Bone Morphogenetic Protein in Spine Surgery: Current and Future Uses : JAAOS - Journal of the American Academy of Orthopaedic Surgeons

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Bone Morphogenetic Protein in Spine Surgery: Current and Future Uses

Even, Jesse MD; Eskander, Mark MD; Kang, James MD

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Journal of the American Academy of Orthopaedic Surgeons 20(9):p 547-552, September 2012. | DOI: 10.5435/JAAOS-20-09-547
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Bone morphogenetic protein (BMP) was discovered by Marshall Urist in 1965. Since then, more than 20 types of BMPs have been identified, but only BMP-2, -4, -6, -7, and -9 have been shown to have significant osteogenic properties.1-3 Much preclinical research has documented the effectiveness of these BMPs in forming new bone in various animal models.1 Currently, BMP-2 and -7 are the only two BMPs available for clinical use in spine fusion surgery. BMP-2 has been approved by the US FDA only for anterior lumbar interbody fusion, and BMP-7 only for humanitarian use.

Since its introduction, clinicians have adopted BMP-2 as a potential bone graft substitute for a variety of spinal applications, mostly for off-label (ie, physician-directed) use. However, recent reports cite potential complications and safety issues with the use of BMP-2.4-13 Being questioned is whether BMP-2 is as safe as it was thought to be when it was initially introduced.

This issue has been further complicated by revelations that several surgeons involved in the original clinical trials may have had substantial conflicts of interest, with the potential for bias in the publications.5 Clinicians are therefore uncertain what the current and future uses of BMP should be.

Bone Morphogenetic Proteins As Osteogenetic Agents

BMPs are potent biologic agents that stimulate osteogenesis and form new bone. Numerous preclinical studies have clearly documented this in animal models.1-3 The body of literature to date supports the premise that BMP-2 is more osteogenic compared with the other BMPs; therefore, the available clinical data predominantly involve BMP-2.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal surgery was first studied clinically in anterior lumbar interbody fusion. rhBMP-2 was soaked on a collagen sponge and used in tapered titanium cages in 143 patients; autograft iliac crest was placed in the cage in 136 patients.14 The rhBMP-2 group was reported to have a 94.5% fusion rate, compared with an 88.7% fusion rate in the autograft group. Both groups had similar improvements in clinical outcome measures through the duration of the study. Two other prospective studies also documented the clinical effectiveness of achieving a solid arthrodesis with rhBMP-2 compared with autograft using cortical allograft dowels.15,16 These studies and others helped Medtronic achieve FDA approval for its rhBMP-2 product (Infuse Bone Graft; Medtronic, Memphis, TN) and allowed clinicians to begin using this product for spine fusions. BMP-2 was only FDA approved for use in anterior lumbar interbody fusions with tapered titanium cages, but after its introduction, the off-label uses of BMP-2 (ie, posterolateral lumbar fusions, cervical spine fusions) have been reported to constitute 85% of its usage.17

Many other clinical studies ensued demonstrating the effectiveness of rhBMP-2 in achieving high rates of fusion in different types of spine surgeries (Table 1). The reported fusion rates ranged from 88% to 100%. Although these early studies were industry sponsored, there is little debate or controversy regarding the efficacy of rhBMP-2 in achieving a relatively high rate of fusion in spinal surgery.

Table 1:
Fusion Rates and Adverse Events Related to the Use of Recombinant Human Bone Morphogenetic Protein-2

In addition to achieving a high rate of fusion with rhBMP-2, the clinical outcomes, as measured by the Medical Outcomes Study 36-Item Short Form survey (SF-36), also demonstrated equal outcomes compared with patients who underwent iliac crest bone graft (ICBG).7,10,14,18-26,28 Interestingly, in all of these studies, the control groups of patients who underwent ICBG harvesting did not have a greater number of adverse events than did the patients in the rhBMP-2 groups, in whom no ICBG was taken. This fact implies that taking the ICBG did not seem to cause worse functional outcomes. Thus, rhBMP-2 does seem to be equal to ICBG in regard to fusion rates as well as clinical outcomes when used properly in the lumbar spine. However, no studies to date have proven that the use of rhBMP-2 is superior to ICBG in achieving clinical success.

