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Published 4/1/2009
Annie Hayashi

BMPs: The new standard of care for nonunions?

Autogenous iliac crest bone graft has been the gold standard for the treatment of bone defects and nonunions. But in a symposium sponsored by the Orthopaedic Research Society/Orthopaedic Trauma Association, panelists challenged that gold standard for all clinical situations. In their views, the use of recombinant bone morphogenetic proteins (BMPs) is more effective for treating tibial fractures and nonunions.

The panel on “BMPs: Current evidence and future solutions” was moderated by Theodore Miclau, MD, and included Thomas A. Einhorn, MD; Emil H. Schemitsch, MD; Marc F. Swiontkowski, MD; and Mohit Bhandari, MD.

No two BMPs are alike
According to Dr. Einhorn, the different types of BMPs perform different functions.

“BMPs 2, 3, 4, 7, and 8 are particularly expressed during fracture healing,” he explained. “Their antagonists also have a specific pattern of expression—primarily during the early phase of fracture healing.

“So the extracellular antagonist of the BMPs is expressed at the same time as the message for the BMP that then serves as an interim control method,” he said. “BMP-2 is essential for osteogenesis but not for recruitment of osteogenic stem cells.”

BMP-2 activity is required for the initiation of fracture healing. “It is essential for osteoblast differentiation and specifically required for bone healing,” Dr. Einhorn explained.

In a study he cited, mice genetically engineered to develop without BMP-2 showed no fracture healing. In contrast, the control mice went through the predicted stages of repair in the appropriate temporal sequence.

“Mice heterozygous for BMP-2 expression showed a less robust fracture healing response but nevertheless were able to successfully heal by day 20. In sharp contrast, fractures never healed in mice that lacked limb-specific BMP-2,” he reported.

BMPs: New standard of care?
“In the United States alone, almost 2 million bone graft procedures are done every year—creating a huge burden of fracture care,” said Dr. Schemitsch.

The morbidity of autogenous iliac crest bone grafting is significant, with major complication rates ranging from 10 percent to 25 percent.

“Osteoconductive bone substitutes offer an attractive alternative,” he said. The trauma applications for BMPs include treatment for tibial nonunion, atrophic long bone nonunion, and open tibia fractures.

But the use of BMPs alone cannot guarantee a successful outcome. Surgeons must follow the required steps in treating fractures, such as removing implanted hardware, débriding the nonunion to the bleeding bone, creating a good mechanical environment, and achieving stable internal fixation.

“Only then do we add BMP-7 to the nonunion site. It is absolutely critical that the requirements of the orthopaedic operation be performed before using the BMP,” he said.

How much is too much?
With a single BMP intervention costing as much as $5,000, cost has become a major issue for clinicians, patients, and payors, according to Dr. Swiontkowski.

“From a hospital’s perspective, it can overwhelm the group payment system for an individual’s injury,” he said.

Using data from Bruce Ziran, MD, Dr. Swiontkowski looked at high- and low-volume centers. He applied the risk reduction methodology and the assumptions of the limb salvage versus amputation Lower Extremity Assessment Project (LEAP) trial, a longitudinal outcome study conducted over 7 years on a group of patients—one-third of whom had their limbs amputated and two-thirds with limb salvage.

The study, which was conducted in 8 U.S. centers, calculated costs for 2 years and estimated lifetime costs. The 2-year costs for limb salvage were $81,316, while the 2-year costs for amputation were $91,106. The lifetime costs were $163,282 for limb salvage and $509,275 for amputation.

A similar analysis, done from the payor perspective by Alan L. Jones, MD, examined the rate of secondary interventions in all tibia fractures. Without the use of BMP, the cost was $20,217 compared to $16,734 when BMP was used.

From a hospital perspective, the net loss without the use of BMP was $9,329, which increased to $13,733 with the use of BMP.

“Is it worth it?” asked Dr. Swiontkowski. “Yes, for high grade open tibia fractures.”

But he added that it is “incredibly price sensitive and I don’t think the protein should be used as insurance. It cannot compensate for poorly done surgeries.”

Does the evidence support the need?
Limb injuries constitute the leading cause of all trauma hospital admissions in the United States, according to Dr. Bhandari, who also believes that BMPs have a strong biologic rationale and “the potential to significantly reduce the burden from trauma, improve quality of life, and save healthcare dollars.”

But to support autograft treatment method over BMP treatment would require randomized clinical trials, said Dr. Bhandari, with particular attention to the following methodological issues:

  • The need for current best evidence, which implies a hierarchy of evidence with randomized controlled trials at the top
  • Ensuring a narrow confidence interval within the zone of equivalence for two alternative therapies
  • Redirecting the focus to the num­ber of outcome events rather than the P value, because fewer outcome events render results very unstable and susceptible to change
  • Caution when it comes to subgroup analyses because most are incorrectly conducted in the orthopaedic literature.

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org