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BMP-2 and BMP-7 continue to show success in long bone fractures and nonunions
However, high costs and unknown risks of BMP still make bone graft the gold standard.
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Recombinant human bone morphogenetic proteins have come a long way since their introduction into the clinical world 10 years ago. Several studies support the use of BMP-2 and BMP-7 for complicated cases of open tibial shaft fractures and for tibial nonunions.
However, surgeons still consider iliac crest bone graft the gold standard for long bone nonunions – especially as a first-line procedure – because of the high costs and unanswered questions that remain for recombinant human bone morphogenetic proteins (rhBMP).
“For standard long bone fractures without bone loss or very severe soft tissue injury there is no evidence that [bone morphogenetic protein (BMP)] is helpful and certainly it is not cost effective,” said Paul Tornetta III, MD, Orthopedics Today editorial trauma section editor.
Orthopedics Today recently spoke with leaders in this area to assess the state of the science for BMP-2 and BMP-7.
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Images: Giannoudis PV |
A short BMP history
In 2001, the FDA approved BMP-7, marketed as OP-1 (Stryker Biotech) under the Humanitarian Device Exemption, for use in long bone nonunions, and since then the FDA approved OP-1 for recalcitrant nonunions, according to William T. Obremskey, MD, MPH, of Vanderbilt University in Nashville, Tenn.
BMP-2 has been used since 2002 in the cervical spine. In 2004, the FDA approved BMP-2, marketed as Infuse (Medtronic Sofamor Danek), for treating open tibial shaft fractures. “It was not FDA-approved for use in nonunions and still is not FDA-approved for use in nonunions,” Obremskey told Orthopedics Today.
However, a recent study by Alan Jones, MD, and colleagues (see accompanying article on facing page), convinced Obremskey that BMP-2 use in an off-label manner for some nonunions may be effective.
Although some surgeons are still skeptical about using BMP in noncomplicated open tibial shaft fractures, others say that the literature supports its use.
“There are good randomized studies in the literature that show that adding this material to an open tibial shaft fracture can reduce the nonunion and delayed union rate and reduce the incidence of reintervention,” Michael D. McKee, MD, FRCS, of St. Michael’s Hospital in Toronto, told Orthopedics Today.
Further, as other bone substitutes made their way to the market, BMPs have shown “the most powerful osteoinduction properties of any of the bone graft substitutes,” including allograft chips and demineralized bone matrix, McKee said.
Despite these success stories, most surgeons save BMP use for nonunions and revisions of previous long-bone fracture fixation because of the high costs and success rates with other healing options, said Peter V. Giannoudis, MD, of St. James University Hospital in Leeds, United Kingdom.
For example, reamed, locked nails yield a 95% success rate with femoral shaft fractures.
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Images: McKee MD |
“Naturally, any fracture should progress to union … without any further intervention … during the primary surgical intervention,” Giannoudis told Orthopedics Today. “However, a number of fractures do progress to nonunion and depending on the anatomical site, as well as the associated risk factors, you may have a nonunion rate of 5% to 10% in all the fractures that we routinely stabilize.”
“If your initial treatment fails … then the second go around, … it probably becomes cost-effective to use [BMP] in a nonunion situation,” McKee said.
BMP-2 and BMP-7 provide a major benefit over the gold-standard iliac crest bone graft: lack of donor site morbidity. Findings for BMP-2 and BMP-7 show equivalent healing rates to iliac crest bone graft for nonunions – and without wound hematoma, numbness of the thigh and prolonged pain, which are common with autograft use, McKee said.
Gary E. Freidlaender, MD and colleagues demonstrated this in a randomized trial on BMP-7 in tibial nonunions, according to McKee.
Obremskey and his colleagues studied the nonunion healing rates of BMP-2 with allograft compared to autograft in a retrospective study at Vanderbilt University. At 6 months postop, they found a slightly lower union rate for the BMP-2 and allograft patients, but it was not statistically significant, Obremskey said.
Most notably, they found that “patients in the BMP and allograft group had approximately a 1-day shorter length of stay, 1-hour shorter operation and a blood loss of 250 mL less,” Obremskey said. “These values were all statistically significant.”
Obremskey and colleagues were to present their study results at the Orthopaedic Trauma Association 22nd Annual Meeting, this month.
Costs pan out over time
While the costs remain high for BMPs, surgeons are awaiting a study to show that the extra cost could be worth it. The industry has placed high price tags on BMP-2 and BMP-7 – an average $5,000 per kit. Small and medium BMP-2 kits cost around $1,500 to $3,000, respectively, Obremskey said.
For this reason, “You don’t want to use [BMP] indiscriminately,” McKee said. “You want to pick who’s going to benefit from it. And most of the research that we do is trying to identify how it works, where it works best and when especially to use it.”
Giannoudis and his colleagues conducted a cost analysis comparing BMP-7 alone to BMP-7 and bone grafting and their results are due to be published in Injury in December.
They found that the high cost of treating complex or persistent long-bone nonunions could actually be reduced with the use of BMP-7. In fact, the mean price of treatment per fracture dropped from $25,826.51 to $13,689.14 after using BMP-7.
McKee’s hospital found that using BMP over iliac crest bone graft harvest saves a patient 1.25 to 1.5 days in the hospital. Patients with nonunions can often be a drain on the system as well. McKee said he has seen patients with nonunions 2 years or 3 years after their fractures and with two or three unsuccessful surgeries.
Some of these patients are drug dependent, all are in pain, some become depressed, many lose their jobs and some even go on to amputation, McKee said.
“If you can eliminate that cost … by using this material in an earlier stage, then I think in every possible way you look at it – economically, socially, morally, medically — it’s worth using.”
Surgeons still have many questions when it comes to BMP use: What is the ideal timing for administration of BMP, what are the long-term risks and are there risks for allergic reactions?
“We should keep these issues in the back of our minds and maybe after 10 years when we can have more experience using them it should be clear that indeed there is no concern at all to use them in the clinical setting,” Giannoudis said.
“It is time to consider a prospective multicenter study on the utilization of BMP-2 vs. autograft in long bone nonunions,” Obremskey said. He points out, however, that an investigational new drug application is required for a prospective IRB-approved study.
Until these questions are answered, surgeons should aim for an optimal healing environment when placing the BMP: reasonable mechanical stability, ample soft tissue coverage, no or minimal infection and reasonable blood supply, McKee said. Surgeons must also inform patients of the involved risks whenever using BMPs off-label, Obremskey said.
More exciting developments could even be on their way. McKee said that optimal healing might actually require several portions of active BMPs – not just BMP-2 and BMP-7.
He added: “At some point in the future we may well be able to use a compound that has different aliquots of different BMPs to replicate the natural healing process as carefully as possible.”
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Images: Obremskey WT |
For more information:
- Obremskey WT, Kregor PJ, Tressler MA, et al. Bone morphogenetic proteins compared to iliac crest bone graft in long bone nonunions. To be presented at the Orthopedic Trauma Association 22nd Annual Meeting. Oct. 5-7, 2006. Phoenix.
- Dr. McKee performs research work for Stryker Biotech and occasionally receives speaker’s fees from the company. He does not own stock nor is he a paid consultant for Stryker Biotech.
- Orthopedics Today was unable to determine whether Drs. Tornetta, Obremskey and Giannoudis have a direct financial interest in the products discussed or if they are paid consultants for any companies mentioned.