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Pseudomorbidity in iliac crest bone graft harvesting: the rise of rhBMP-2 in short-segment posterior lumbar fusion
The Spine Journal 9 (2009) 873–879
Editorial
Pseudomorbidity in iliac crest bone graft harvesting: the rise of rhBMP-2 in short-segment posterior lumbar fusion Eugene J. Carragee, MDa,*, Christopher M. Bono, MDb, Gaetano J. Scuderi, MDc a
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA b Orthopedic Spine Service, Brigham and Women’s Hospital, Boston, MA 02478, USA c Department of Orthopaedic Surgery, Stanford University Hospital and Clinics, Stanford, CA 94305, USA Received 1 September 2009; accepted 9 September 2009
Readers of this month’s issue will find three articles commenting upon the possible morbidity associated with autologous grafting procedures [1–3]. One [1] discusses a large experience using autologous fibula grafting for cervical reconstruction after corpectomy. In this study, it is clear that the autologous technique has serious and frequent problems. The other two studies in this issue [2,3] look at the most common cited complication associated with posterior iliac crest bone graft (ICBG) harvesting, pain. Taken as part of a larger trend in spine surgery, it can be seen that autologous bone, long considered the ‘‘gold standard’’ for promoting spinal fusion, is having its foundation deconstructed. In many practices, autologous grafting techniques have been replaced by alternative sources of commercially prepared osteoinductive and/or osteoconductive materials. The articles in this issue again point out the suspected serious problems of donor site morbidity and its relative risk in this time of commercial alternatives. The studies in this issue of The Spine Journal address the hypothesis that donor site morbidity is a serious problem that can be prevented through the use of these commercially available substitutes.
This Editorial was reviewed by The Spine Journal deputy editors Dr. Paul Bishop, Dr. Conor O’Neill, Dr. Daniel Resnick, Dr. Jeffrey Wang, and Dr. Bradley Weiner, who approved its content. FDA device/drug status: not applicable. Author disclosures: EJC (stock option, Simpricia, Bioassetts, Cytonics; private investments, Simpricia; consulting, Medtronic, Synthes; trip/travels, US Army; scientific advisory board, Intrinsic Orthopedics, Cytonics; other office, Bioassetts; grants, AO Foundation; fellowship grant, Depuy Spine); CMB (royalties, Life Spine; consulting, Depuy Spine, Medtronic Sofamar Danek; speaking/teaching arrangements, Depuy Spine, Stryker Spine; board of directors, North American Spine Society; other office, Applied Spine; research support, Archus Orthopedics, Synthes Spine; grants, Stryker Spine; fellowship support, Depuy Spine); GJS (stock ownership, Cytonics; private investments, K2 Medical; board of directors, Cytonics; scientific advisory board, Cytonics). * Corresponding author. Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway, Mail Code 6342, Redwood City, CA 94063,USA. Tel.: (650) 721-7607; fax: (650) 721-3470. E-mail address: [email protected] (E.J. Carragee). 1529-9430/09/$ – see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.spinee.2009.09.001
We wonder, however, if there is a sound scientific basis to justify the large-scale shift away from autogenous grafting in the most common scenariodone- and two-level posterior lumbar fusion. After considering the evidence, which we review in this editorial, we believe that the literature does not support a finding of significant morbidity with this technique, and the recent, widespread shift to commercial alternates is unwarranted and ill-advised. Structural fibular autograft Perhaps the use of large segment fibula strut grafts is the easiest case to analyze. The article by Nassr et al. [1], ‘‘Donor-site complications of autogenous nonvascularized fibula strut-graft harvest for anterior cervical corpectomy and arthrodesis in 163 consecutive cases,’’ focuses on the experience of the senior author in a series of patients with multilevel stenosis and myelopathy. These authors report functionally impairing donor site complications, so much so that the senior author no longer regularly uses this technique. Complications such as tibial stress fractures, ankle instability, and neuromas were reported. Five patients (3%) underwent additional surgery, secondary to complications directly related to the donor site. Cellulitis was seen in 9% of patients. Five patients (3%) developed a tibial stress fracture that necessitated immobilization. This study confirms previous reports of donor site morbidity from fibular graft harvesting [4]. Although fibula autograft may allow complete incorporation that is not frequently seen with allograft [5,6], the authors suggest that large structural autograft will have an increasingly limited role because of donor site morbidity and the availability of commercial alternatives. We certainly agree with their assessment.
