Steven Glassman charts the development of bone morphogenetic proteins (BMPs) and their use in spinal procedures, as well as current and future uses.
BMP was discovered by Marshall Urist, and first reported in Science in 1961. A company named Genetics Institute ultimately isolated the protein, and recombinant BMP was first manufactured in 1989. Over the next 10 years, extensive basic science and animal research was undertaken to determine the appropriate carrier, delivery mechanism, dose and concentration for clinical use in spinal fusion.
The preparatory animal studies were most successful for anterior interbody fusion and a subsequent US Food and Drug Administration (FDA) trial led to the approval of Infuse Bone Graft in combination with LT cages for L5-S1 anterior interbody fusion. Animal models for posterolateral fusion turned out to be more difficult and, in particular, primate studies suggested that posterolateral fusion would require a different carrier and a significantly greater dose and concentration of BMP as compared to anterior interbody fusion.
With the clinical availability of BMP, usage increased rapidly. Not surprisingly, most of the BMP usage was not for anterior interbody fusion, but for the more commonly performed posterior procedures, including posterolateral fusion and TLIF. Within a few years, BMP was used in a very substantial percentage of the lumbar fusion procedures performed across the country. Despite using the clinically available dose and concentration intended for single level anterior interbody fusion, initial reports indicated acceptable posterior fusion rates, even in multilevel procedures.3
With wider use of BMP, a number of complications were more frequently observed. By and large, these complications reflected the underlying activity of the protein. BMP induces rapid bone turnover, and while this generally results in fusion healing, an initial period of osteolysis was sometimes observed. This was most frequently problematic with anterior fusion using femoral ring allografts, as the intrinsic stability of the construct was not sufficient to withstand the initial phase of osteolysis. BMP also has chemotactic properties, and thus complications related to oedema and swelling were noted. The most dramatic example of complications secondary to tissue swelling was in anterior cervical applications, where cases of respiratory distress, re-intubation and even death were reported.4 This resulted in an FDA black box warning against the use of BMP in the cervical spine.
Probably the most common complications were secondary to the intended effect of BMP, that is bone formation. Particularly in TLIF, BMP in and around the foramen or spinal canal occasionally resulted in bony overgrowth and, in some instances, significant neural compression. This appeared to be most common with minimally invasive approaches, where the desire for BMP to avoid bone grafting was greatest, but the very limited space led to concentration of the protein and a higher risk of bony overgrowth. At that time, surgeons seemed to be managing the complication profile effectively, using progressively smaller doses of BMP without obvious deterioration in fusion rate.5
In 2011, after nine years of widespread clinical use, BMP was clearly accepted as a treatment option for spinal fusion surgery. Surgeons seemed well aware of the risk profile and, in particular, BMP use in the cervical spine was a controversial topic. There was also an obvious trend toward smaller doses for most applications. The primary concern, however, was cost. There was certainly discussion about the need to better define those procedures for which BMP might be both efficacious and cost-effective, but there was little evidence that surgeons were modulating their BMP usage on that basis.
The landscape around BMP use changed dramatically with the publication of a special edition of The Spine Journal dedicated to BMP in June 2011. In peer reviewed articles and editorial comment, this edition of The Spine Journal stated that the complications associated with BMP were orders of magnitude greater then had been previously reported.6 Of particular impact, one article suggested that the use of BMP was associated with the development of cancer.7 These findings were reported widely in the lay press, and BMP use dropped precipitously.
Over subsequent years, extensive resources were dedicated to a re-examination of existing BMP data as well as in-depth study of the known BMP complications.8,9 This work largely confirmed earlier literature, and contradicted the dramatic assertions of an under-reported or inaccurately described complication profile. Large database studies comparing spinal fusion procedures with and without BMP validated the concern for increased complications in the anterior cervical spine, but demonstrated no difference in complication rate for posterior cervical, thoracolumbar, or lumbar applications.10 Further, multiple studies from a variety of large databases, as well as the National Cancer Institute, demonstrated no relationship between BMP and the development of cancer.11,12 Similarly, a large single-center analysis of adult deformity patients treated with very high doses of BMP also found no increase in cancer rates.13
So where are we after what turned out to be largely a false alarm, and then another 10 years of BMP availability? At present, BMP use has rebounded to approximately 90% of the frequency reported prior to 2011 on a per-case basis, although the dose per case is significantly lower. The most well accepted indications are anterior interbody fusion (the “on-label” indication), adult spinal deformity and pseudarthrosis. For adult spinal deformity, there is some evidence that BMP in modest doses may be cost-effective, based upon the frequency of pseudarthrosis and the high cost of revision in those patients.
