Bone Morphogenic Protein (BMP) is a naturally occurring protein found in human bone and is a strong stimulant to bone formation. This protein is normally sequestered in the bone (isolated in pockets within the bone and not exposed to the general circulation).
When a bone fractures, this injury not only breaks the bone but also tears the surrounding blood vessels. These torn vessels continue to pump blood and eventually produce a hematoma (a clotted pool of blood) in the injury area. The hematoma then triggers specific cells to migrate into the blood clot. The cells that initially migrate in are white blood cells. These white blood cells clean up the debris from one fracture end to the other and promote new blood vessels to enter the injury area. This allows the entry of bone forming cells (osteoblasts) to lay down a protein backbone somewhat like a runway is designed to land a plane.
The broken bone ends expose the sequestered BMP proteins to this clot and stimulate bone formation. Stem cells which are pluripotential cells (they can turn into any type of cell line when exposed to the right proteins) migrate into this injury region. Exposure to BMP triggers these stem cells to turn into bone cells. These newly transformed bone cells then do their job and start to create a bone-friendly environment. Other specialty bone cells then migrate along these protein pathways and lay down haphazard crystals of bone (calcium hydroxyapatite). This is called “woven bone”.
Osteoblasts (bone forming cells) then coalesce these crystals into solid cortical struts that can withstand body weight and impact forces. Wolfe’s law then applies here. Loaded bone will lay down more bone along the lines of stress and unloaded (non-stressed) bone will dissolve away. Wolfe’s law “cleans up” these irregular patterns of bone formation into bone columns (cortical bone) that coincide with lines of stress (gravity and loading).
The original work to discover BMP was performed by Marshall Urist at UCLA. By observation, he obviously knew that bone would only start growing when the bone was fractured. Dr. Urist reasoned that there was an endogenous substance that induced bone growth and spent many years distilling out this elusive protein.
Urist in “Science” published the initial discovery in 1965. Dr. Urist then proposed the name “Bone Morphogenetic Protein” (BMP) in the Journal of Dental Research in 1971.
It turns out that there were a number of different proteins that stimulate bone formation. In the beginning of this century, BMP-2, BMP-5 and BMP-7 were all identified as active proteins and used in surgery. These proteins were commercialized with mixed results. Over the years, BMP-2 (“Infuse” made by Medtronic) has been demonstrated to be the most effective protein for bone production.
Use and Application
The BMP protein is applied to the surgical site in conjunction with a collagen sponge. Collagen is a common protein that is contained in all tendons, ligaments and is also the substructure of bone. The collagen sponge in this case is just the delivery vehicle to place the BMP in the proper position. The BMP protein is contained in a glass vial in solution and “dripped” onto the sponge. After about 10 minutes of exposure, the BMP protein “sticks” to the sponge. The sponge can then be cut up and mixed with morselized host (autograph) bone graft to create a slurry that is a very powerful bone forming material.
Iliac Crest Bone Graft (ICBG) and Other Graft Materials
What was the “gold standard” for graft before BMP was used? This was bone harvested from the iliac crest (pelvis) and called iliac crest bone graft (ICBG). The harvesting of this graft normally required another separate incision or a longer incision from the original lumbar spine surgery. The cap of hard bone (cortex) covering the back of the pelvis was removed and the soft spongy bone inside the pelvis was “scooped out”. Unfortunately, this graft site was uncomfortable or even painful in some individuals for months to years after surgery.
Other substances were developed that have been used to try and replace ICBG including cadaver bone, processed cadaver bone, and calcium “chips” Bone aspiration is also used to suck cells out of the iliac crest through a thick needle and apply them to an artificial bone medium to try and reproduce the efficacy of the iliac crest graft. Unfortunately, nothing had been as effective as ICBG for fusion. That is, until the advent of BMP.
BMP-2 has caused significant improvement in fusion rates and time to fusion. In the past, posterior lumbar fusions and TLIFs using ICBG would take at least one year to reach mature fusion status. The overall fusion rate with ICBG was about 85-89%. With BMP now being used, the fusion rate, at least in my hands is about 98-99% and the time to solid fusion is generally under six months.
