We appreciate all of the comments from Dr.Smoljanovic and colleagues. It is clear from their comments that they have given this topic substantial consideration, particularly regarding vertebral osteolysis following the use of rhBMP-2 for interbody fusion. We recognize the point that the authors made in a previous letter to the editor in Spine (1) regarding the findings of Burkus et al (2). In that letter, the authors identify a figure from the paper by Burkus et al (2) in which there appears to be vertebral osteolysis at 6 months follow up that went unreported (1). The findings that we presented in this article, however, were based on the original, peer-reviewed publications by Burkus et al. (2, 3, 4). The writing of our paper predates the publication of this previous letter to the editor as well as many of the references cited in the current letter, two of which are still in press. We realize that additional information regarding the use of BMP in lumbar fusion surgery is available since the writing of our paper (i.e. October/November of 2007).

In regard to the incidence of vertebral osteolysis, Smoljanovic et al.point out that other studies suggest that vertebral osteolysis following the use of rhBMP-2 is far more common than the incidence that we quoted (7% to 18%). The papers referenced by the authors, however, have significant limitations that should be noted in regard to the incidence of vertebral osteolysis. McClellan et al (5) reported on 26 patients who underwent TLIF over a 16 months period by 7 spine surgeons at the same institution. One significant limitation, however, is that the study included only those patients who underwent postoperative CT scan. The study does not state how many patients underwent TLIF procedures over this 16 month period by the 7 participating surgeons who did not have postoperative CT scan and therefore were not included in the study. It is likely, given the time period and the number of participating surgeons, that this number is far greater than the 26 patients who were included in the study. One could argue that those who underwent postoperative CT scan are more likely to have had a problem after surgery (e.g. vertebral osteolysis) compared to those who did not get a postoperative CT scan. Therefore, the reported incidence of vertebral osteolysis by McClellan et al (5) is likely not accurate for the entire group of TLIF patients and may be an overestimate. The study referenced by Vaidya et al (6) evaluated vertebral osteolysis using plain radiographs. However, osteolysis can be difficult to see on plain radiographs. This is especially true for TLIFs performed at the L5-S1 level, due to the overlap of the ileum on the radiographs. In the study by Vaidya et al, over 50% of the TLIF patients had surgery at the L5-S1 level. Indeed, the authors of this letter to the editor state that CT scan rather than plain radiography should be used to assess for vertebral osteolysis.

Smoljanovic et al. are mistaken when they suggest that we associate repeat exposure to BMP with postoperative radiculitis, vertebral osteolysis and edema, and neurocompressive ectopic bone. We actually stated very clearly that there is no clinical evidence that re-exposure to BMP is detrimental and we reference the study by Carreon et al (7) that studied cases of BMP re-exposure and found no added morbidity. The authors of this letter also strongly disagree with the notion that the pathophysiology and relevance of vertebral osteolysis is not currently well understood. They correlate the amount of vertebral osteolysis with the area of contact between the BMP/absorbable collagen sponge and cancellous bone. The references that this statement is based on include three review papers, one of which is still in press. We did acknowledge in our paper that there may be an association between vertebral osteolysis and violation of the endplate and exposure of the underlying cancellous bone to the BMP. Studies also suggest that BMP stimulates osteoclastic activity, which may contribute to osteolysis (8, 9). Although there is a large amount of animal data on the use of BMP, including the study referenced in this letter that uses a nonhuman primate long-bone defect model (10), animal studies that specifically address the issue of vertebral osteolysis and BMP use and definitively describe the pathophysiology of this process are lacking. We recognize that vertebral osteolysis following the use of BMP in interbody fusion represents an important issue that may be more common than we realize. Fortunately, most studies report that it is a self-limiting process that eventually leads to a successful fusion. It nonetheless warrants further basic science and clinical study.

References

1. Smoljanovic T, Pecina M. Re: Burkus J K, Transfeldt E E, Kitchel S H, et al. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine 2002;27:2396-408. Spine. Jan 15 2008;33(2):224.

2. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. Oct 2002;15(5):337-349.

3. Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine. Nov 1 2002;27(21):2396-2408.

4. Burkus JK, Sandhu HS, Gornet MF. Influence of rhBMP-2 on the healing patterns associated with allograft interbody constructs in comparison with autograft. Spine. Apr 1 2006;31(7):775-781.

5. McClellan JW, Mulconrey DS, Forbes RJ, Fullmer N. Vertebral bone resorption after transforaminal lumbar interbody fusion with bone morphogenetic protein (rhBMP-2). J Spinal Disord Tech. Oct 2006;19(7):483-486.

6. Vaidya R, Sethi A, Bartol S, Jacobson M, Coe C, Craig JG. Complications in the use of rhBMP-2 in PEEK cages for interbody spinal fusions. J Spinal Disord Tech. Dec 2008;21(8):557-562.

7. Carreon LY, Glassman SD, Brock DC, Dimar JR, Puno RM, Campbell MJ. Adverse events in patients re-exposed to bone morphogenetic protein for spine surgery. Spine. 2008;33(4):391-393.

8. Wutzl A, Brozek W, Lernbass I, et al. Bone morphogenetic proteins 5 and 6 stimulate osteoclast generation. J Biomed Mater Res A. Apr 2006;77(1):75-83.

9. Okamoto M, Murai J, Yoshikawa H, Tsumaki N. Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res. Jul 2006;21(7):1022-1033.

10. Seeherman H, Wozney JM. Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev. Jun 2005;16(3):329-345.

To the Editor:

We wish to point out several inaccuracies in the recent review by Rihn et al. about the use of recombinant human bone morphogenetic proteins (rhBMP) in lumbar spine surgery (1).