Suspected donor site morbidity and the declining use of iliac crest autograft On the other hand, two papers reporting on the suspected morbidity of harvesting nonstructural ICBG for common
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short-segment lumbar fusions, in our opinion, rests on much weaker and flawed evidence. Certainly, the older literature concerning long-segment fusions for deformity, neuromuscular disease in patients with pelvic dysplasia, or repeated harvesting for spinal nonunions noted serious, and sometimes catastrophic, graft site complications. These clinical scenarios were once common in managing the postpolio deformities after the epidemics in the 1930s, 1940s, and 1950s. The risks in these situations are well recognized. Today, most spinal fusion is performed in a much healthier group, usually with little or no pelvic dysplasia, and requires much smaller ICBG volumes. Furthermore, modified and less destructive techniques in obtaining ICBG have fewer complications and higher satisfaction rates [7]. These techniques include using a more vertically oriented incision (to reduce cluneal nerve injury) or a single incision for graft harvesting and low lumbar exposure [8,9]. Serious complications in these settings can be as low 0.7% [10] Nonetheless, the rate of ICBG use relative to commercial substitutes has sharply declined. Although data on crest graft usage are not comprehensive, the trend seems to be down, and the use of alternative methods, particularly recombinant human bone morphogenetic protein-2 (rhBMP-2), has risen dramatically. Between 2002 and 2006, the use of bone morphogenetic protein has increased from !1% of fusion procedures in the United States to 25%. rhBMP appears to be used in nearly 40% of lumbar fusions [11]. Remarkably, in 2006, 85% of the bone morphogenetic protein use was in one- or two-level fusions. Supporting this trend, the article by Kim et al. [2], entitled ‘‘Prospective study of iliac crest bone graft harvest site pain and morbidity,’’ in this issue of The Spine Journal, focuses on complications after ICBG harvesting in a cohort of 104 patients. The authors reported significant ‘‘functional limitations’’ associated with pain in the area of the ICBG harvest site. At one year after surgery, this was reported in 6% to 15% of patients depending on the activity examined. Purportedly, all of the pain and dysfunction in this region was exclusively because of the bone graft harvesting. These rates of functional limitation were noted to be higher than those previously reported [12]. Other investigators have also identified subjective complaints around the donor site area, including functional limitations in ambulation, work, and activities of daily living [13–15]. They relate all these symptoms to the donor site, per se. Also in this issue, Dimar et al. [3] report that 60% of 224 patients undergoing ICBG harvesting for single-level fusions ‘‘complained of graft site pain’’ 2 years after surgery. Closer review shows that this pain was ‘‘elicited by palpating for tenderness over both posterior iliac crests.’’ It is not clear what the pain level was with this maneuver on the contralateral side or whether this finding, a common ‘‘trigger point’’ in patients with degenerative lumbar pathology, was actually present before surgery. Despite this ‘‘provocative’’ examination, the pain level was modest. At 3 months after surgery, the pain
level was 6.3 on a 20-point scale. The rate of wound complications at the graft site was less than 1%. Despite harvesting extremely small quantities of ICBG in some patients (as little as 7 cm3) [16], the fusion rate was fairly good. Using several methods to assess intertransverse process fusion rates, 84% to 90% of the spines appeared to have solidly fused using ICBG alone. It is very important to note that in the Dimar et al. study [16], all local autologous bone graft was actually discarded by the study surgeons. In the degenerative spine, this is often a substantial quantity of good bone graft material. Also by protocol, a formal facet arthrodesis was not required, and bone graft was not impacted into a prepared joint space. The wasting of perfectly good bone graft material and the failure to perform a meticulous facet arthrodesis (although perhaps appropriate in a research study) are very dubious practices in real life. This protocol, without doubt, handicaps the fusion outcome in these study subjects compared with usual practice. We doubt if surgical outcomes in this group reflect those that would be achieved using more standard arthrodesis techniques [17].