“On Label” vs. “Off Label” Use of BMP
BMP can be used as an “on label” or “off label” substance. On label use means that the approved material is used in similar circumstances to the initial approval study that demonstrated its effectiveness. To understand what this means, you have to understand the approval process for new medications and materials.
BMP was initially approved for anterior surgery of the lumbar spine in 2002. This was through a study performed by Dr. Zdeblick in Wisconsin. Dr. Zdeblick initially used BMP-2 in conjunction with an anterior approach (an incision through the belly) using a “cage” (a metal barrel with a screw–thread like outer surface) that would screw into the “cleaned out” disc space between the front of the vertebra. This cage mechanism would distract the two bony vertebral surfaces, the screw threads would bite into the vertebral endplates and the BMP exposed in the holes in the cage would go on to produce the fusion.
Based upon the high fusion rate of this study, the FDA approved the use of BMP-2 or Infuse for “anterior spine fusion with an LT cage”. In 2008 BMP-2 was approved to repair posterolateral lumbar pseudoarthrosis (failure of attempted fusion in the back of the spine) and next to treat open tibia shaft fractures (lower leg shin bone fractures) with intramedullary nail fixation (a rod into the center of the leg bone).
To use BMP “on label” now for spine surgery, a surgeon would have to perform an anterior fusion with a barrel-like cage. This has become an uncommon procedure.
The reason this procedure is not used commonly is that anterior fusion of the spine requires an approach that cuts through the muscular wall of the belly. The great vessels (aorta and vena cava) and the intestines are moved to the side and the front of the spine is exposed.
There are potential complications (problems) of the “through the belly” approach, which includes small bowel obstruction, abdominal wall hernias and retrograde ejaculation. Great vessel injury could also occur.
In general, anterior surgery also does not address any nerve compression issues. The newer TLIF and PLIF techniques (transforaminal and posterior lumbar Interbody fusion), which consist of surgery only from an incision in the back of the spine, can reproduce the anterior surgery benefits with less significant complications. These posterior procedures can also allow exposure to the nerves, allowing decompression if necessary.
This approval by the FDA to allow the use of BMP allows not only the “on label” approach but also the use of BMP in an “off-label” use. This means that BMP approval allows surgeons to use the BMP as an “off label” product anywhere in the spine. BMP-2 is now commonly used for posterior lumbar procedures.
The FDA however recently released a cautionary letter recommending that BMP-2 not be used in anterior cervical fusions (the front of the neck) as BMP can cause soft tissue swelling with postoperative compromise of the patient’s airway.
Precautions/Complications with the use of BMP-2
BMP-2 is a powerful growth-inducing agent. There are some potential complications that can occur with its use.
BMP is an agent that can irritate and inflame nerves. In posterior fusions that enter the disc space (TLIFs and PLIFs), BMP is placed within the disc. This BMP can elude out of the disc space and irritate the nerve root. When this happens, the patient can develop leg pain.
A technique can be used to “seal” the nerve/disc interspace and reduce the chance of exposure. In this technique, two separate structures, the implanted cage and a sealant used in the disc space can shield the nerve. The implanted cage creates a barrier as it contains only autograft bone (ground up facet bone) as well as the PEEK (plastic or polyether-ether ketone) material that the cage is made of. The BMP is placed deep within the disc space and then driven deeper into this space by using tamps after BMP insertion. The cage is then placed behind the BMP to “block” the exit zone to the root.
Finally, a sealant (Duraseal), designed to be used adjacent to the dura (the nerve root membrane) is placed into the disc space to create a barrier. This minimizes the potential for the BMP to reach the nerve root and cause inflammation. There still are cases of nerve root inflammation that do occur even with this technique and some of these cases are permanent but this technique has significantly reduced the prevalence of these cases.
BMP can produce abnormal bone formation called heterotopic ossification in places that are not designed for bone growth (like the nerve root foramen). Heterotopic bone can occasionally be an issue with BMP. There seems to be a relationship between the concentration of BMP and the reaction of the body to these different concentrations. Higher concentrations form bone but lower concentrations may form fibrous tissue.