Bone Morphogenetic Protein as a Potential Replacement for Iliac Crest Bone Graft

The most commonly reported complication from harvesting ICBG is pain at the donor site. Numerous studies have documented this experience, and it is generally accepted as a known risk by both the surgeon and the patient.29-31 However, it is often not clear whether the purported hip pain after posterior spinal fusion surgery is actually the result of the bone graft harvest or difficulty in identifying the source of the pain. In a recent study, Howard et al31 looked at the incidence and severity of pain over the low back surgical site and right and left posterior iliac crests at a minimum of 2 years after posterolateral fusion done with either rhBMP-2 or with ICBG harvest (through the same midline incision). They found no significant differences in the proportion of patients reporting tenderness over both or either iliac crest between the two groups. These results highlight the difficulty in determining which reported pain is residual low back pain and which is from the graft harvest itself.31

Furthermore, in the corporate-sponsored randomized clinical trials reported to date that compare ICBG to rhBMP-2,14,18-22,27,28 the SF-36 outcomes have never been able to demonstrate a decrease in functional outcomes in patients undergoing ICBG harvest. If the pain associated with ICBG harvest is as severe as is assumed, then the completed SF-36 surveys should reflect that fact in the physical outcome measures. However, none of these randomized clinical trials has demonstrated that this level of pain is occurring. On the contrary, data from one of the FDA trials (ie, Amplify, a high-dose rh-BMP-2; Medtronic) shows that patients who underwent ICBG harvest actually had greater improvement in back and leg pain scores at the 6-week postoperative mark than did patients in the rhBMP-2 group.27

Of course, other factors should be considered when making the decision whether ICBG should be harvested. It has become generally accepted that there is more blood loss and operating room time associated with ICBG harvest than with the use of rhBMP-2, so the surgeon's clinical judgment must come into play. For example, the poor quality of the ICBG as an osteoinductive agent in an elderly female patient with osteoporosis who smokes may sway the surgeon into using such products as rhBMP-2.

Complications of ICBG occur, and the costs to the patient physically include chronic pain, nerve, arterial, and ureteral injury; herniation of abdominal contents; sacroiliac joint instability; pelvic fractures; hematoma; and infection; as well as financial costs, as described by St John et al.32 However, Carragee et al30 stated that

we believe that the literature does not support a finding of significant morbidity with this technique, and the recent, widespread shift to commercial alternatives is unwarranted and ill-advised.

Safety of Bone Morphogenetic Protein Use

As with any new drug or medical device, the acquisition of long-term data is associated with descriptions of new and unanticipated complications. The initial literature14,18-22,27,28 (all industry sponsored), representing 780 combined patients regarding the use of rhBMP-2, reported no adverse events directly related to BMP usage (Table 1), which led to its FDA approval. These data set the stage for immediate acceptance by spine surgeons to use rhBMP-2 liberally. Because of the appearance of a no-risk profile, the increasing use of rhBMP-2 was dramatic, from 0.7% of all fusions in 2002 to >50% of anterior lumbar interbody fusions and 43% of posterior lumbar and transforaminal lumbar interbody fusions in 2007.30,31 The original industry-sponsored studies also appeared to condemn the alternative to rhBMP-2 by reporting ICBG harvesting complication rates of 40% to 60%,22 much higher than the historical incidence of 3% to 30%.12

However, following the successful introduction of rhBMP-2, clinical safety issues were brought to light, and many independent, non-industry-sponsored articles were published that demonstrated a multitude of adverse events associated with rhBMP-2 (Table 1). Complications such as retrograde ejaculation, osteolysis, seroma formation (Figure 1), postoperative radiculitis, ectopic bone formation (Figure 2), and massive soft-tissue swelling (Figure 3) have now been documented to be associated with the clinical use of rhBMP-2. Although these complications are not unique to the use of rhBMP-2, their prevalence seems to be elevated with the use of rhBMP-2 compared with ICBG.25

Figure 1:
Sagittal magnetic resonance image of the cervical spine demonstrating a large seroma following cervical laminectomy and fusion with rhBMP-2. (Reproduced with permission from Robin BN, Chaput CD, Zeitouni S, Rahm MD, Zerris VA, Sampson HW: Cytokine-mediated inflammatory reaction following posterior cervical decompression and fusion associated with recombinant human bone morphogenetic protein-2: A case study. Spine [Phila Pa 1976] 2010;35[23]: E1350-E1354.)
Figure 2:
Axial CT scan of the lumbar spine demonstrating ectopic bone formation (arrow) in the left neural foramen impinging on the exiting nerve root in a patient who underwent a transforaminal lumbar interbody fusion with rhBMP-2. (Reproduced with permission from Rihn JA, Gates C, Glassman SD, Phillips FM, Schwender JD, Albert TJ: The use of bone morphogenetic protein in lumbar spine surgery. J Bone Joint Surg Am 2008;90[9]: 2014-2025.)
Figure 3:
Lateral radiograph of the cervical spine demonstrating massive soft-tissue swelling (arrows) following anterior cervical diskectomy and fusion surgery using rhBMP-2. (Reproduced with permission from Smucker JD, Rhee JM, Singh K, Yoon ST, Heller JG: Increased swelling complications associated with off-label usage of rhBMP-2 in the anterior cervical spine. Spine [Phila Pa 1976] 2006;31[24]: 2813-2819.)