Unvalidated donor site pain assessment Still, it remains unclear if the pain and functional limitations referred to the gluteal area in these studies are, in fact, because of residual donor site problems. It seems clear that pain in this region may also be because of continued preoperative gluteal pain or new gluteal pain referred from new spinal pathology (nonunion, instrumentation complications, adjacent segment pain, etc) or pain that is secondary to sacroiliac pain associated with changing gait mechanics or arthritis. As mentioned, a criticism of these studies is that neither was there an attempt to determine the preoperative level of gluteal area pain and perceived impairment nor was postoperative pain assessed for the contralateral gluteal area, which may have been the same as, or greater than, that on the harvested side. In addition, neither the patient nor the examiner appears to have been blinded to the side where the crest graft was taken. The authors also did not report the incidence of clinical or radiographic sacroiliac joint disease in these cohorts having low lumbar fusion. All these variables may be confounding factors associated with continued gluteal pain after lumbar surgery. Other authors have attempted to distinguish continued low back pain from graft site pain [18–22]. Fernyhough et al. [18] noted difficulty in differentiating donor site pain from other possible pain generators. They found that significant possible harvest site pain was less frequent in those patients undergoing fusion surgery for stenosis compared with ‘‘degenerative disc disease.’’ Delawi et al. [19] reported more than three times the rate of donor site area pain in those patients undergoing iliac crest graft for low (L3– S1) compared with high (T2–L2) spine fusions. That is, patients undergoing ‘‘high’’ fusion, with little chance of
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referred spinal pain to the harvest site area, had significantly less pain, compared with the group undergoing a ‘‘low’’ spinal fusion (14% vs. 41%). Another prospective study found that pain near the harvest site was reported more frequently after lumbar fusion compared with cervical or thoracic procedures, again underlining the difficulty in delineating pain from surgery or donor site. [20]. A recent study of 92 patients who had ICBG harvested from one posterior crest looked at pain diagrams with Visual Analog Scale measures over both crests. They found that 74 patients (80%) had no reported difference in pain between the ICBG site and the contralateral side. Of patients with more pain on one side than the other, there was no significant difference in the proportion having greater pain on the ICBG site [21]. These data suggest that the self-reported pain about the iliac crest after lumbar surgery, as described in this issue of The Spine Journal, is unlikely to be exclusively a result of ICBG harvesting. Still, suppose one was to assume the highest estimate by Kim et al., 15% impairment due to gluteal pain ipsilateral to the harvesting site, is accurate [2]. And suppose, as an estimate, that 25% to 50% of that impairment burden is due solely to the bone graft harvesting (a very generous estimate). This would mean that if an equally effective bone graft alternative were used, the number needed to treat to prevent just one significant bone graft harvesting complication would be between 14 and 28, an extremely small effect size. That is, most patients would receive no benefit from switching to the alternative method. And yet, the best evidence would suggest that even that estimate is too high.
Best evidence: randomized clinical trials The most compelling argument against a clinically important morbidity from ICBG harvesting for short-segment posterior lumbar fusions is found in multiple randomized controlled trials. The best evidence from randomized clinical trials [16,23–26] consistently show that there is little, if any, negative clinical effect from taking ICBG for posterior-lateral fusion. This has been pointed out by Kang [27] and Papakostidis et al. [28]. There have been three Food and Drug Administration– regulated, randomized, nonblinded investigational device exemption trials of rhBMP-2 matrix for posterolateral lumbar spinal fusion compared with ICBG [16,24,25] and one comparing osteogenic protein-1 (OP-1) with ICBG [29]. In no study was there any significant increase in back pain scores or functional disability at any time after surgery for those subjects undergoing the ICBG harvesting (Figs. 1–4). This is a remarkably consistent and astonishing finding for a procedure purported to be so painful and disabling. If the ICBG harvesting has any deleterious effect, it did not appear to affect postoperative pain, function, or occupational activities in the best comparative trials we
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Fig. 1. Randomized clinical trialdsmokers vs. non-smokers: (Top) the mean back pain Visual Analog Scale (VAS) and (Bottom) the mean leg pain VAS of smokers and nonsmokers undergoing fusion with iliac crest bone graft (ICBG) or recombinant human bone morphogenetic protein-2. At no point is the back or leg pain symptoms significantly worse in patients having ICBG harvesting. Note that in the ICBG group, all local autograft harvested were discarded, and facet fusions not performed. From Glassman SD, Dimar J III, Burkus K, et al. The efficacy of rhBMP-2 for posterolateral lumbar fusion in smokers. Spine 2007;32:1693–8. Copyright 2007 Lippincott Williams & Wilkins [26].