As we pointed out in a previous letter to the editor(2), the dose of rhBMP-2 used per level of lumbar interbody fusion (LIF) was decreased by 30% between the cited studies (3,4)even though the publications reported two sequential phases of a Level I study conducted under strict control of the Food and Drug Administration.

We also disagree with the authors (1) that no transient vertebral osteolysis was associated with the use of rhBMP-2 in the first phase, as unreported vertebral resorption has been identified (5) at CT scans 6 months after rhBMP-2 application (Figure 10) (4). An analysis by our group(6) of reported transient vertebral resorption revealed that patients in whom the resorption developed after rhBMP-2 application in LIF were often susceptible to spacer subsidence, loss of correction, graft migration and the failure of spinal interbody fusion even with additional stabilization of fused levels.(6).What is of interest is how such large resorptions (5) were not associated with any spacer subsidence or loss of correction, especially as no additional instrumentation was used (3,4). Two papers report an incidence of resorption after LIF assisted by rhBMP-2 that is substantially higher than the 7% (7) and 18% (3,8) mentioned by Rihn et al. (1). In addition, McClellan et al. and Vaidya et al. reported an incidence of 69% (9,10), while most recently Vaidya et al. reported an incidence of 82% (11).

Furthermore, Rihn et al.(1) associated repeat BMP exposure with postoperative radiculitis, vertebral osteolysis and edema, and neurocompressive ectopic bone. We do not know how many patients have actually experienced repeat BMP exposure to date, but the analysis of the resorptions revealed that the size of the contact surface between rhBMPs soaked into an absorbable collagen sponge (rhBMPs/ACS) and trabecular bone was responsible for occurrence and clinical manifestations of the resorptions (6,12).The clarification of the finding was offered by Seeherman and Wozney who have shown that rhBMP-2/ACS placed in contact with trabecular bone of the distal femoral core defect in nonhuman primates resulted in significant transient bone resorption at 2 weeks after the surgery (13). This was not the case when a carrier with a slower release of rhBMP (calcium phosphate matrix) was used. The rapid release of rhBMPs at the bone surface which is in contact with the collagen sponge creates favorable conditions for significant osteoclastic reaction prior to the bone formation phase.

Finally, we disagree strongly that the pathophysiology and relevance of the vertebral osteolysis are unknown (1). To avoid occurrence of clinically significant resorption during lumbar interbody fusion(LIF), surgeons should avoid creation of larger contact surfaces between rhBMPs/ACS and trabecular bone. If this is not possible because of the nature of the procedures, manufacturers should consider introducing new carriers with slower initial release of rhBMPs for applications in proximity of trabecular bone. Until then, patients who undergo LIF assisted with rhBMP-2/ACS should be followed using the recently clarified (14) CT scan protocol (15). Although the main determinations of final outcome are the size of the area under the resorptions and the stability of additional spinal instrumentation, early CT scans will detect or confirm the resorptions in the lumbar area even in asymptomatic patients which will allow restriction of activity in such patients until the bone formation phase overtakes the osteoclastic reaction (14).

The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

References

1. 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;90:2014-25.

2. Smoljanovic T, Pecina M. Unexplained decreasing of rhBMP-2 dose. J Bone Joint Surg Am. Electronically published letter. 23rd October 2007. Available from: http://www.ejbjs.org/cgi/eletters/87/6/1205#5117.

3. Burkus JK, Sandhu HS, Gornet MF. Influence of rhBMP-2 on the healing patterns associated with allograft interbody constructs in comparison with autograft. Spine. 2006;31:775-81.

4. Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine. 2002;27:2396-408.

5. Smoljanovic T, Pecina M. Re: 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;27:2396-408. Spine. 2008;33:224.

6. Smoljanovic T, Bicanic G, Bojanic I. Update of comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery. 2009;In press.

7. Lewandrowski KU, Nanson C, Calderon R. Vertebral osteolysis after posterior interbody lumbar fusion with recombinant human bone morphogenetic protein 2: a report of five cases. Spine J. 2007;7:609-14.

8. Burkus JK, Sandhu HS, Gornet MF, Longley MC. Use of rhBMP-2 in combination with structural cortical allografts: clinical and radiographic outcomes in anterior lumbar spinal surgery. J Bone Joint Surg Am. 2005;87:1205-12.

9. McClellan JW, Mulconrey DS, Forbes RJ, Fullmer N. Vertebral bone resorption after transforaminal lumbar interbody fusion with bone morphogenetic protein (rhBMP-2). J Spinal Disord Tech. 2006;19:483-6.

10. Vaidya R, Weir R, Sethi A, Meisterling S, Hakeos W, Wybo CD. Interbody fusion with allograft and rhBMP-2 leads to consistent fusion but early subsidence. J Bone Joint Surg Br. 2007;89:342-5.

11. Vaidya R, Sethi A, Bartol S, Jacobson M, Coe C, Craig JG. Complications in the use of rhBMP-2 in PEEK cages for interbody spinal fusions. J Spinal Disord Tech. 2008;21:557-62.

12. Smoljanovic T, Grgurevic L, Jelic M, Kreszinger M, Haspl M, Maticic D, Vukicevic S, Pecina M. Regeneration of the skeleton by recombinant human bone morphogenetic proteins. Coll Antropol. 2007;31:923-32.

13. Seeherman H, Wozney JM. Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev. 2005;16:329-45.

14. Smoljanovic T, Bojanic I, Dapic T. Significance of Early CT Evaluation after the Lumbar Interbody Fusions Assisted with rhBMP-2. Am J Neuroradiol. 2009;In press.

15. Williams AL, Gornet MF, Burkus JK. CT evaluation of lumbar interbody fusion: current concepts. AJNR Am J Neuroradiol. 2005;26:2057-66.