primarily a surgeon’s challenge.”

Stem cells and fracture healing

Researchers may be moving closer to understanding how the body heals itself from injury. “If we can understand the mechanisms of that, then there will be lots of treatment opportunities,” Marsh said.

Marsh highlighted animal studies by fellow Belfast researchers that addressed three important questions: Does inhibiting inflammation inhibit repair? Can there be too much inflammation as a result of soft tissue injuries that accompany fractures? Finally, is there a systemic stem cell response to fracture repair?

Chris Connolly, PhD, studied the effects of COX-2 inhibition on the healing of fractures in mice. Connolly sought to discover whether or not COX-2 inhibitors interfere with healing, since they reduce inflammation.

Marsh said the findings showed that COX-2 inhibitors interfered with bone healing by slowing the early proliferation stage as well as the later differentiation stage. The inhibitors also prompted more cartilage production, Marsh said.

Muscle inflammation

A study by John Bunn, PhD, examined the effect of muscle inflammation on bone healing. Also using mice, Bunn used antibodies to block inflammatory cytokines. That blockage allowed the bone to heal better, Marsh said.

“Much less bone formed when there was an adjacent muscle crush, even though the fractures were exactly the same,” Marsh said. “This may well lead to something chemically useful if we can tie this down a bit more firmly that the inflammatory cytokines following muscle damage hurt fracture healing.”

The third study that Marsh reviewed probed the question of stem cell involvement in fracture healing.

“We knew that all of us have in our blood streams a very small number of circulating mesenchymal stem cells,” Marsh said, but whether or not they contribute to fracture healing was unknown.

First, the study compared blood samples of fracture victims with people with no fractures and showed that only the former group contained stem cells that could form bone. In a second experiment, bone marrow was taken from rabbits, stem cells were cultured and labeled, and the researchers injected them into the tibial marrow cavity. They then created an ulnar fracture and demonstrated labeled cells taking part in the healing callus after several weeks.

“These cells are being plucked out of the bloodstream by a specific receptor-driven mechanism and recruited into the fracture. It’s as if the whole skeleton realizes that there was a fracture and sent reinforcements,” Marsh said.

Ongoing stem cell questions

These findings suggested that stem cells do take part in fracture healing, but how to use them is still a question that will require more research, Marsh said.

“If we could learn what is the systemic signal that leads the entire skeleton to release cells [that] take part in healing, what a therapeutic marvel that would be.”

For more information:

• Marsh D. Burning issues in fracture science and management. The Robert Jones Lecture. Presented at the British Orthopaedic Association Annual Congress. Sept. 17-19, 2003. Birmingham, England.