have. Multiple randomized controlled trials, all showing the same finding of no apparent increase in clinical problems from the ICBG harvesting, is strong Level 1 evidence. Even a close examination of very early pain and function scores (6 weeks to 3 months after lumbar fusion), as reported in the rhBMP-2 versus ICBG trials (Figs. 1–4), fails to show the expected early effect of ICBG harvesting. Fig. 1 shows that the best back and leg pain scores at 6 weeks postoperation is actually in the ICBG (nonsmoker) group. Again, in Fig. 4, there is slightly greater disability in the rhBMP-2 group at 6 weeks. Unless the rhBMP has some independent early morbidity, we would expect the ICBG group to have, at the very least, worse scores for 1 or 2 months as the ICBG site heals. These findings suggest that the rhBMP may, in fact, have a clinically deleterious effect in the early postoperative period. As previously
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Fig. 2. Randomized clinical trail in subjects older than 60 years: (Top) the mean back pain Visual Analog Scale (VAS) and (Bottom) the mean leg pain VAS of the older subjects undergoing fusion with iliac crest bone graft (ICBG) or recombinant human bone morphogenetic protein-2. At no point is the back or leg pain symptoms significantly worse in patients having ICBG harvesting. Note that in the ICBG group, all local autograft harvested were discarded, and facet fusions not performed. From Glassman SD, Carreon LY, Djurasovic M, et al. RhBMP-2 versus iliac crest bone graft for lumbar spine fusion: a randomized, controlled trial in patients over sixty years of age. Spine 2008;33:2843–9. Copyright 2008 Lippincott Williams & Wilkins [24].
reported with rhBMP-2 use in other spinal surgery approaches, this early effect is possibly because of local inflammatory effects in the wound or neuroinflammatory effects at the nerve roots [11,30–34]. Finally, data regarding the purported harvest site pain in some randomized clinical trials have extremely poor face validity. Fig. 5, bottom from the randomized controlled trial by Vacarro et al. [29], comparing ICBG with OP-1, shows the prevalence of pain, supposedly a result of ICBG harvesting for lumbar fusion. These authors report a decrease in pain around the harvest site over the first 3 months followed, paradoxically, by a dramatic increase in pain at 6 and 9 months. This finding is inconsistent with expected bone and soft tissue
Fig. 3. Randomized clinical trial comparing an ‘‘optimized recombinant human bone morphogenetic protein-2 formulation’’ with iliac crest bone graft (ICBG). (Top) The Oswestry Disability Index (ODI) and (Bottom) back pain scores show no significant clinical effect of ICBG harvesting at any time point after surgery. Note that in the ICBG group, all local autograft harvested were discarded, and facet fusions not performed. From Dimar JR II, Glassman SD, Burkus JK, et al. Clinical and radiographic analysis of an optimized rhBMP-2 formulation as an autograft replacement in posterolateral lumbar spine arthrodesis. J Bone Joint Surg Am 2009;91:1377–86. Copyright owned by The Journal of Bone & Joint Surgery [16].
healing and strongly suggests that increases in pain are primarily related to the lumbar spine or other factors. Ahlmann et al. [7], reporting on complications and pain after large-volume (mean 55 ml) posterior iliac crest harvesting for limb salvage procedures, found no cases of persistent donor site pain in 42 consecutive subjects. Similarly, one of us (EJC) has closely followed subjects, without any baseline low back pain symptoms, who underwent ICBG harvesting (for nonlumbar problems) as part of a prospective study of discography in asymptomatic subjects [35,36]. Fig. 5, top shows the reported prevalence of moderate or severe iliac crest donor site pain after harvesting in subjects treated for nonlumbar conditions. Pain around the ICBG site appears to taper down to general population (moderate/severe) levels within 6 months after harvesting.
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Fig. 5. (Top) Expected and conventional decline in donor site pain in patients having iliac crest bone graft harvesting for nonlumbar spine problems (eg, C1–C2 fusion, femoral nonunion). By 6 months, pain in gluteal area approximates LBP prevalence in the general population. (Bottom) Paradoxical decrease followed by increase in ‘‘donor site pain’’ 3 months after lumbar surgery [29]. While bone graft site pain is seen to decrease to very low rates in nonspinal procedures, gluteal area pain increases with time after low back surgery.