The location of the BMP material might also have some effect. Surrounded by the two bony disc “walls”, bone seems to form well in the disc space. Bone also forms well when placed on top of the transverse processes and the facets/lamina in a posterior fusion location. If heterotopic ossification occurs and causes nerve root compression, an additional surgery might be warranted to remove this bone.
BMP can also cause bone loss (called osteolysis) in certain circumstances. I have seen this osteolysis occur in the vertebral body (in rare cases involving up to 20% of the bone of the vertebral body). In just about every case of osteolysis, this bone absorption resolves in six to nine months and fills in with normal bone. I have never seen a patient have issues with osteolysis.
BMP-2 (Infuse) and Neoplasm Risk
There has been a question of whether BMP-2 has a role in neoplasms. BMP is a protein that can be thought of as a “hormone” that is designed to stimulate growth of bone and other tissues. One study using much higher doses of BMP than used today (4-12 times as much per level) indicate possible increased cancer risk. Other studies indicate that patients who have had BMP implanted for spine fusion have reduced cancer risk.
I can say that in my practice, the incidence of cancer is no higher in patients who have had BMP used compared to those who have never been exposed to BMP. My colleagues also have confirmed my experience.
From the American Academy of Orthopaedic Surgeons website:
“Even though little evidence exists that either of these powerful materials is carcinogenic, the product inserts list specific warnings and contraindications regarding their use in tumorous areas, skeletally immature patients, and women who are pregnant or may become pregnant. The use of these products in those instances is essentially “off-label.”
“RhBMP-2 (Infuse) has been shown to inhibit tumorous cell lines from prostate, ovarian, and breast cancer. Unpublished data from the manufacturer would indicate an inhibitory effect on human sarcomas, prostate, breast, and lung carcinoma. Despite any direct evidence of carcinogenesis, the manufacturers, in their product insert, have supplied contraindications regarding tumor situation”. These restrictions are:
- Pregnant women or women who are about to become pregnant
- Skeletally immature patients
- A site of a resected tumor
- Patients with an active malignancy or patients undergoing treatment for malignancy
- Warnings: Women of childbearing potential should be advised to take measures to prevent pregnancy for 1 year following treatment with rhBMP-2 (Infuse).
Recently, Golden et al responded electronically to a letter to the editor (Journal of Bone and Joint Surgery, Jan. 22, 2008) regarding the clinical safety of rhBMP-2. The questions asked concerned the following areas:
- Any report of the development of primary and secondary tumors in patients treated with rhBMP
- The surveillance of patients for the development of tumors
- The need for comparative studies of tumor prevalence of rhBMP-2 in treated and untreated patients
“The authors responded that surveillance of the estimated 500,000 patients worldwide to whom rhBMP-2 has been administered to date has yielded no reported osseous malignancies related to its clinical use and that ongoing monitoring is being done.
They further commented on an analysis of the frequency of malignancies diagnosed in rhBMP-2-treated patients in clinical studies compared to the general population stratified for gender, age, and race using a standardized incidence ratio and SEER (Surveillance, Epidemiology and End Results) cancer registry data. No increased frequency of malignancies has been observed to date in the treated population as compared to the general population.
Because the data on safety remain incomplete, guidance on the use of BMPs in cancer patients remains incomplete. With limited FDA-approved indications for rhBMP-2 and the current label guidance supporting the contraindication of their use in cancer patients, orthopedic surgeons must exercise caution”.