As has always been the case, BMP is most commonly used for posterior degenerative lumbar indications. For posterolateral fusion, the risks are low and the literature suggests cost-effectiveness for older patients undergoing multilevel fusion.14 For TLIF, the underlying nonunion rate is lower and the risk for radiculopathy secondary to ectopic bone formation is slightly higher, so demonstrating a cost–benefit advantage will be more difficult. On the flip side, the cost trade-off may be worthwhile in MIS-TLIF if disc preparation is suboptimal or risk for pseudarthrosis is elevated.
BMP use in the cervical spine is less common. Although the significant complications that led to the FDA black box warning were essentially all in the anterior cervical spine, the warning covers cervical use in general. This may certainly be a deterrent. Some surgeons are using very small doses of BMP, and also adding a sealant over the disc space for multilevel ACDF. For me, the risk outweighs the benefit. The safety profile for posterior cervical applications appears more benign, and could be weighed against patient specific risk factors and the difficulty of accessing the iliac crest in some instances.
As was the case in 2010, the decision-making process around BMP for spinal fusion in 2020 is primarily a cost–benefit analysis. There is mounting experience, and a little bit of evidence, suggesting that smaller doses are effective.15 That would obviously help the cost–benefit equation. Ongoing research into BMP binding proteins and other adjunctive strategies raises the possibility that even smaller doses may be a viable alternative in the future.16 The effectiveness of new alternatives based upon implant materials, surface coatings, or biologic strategies are all under study. It seems a little bit ironic that the question surgeons ask at this point is not “how does the fusion rate compare to iliac crest graft?”, but rather, “how does the fusion rate compare to BMP?”
Steven Glassman is the managing director of Orthopaedic Surgery at Norton Healthcare, Louisville, USA, and a former president of the Scoliosis Research Society (SRS).
- Urist MR. Bone: formation by autoinduction. Science. 1965; 150 (3698): 893–9
- Burkus JK, Transfeldt EE, Kitchel SH, et al. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine 2002; 27(21): 2396–408
- Glassman SD, Carreon LY, Campbell MJ, et al. The perioperative cost of Infuse bone graft in posterolateral lumbar spine fusion. Spine J. 2008; 8(3): 443–8.
- Shields LB, Raque GH, Glassman SD, et al. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine. 2006; 1;31(5): 542–7.
- Mannion RJ, Nowitzke AM, Wood MJ. Promoting fusion in minimally invasive lumbar interbody stabilization with low-dose bone morphogenic protein-2-but what is the cost? Spine J. 2011; 11(6): 527–33.
- Carragee EJ, Ghanayem AJ, Weiner BK, et al. A challenge to integrity in spine publications: years of living dangerously with the promotion of bone growth factors. Spine J. 2011;11(6): 463–8.
- Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011; 11(6): 471–91.
- Fu R, Selph S, McDonagh M, et al. Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med. 2013; 158(12): 890–902.
- Simmonds MC, Brown JV, Heirs MK, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med. 2013; 158(12): 877–89.
- Cahill KS, McCormick PC, Levi AD. A comprehensive assessment of the risk of bone morphogenetic protein use in spinal fusion surgery and postoperative cancer diagnosis. J Neurosurg Spine. 2015; 23(1): 86–93.
- Beachler DC, Yanik EL, Martin BI, et al. Bone morphogenetic protein use and cancer risk among patients undergoing lumbar arthrodesis: A case-cohort study using the SEER-Medicare database. J Bone Joint Surg Am. 2016; 98(13): 1064–72.
- Kelly MP, Savage JW, Bentzen SM, et al. Cancer risk from bone morphogenetic protein exposure in spinal arthrodesis. J Bone Joint Surg Am. 2014; 96(17): 1417–22.
- Mesfin A, Buchowski JM, Zebala LP, et al. High-dose rhBMP-2 for adults: major and minor complications: a study of 502 spine cases. J Bone Joint Surg Am. 2013; 95(17): 1546–53.
- Glassman SD, Howard J, Dimar J, et al. Complications with recombinant human bone morphogenic protein-2 in posterolateral spine fusion:a consecutive series of 1,037 cases. Spine. 2011; 36(22): 1849–54.
- Lytle EJ, Slavnic D, Tong D, et al. Minimally effective dose of bone morphogenetic protein in minimally invasive lumbar interbody fusions: Six hundred ninety patients in a dose-finding longitudinal cohort study. Spine. 2019; 44(14): 989–995.
- Refaat M, Klineberg EO, Fong MC, et al. Binding to COMP reduces the BMP2 dose for spinal fusion in a rat model. Spine. 2016; 41(14): E829–36.