Fig. 4. Randomized clinical trial of recombinant human bone morphogenetic protein-2 (on collagen sponge) compared with iliac crest bone graft (ICBG) (control) for single-level posterior-lateral fusion. Note even at 6 weeks after surgery, there is no apparent functional effect of having ICBG harvested. Note that in the ICBG group, all local autograft harvested were discarded, and facet fusions not performed. From Dawson E, Bae HW, Burkus JK, et al. Recombinant human bone morphogenetic protein2 on an absorbable collagen sponge with an osteoconductive bulking agent in posterolateral arthrodesis with instrumentation. J Bone Joint Surg Am 2009;91:1604–13. Copyright owned by The Journal of Bone & Joint Surgery [25].
The best evidence from these rigorously controlled trials suggest strongly that the later pain after lumbar surgery reported by Vacarro et al. [29] and others [2,3,13,16] is very unlikely a result of ICBG harvesting morbidity and more likely related to primary lumbar pathology.
At-risk patients, risks and costs We certainly recognize that autograft bone does represent a finite source of graft material. This is an important clinical concern in the multiply operated spine, the patient with serious risk factors for nonunion, and in the patient undergoing a long fusion. In addition, certain individuals with inflammatory or metabolic disease or complicating pharmacologic effects may be poor candidates for obtaining autologous graft. As previously mentioned, patients with developmental or neuromuscular disease may simply have inadequate anatomy for bone graft harvesting under any circumstances. The new commercially available substitutes
represent a great advance in caring for these patients. The basic science and clinical researchers who have pursued and achieved these goals have done valuable work and should be highly commended for their efforts. However, these clinical scenarios are the exception rather than the rule. These patients constitute a small minority of patients considering spinal fusion. Certainly, most primary lumbar fusions in adults are one- or two-level fusions without contraindications to bone graft harvesting. While iliac crest bone is available in limited amounts, so is money. Cost is an important consideration in using commercial bone graft alternatives. Direct costs are far greater when using rhBMP-2 or other substitutes [37,38]. For instance, the cost of rhBMP-2 ranges from $2,500 to $4,500 per level and involves increased hospital charges of 14% to 37% per patient. Although $9,000 just for rhBMP-2 may not seem to be much in the era of AIG bailouts and $40 million executive bonuses, it may pay to reflect that this is about 20% of the median household income in the United States for a full year of work. It is also important to understand that this money takes a slice out of a finite pie available for the care of many patients. Is this the best way to spend $10,000? Our patients often get such brief rehabilitation treatments, overstressed nursing care, and sometimes nearly absent home-care resources. If the typical surgeon had an additional $5,000 to $9,000 to improve the care of a single patient having a short-segment fusion, would a dose or two of rhBMP-2 be how we would really choose to spend it? Finally, and perhaps most importantly, the long-term risks from powerful growth factors are not clear at this time [11].
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The possibilities of neuroinflammatory effects, ectopic bone formation, and malignant transformation have been a concern from the inception of these products. We note with some concern that the recent randomized clinical trial by Dimar et al. [16] reported eight new malignancies in the rhBMP-2 group and only two in the ICBG group (p5.1); not statistically significant by the authors’ standard, but not particularly comforting either. The p value indicates that the chance of this being a real, and not random, effect is 90%.
Who advocates against IBCG harvesting? Nevertheless, the recent publications advocating against ICBG for posterolateral fusion have focused on persistent severe pain and unlikely complications, such as pelvic fractures, as described above [39,40]. There has been little or no mention of the serious methodological limitations we have observed in these studies. We are concerned, as Kang has pointed out [27], that all the recent comparative data on donor site pain were derived from industry-sponsored research. Our review of the recent literature for this editorial similarly found these potential conflicts of interest from the authors in every comparative trial reporting potential benefits of commercial alternatives to IBCG in the setting of short-segment posterior lumbar fusion. Granted, in many instances commercial support is necessary in developing new tools for health care, and we have stressed the importance of this relationship in past editorials [41]. We want to assume that all authors try to avoid any bias in reporting. Given that industry-sponsored clinical trials have been clearly associated with a disproportionate reporting of outcomes favorable to the sponsor [42], we cannot preclude bias, even if it is unintended. This organic biasby-sponsor must be taken into consideration when examining the literature concerning alternatives to host grafting, all of which use commercial implantable products [42,43]. The ICBG harvesting procedure, however, has no apparent sponsor. The benefits of its use are dispersed across many patients and a foundering system of care at large. There is no one to bang the drum.