The use of BMP-2 in spine surgery remains controversial, with some authors suggesting it increases the risk of complications and two recent independent reviews of the original industry-sponsored trial data (the Yale Open Data Access project, or YODA) concluding that BMP-2 did not improve clinical outcomes compared to iliac crest bone graft (ICBG). While Carragee et al. concluded that BMP-2 may be associated with complications such increased post-operative pain, wound healing problems, and retrograde ejaculation, most concerning was a possible association with cancer. The YODA papers found a 2-3 fold increased risk of cancer in the BMP patients compared to the ICBG patients, and this difference was found to be statistically significant in one of the two reviews. More recently, Carragee et al. published an analysis of the AMPLIFY study data (this older product has 4-10 times the dose of current BMP-2 DC) and concluded that the rate of new cancer events in the BMP-2 patients was 6 times as high as in the ICBG patients. AMPLIFY is a higher dose preparation of BMP-2, and the study protocol used a 40 mg dose for a one level posterolateral fusion. Inspection of the data table in this paper demonstrates that 7 of the 12 new cancer events reported in the first two years in the BMP-2 group were skin cancers occurring in three patients. In comparing non-skin cancer events reported in the first 24 months, 5 were observed in the BMP-2 group and 2 in the ICBG group. Given the low numbers of cancers reported in the clinical trials, it is hard to draw strong conclusions based on these data.
It is on this background that Drs. Cooper and Kou, in a study that was sponsored by Medtronic, decided to query the Medicare database in order to study a large cohort of patients and determine if there was an association between BMP-2 and cancer. They evaluated all Medicare patients undergoing lumbar fusion from 2003-2008, excluding those with a prior or current diagnosis of cancer. They included over 146,000 patients, with BMP-2 having been used in about 15%. They subsequently followed these patients into the future for an average of 4.7 years and compared the rates of cancer among those who received BMP and those who did not. In order to bolster their results, the authors ran the analyses using 3 different definitions of cancer, ranging from a highly sensitive definition requiring just one code for cancer to a more stringent definition requiring two separate diagnosis codes for the same cancer as well as a code for cancer treatment. They found that BMP was not associated with overall cancer risk or risks of specific types of cancer. In the analysis using the most stringent definition of cancer, the BMP patients actually had a slightly lower risk of all cancer types and specifically brain cancer.
This analysis based on Medicare data comes to a markedly different conclusion than the other recent papers on this topic. It seems likely that the cause of the discrepant results is the different methodologies employed and the different patient populations in each study. While there were significantly more cancer events in the BMP-2 patients than in the ICBG patients in the AMPLIFY study (the high dose patient population-DC), a single patient experienced 6 of the 20 new cancer events observed over five years, and five of these were skin cancers. Another patient in the BMP-2 group experienced three skin cancers. These two patients accounted for nearly 50% of the new cancer events, and 50% of the new cancer events were basal cell carcinoma, squamous cell carcinoma or melanoma. While it is possible that BMP-2 causes skin and other cancers, it is also possible that two patients prone to skin cancer were randomly assigned to the BMP-2 group and would have developed these cancers without exposure to BMP-2.
Another high dose BMP trial did not demonstrate an increased risk of cancer, though this study remains unpublished and was reported only in the YODA reviews. Bridwell et al. recently published a paper comparing outcomes and complications in about 30 adult deformity patients treated with very high dose BMP-2 (140 mg on average) and a control group treated with ICBG. They reported one patient with an acoustic neuroma in the BMP -2 group and one patient with skin cancer and another with uterine fibroids in the ICBG group.
While the current Medicare study does have all of the limitations of a large database study, it seems likely that coding for the use of BMP-2 and cancer is fairly reliable. With the large numbers involved, the chance of a Type II error is very low, and it seems reasonable to conclude that BMP-2 is not associated with cancer in the Medicare population. It should be noted that squamous cell carcinoma and basal cell carcinoma were not included in the database, so this study does not provide any information about the association with BMP-2 and these types of cancer. Additionally, it should be noted that Medtronic funded the study. Given the conflicting results on this topic, it is likely that the only method to get a more definitive answer would be the creation of a registry that could prospectively track complications in all patients who receive BMP-2.
BMP-2 is a growth substance that triggers stem cells to proliferate and manufacture their own specialty product-bone. If there are precancerous cells identified, could BMP amplify these cells for growth? By the data, it seems that BMP will not turn normal cells into cancerous cells. Since BMP-2 is a growth agent however, precancerous conditions (myeloproliferative disease, pre-leukemia and others) should have careful consideration before the use of BMP-2.