Data are few on the effects of rhBMP-2 and its level of carcinogenicity or its effects in the setting of active malignancy or infection. BMP receptors are known to be found on the cell membrane of certain cancer cell lines.33-35 In their systematic review evaluating rhBMP-2 and its association with primary and metastatic cancer, Thawani et al36 found “no definitive association between BMPs and the promotion of tumorigenesis or metastasis.” However, these authors stated in their conclusion that “rhBMP-2 and rhBMP-7 are contraindicated for use in patients with cancer requiring spinal fusion.”

The FDA reported in its study “notably increased cancer rates in the Amplify group”—almost a fourfold increase, with 9 new malignancies in the group of 239 Amplify patients (3.8%) but only 2 new malignancies in the control group of 224 (0.89%) at 24 months27 (Figure 4). At 60 months, the cancer rates increased to 5% for the Amplify group and 1.8% for the control group. However, few data are available evaluating the rates of cancer in the lower-dose applications of rhBMP-2, which are typically used for interbody and posterolateral fusions.

Figure 4:
Percentage of patients with new malignancies completing follow-up in the Amplify (high-dose bone morphogenetic protein-2; Medtronic, Memphis, TN) group compared with control group after surgery. BMP = bone morphogenetic protein. (Reproduced with permission from Carragee EJ, Hurwitz EL, Weiner BK: Carragee et al respond [in reply to: Dimar JR 2nd, Glassman SD, Burkus JK, Pryor PW, Hardacker JW, Carreon LY: Reply to “A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: Emerging safety concerns and lessons learned. Spine J 2011; 11 (11): 1082-1083] Spine J 2011;11 [11]:1083-1086.)

Safety concerns associated with the use of rhBMP-2 need further study. Because of the reported complications to date, as well as possible associations with carcinogenicity, rhBMP-2 may not be as safe as was initially believed.

Summary and Senior Author's Commentary

The senior author (J.K.) does not believe sufficient convincing data exist to warrant that rhBMP-2 should absolutely replace ICBG autograft as the benchmark in spinal fusion surgery. rhBMP-2 does, however, appear to be an effective product; it induces bone formation and consistently demonstrates comparable fusion rates and clinical outcomes compared with ICBG.

Although use of rhBMP-2 is seemingly safe in most patients, lingering safety issues associated with broad use of BMP have made me cautious. I believe it is now prudent to discuss the reported complications, as well as the association with cancer, with our patients so that informed consent issues do not arise. Although the issue of rhBMP-2 and cancer risks requires further study, one must realize that the use of ICBG has no potential risk for or association with cancer. Therefore, until we have more clinical data, the routine use of rhBMP-2 in every spine fusion is likely not safe. Surgeons should not give up on the art of ICBG harvest or stop teaching it to future spine surgeons.

In addition to the reported risks of using rhBMP-2, we must also be mindful of the cost of BMP technology. When the clinical outcomes are comparable (not superior), is it worth expending an additional $5,000 to every lumbar fusion surgery by using rhBMP-2 rather than undertaking ICBG? Furthermore, whether one uses rhBMP-2 or ICBG may be moot unless we, as spine surgeons, have more clearly defined the actual indications for a fusion itself. With good indications based on evidence-based medicine, the patient will have a very good chance for a successful outcome whether rhBMP-2 or ICBG is used. Meticulous surgical technique in preparing the fusion bed is probably more important for a successful clinical fusion than the actual issue of a grafting agent.

I use rhBMP-2 for complex revision fusion surgery where no more ICBG harvest is available or in very challenging hosts, such as smokers and diabetics—but not routinely. In these particular instances, the cost and effectiveness of using rhBMP-2 are potentially justified. I still routinely make use of ICBG in most of my patients, and I am willing to accept a certain rate of known complications associated with it. I have never used rhBMP-2 in anterior cervical spine surgery. I have never used it in a patient with a history of cancer.

Finally, it is my opinion that the predominant reason for avoiding ICBG is that it is simply more convenient and less work for the surgeon. We surgeons are all occasionally guilty of using new technology in the operating room because of convenience when, in fact, doing so may have no bearing on surgical outcomes.


Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 28 is a level I study. References 14, 16, 18, and 21 are level II studies. References 5-7, 9, 15, 17, 19, 20, 22, 25, and 29 are level III studies. References 10, 23, 24, 26, 31, 32, and 36 are level IV studies. References 4, 11-13, and 30 are level V expert opinion.

References printed in bold type are those published within the past 5 years.

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24.Robin BN, Chaput CD, Zeitouni S, Rahm MD, Zerris VA, Sampson HW: Cytokine-mediated inflammatory reaction following posterior cervical decompression and fusion associated with recombinant human bone morphogenetic protein-2: A case study.Spine (Phila Pa 1976)2010;35(23): E1350-E1354.
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