Conclusion The advent of new alternatives to avoid structural autograft harvesting (for anterior cervical or thoracolumbar reconstruction) or morselized graft in at-risk patients has brought important and welcome options for those challenging and difficult cases. However, we are not convinced that autologous iliac crest grafting should be abandoned in any large proportion of our patients. We are also not convinced that the autologous harvesting for one- and two-level posterolateral fusions has much morbidity. In our opinion, when available, ICBG in experienced hands remains a reasonable and safe procedure for most clinical situations.
For the most common one- or two-level lumbar fusions, there appears to be a lack of convincing evidence of frequent and serious donor site pain. Instead, we find that there is strong Level 1 evidence from four randomized clinical trials that early clinical outcomes are equivalent when commercially available products are used compared with iliac crest graft in this clinical situation. There are potential near-term risks to exposing many patients to these potent growth factors in routine practice. At this point, it is impossible to appreciate the long-term risk of this exposure, especially in younger patients. And some early data cause concern. We recognized the high cost of these growth factors in a time of dwindling resources. We are concerned that a large shift in practice is occurring without sufficient consideration of the facts or discussion of the costs and consequences. References [1] Nassr A, Khan MH, Ali MH, et al. Donor-site complications of autogenous nonvascularized fibula strut-graft harvest for anterior cervical corpectomy and fusion surgery-experience with 163 consecutive cases. Spine J 2009;9:893–8. [2] Kim DH, Rhim R, Li L, et al. Prospective study of iliac crest bone graft harvest site pain and morbidity. Spine J 2009;9:886–92. [3] Dimar JR II, Glassman SD, Burkus JK, et al. Two-year fusion and clinical outcomes in 224 patients treated with a single-level instrumented posterolateral fusion with iliac crest bone graft. Spine J 2009;9:880–5. [4] Tang CL, Mahoney JL, McKee MD, et al. Donor site morbidity following vascularized fibular grafting. Microsurgery 1998;18:383–6. [5] Buttermann GR, Glazer PA, Bradford DS. The use of bone allografts in the spine. Clin Orthop Relat Res 1996;24(3):75–85. [6] Fernyhough JC, White JI, LaRocca H. Fusion rates in multilevel cervical spondylosis comparing allograft fibula with autograft fibula in 126 patients. Spine 1991;16(Suppl):S561–4. [7] Ahlmann E, Patzakis M, Roidis N, et al. Comparison of anterior and posterior iliac crest bone grafts in terms of harvest-site morbidity and functional outcomes. J Bone Joint Surg Am 2002;84:716–20. [8] Hutchinson MR, Dall BE. Midline fascial splitting approach to the iliac crest for bone graft: a new approach. Spine 1994;19:62–6. [9] Banawat JC, Asher MA, Hassanein RS. Iliac crest bone graft harvest donor site morbidity: a statistical evaluation. Spine 1995;20:1055–60. [10] Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma 1989;3:192–5. [11] Cahill KS, Chi J, Day A, Claus E. Prevalence, complications and hospital charges associated with use of bone-morphogenetic proteins in spinal fusion procedures. JAMA 2009;302:58–66. [12] Glassman SD, Carreon LY, Djurasovic M, et al. RhBMP-2 versus iliac crest bone graft for lumbar spine fusion in patients over 60 years of age: a cost-utility study. Spine 2009;34:238–43. [13] Dimar J, Glassman S, Burkus K, Carreon LY. Clinical outcomes and fusion success at 2 years of single-level instrumented posterolateral fusions with recombinant human bone morphogenetic protein-2/compression resistant matrix versus iliac crest bone graft. Spine 2006;31: 2534–9. [14] Ackerman SJ, Mafilios MS, Polly DW Jr. Economic evaluation of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusion: an evidence-based modeling approach. Spine (Phila Pa 1976) 2002;27(Suppl 1):S94–9. [15] Silber JS, Anderson DG, Daffner SD, et al. Donor site morbidity after anterior iliac crest bone harvest for single-level anterior cervical discectomy and fusion. Spine 2003;28:134–9.
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Editorial
Pseudomorbidity in iliac crest bone graft harvesting: the rise of rhBMP-2 in short-segment posterior lumbar fusion Eugene J. Carragee, MDa,*, Christopher M. Bono, MDb, Gaetano J. Scuderi, MDc a
Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA b Orthopedic Spine Service, Brigham and Women’s Hospital, Boston, MA 02478, USA c Department of Orthopaedic Surgery, Stanford University Hospital and Clinics, Stanford, CA 94305, USA Received 1 September 2009; accepted 9 September 2009
Readers of this month’s issue will find three articles commenting upon the possible morbidity associated with autologous grafting procedures [1–3]. One [1] discusses a large experience using autologous fibula grafting for cervical reconstruction after corpectomy. In this study, it is clear that the autologous technique has serious and frequent problems. The other two studies in this issue [2,3] look at the most common cited complication associated with posterior iliac crest bone graft (ICBG) harvesting, pain. Taken as part of a larger trend in spine surgery, it can be seen that autologous bone, long considered the ‘‘gold standard’’ for promoting spinal fusion, is having its foundation deconstructed. In many practices, autologous grafting techniques have been replaced by alternative sources of commercially prepared osteoinductive and/or osteoconductive materials. The articles in this issue again point out the suspected serious problems of donor site morbidity and its relative risk in this time of commercial alternatives. The studies in this issue of The Spine Journal address the hypothesis that donor site morbidity is a serious problem that can be prevented through the use of these commercially available substitutes.
This Editorial was reviewed by The Spine Journal deputy editors Dr. Paul Bishop, Dr. Conor O’Neill, Dr. Daniel Resnick, Dr. Jeffrey Wang, and Dr. Bradley Weiner, who approved its content. FDA device/drug status: not applicable. Author disclosures: EJC (stock option, Simpricia, Bioassetts, Cytonics; private investments, Simpricia; consulting, Medtronic, Synthes; trip/travels, US Army; scientific advisory board, Intrinsic Orthopedics, Cytonics; other office, Bioassetts; grants, AO Foundation; fellowship grant, Depuy Spine); CMB (royalties, Life Spine; consulting, Depuy Spine, Medtronic Sofamar Danek; speaking/teaching arrangements, Depuy Spine, Stryker Spine; board of directors, North American Spine Society; other office, Applied Spine; research support, Archus Orthopedics, Synthes Spine; grants, Stryker Spine; fellowship support, Depuy Spine); GJS (stock ownership, Cytonics; private investments, K2 Medical; board of directors, Cytonics; scientific advisory board, Cytonics). * Corresponding author. Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway, Mail Code 6342, Redwood City, CA 94063,USA. Tel.: (650) 721-7607; fax: (650) 721-3470. E-mail address: [email protected] (E.J. Carragee). 1529-9430/09/$ – see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.spinee.2009.09.001
We wonder, however, if there is a sound scientific basis to justify the large-scale shift away from autogenous grafting in the most common scenariodone- and two-level posterior lumbar fusion. After considering the evidence, which we review in this editorial, we believe that the literature does not support a finding of significant morbidity with this technique, and the recent, widespread shift to commercial alternates is unwarranted and ill-advised. Structural fibular autograft Perhaps the use of large segment fibula strut grafts is the easiest case to analyze. The article by Nassr et al. [1], ‘‘Donor-site complications of autogenous nonvascularized fibula strut-graft harvest for anterior cervical corpectomy and arthrodesis in 163 consecutive cases,’’ focuses on the experience of the senior author in a series of patients with multilevel stenosis and myelopathy. These authors report functionally impairing donor site complications, so much so that the senior author no longer regularly uses this technique. Complications such as tibial stress fractures, ankle instability, and neuromas were reported. Five patients (3%) underwent additional surgery, secondary to complications directly related to the donor site. Cellulitis was seen in 9% of patients. Five patients (3%) developed a tibial stress fracture that necessitated immobilization. This study confirms previous reports of donor site morbidity from fibular graft harvesting [4]. Although fibula autograft may allow complete incorporation that is not frequently seen with allograft [5,6], the authors suggest that large structural autograft will have an increasingly limited role because of donor site morbidity and the availability of commercial alternatives. We certainly agree with their assessment.
Suspected donor site morbidity and the declining use of iliac crest autograft On the other hand, two papers reporting on the suspected morbidity of harvesting nonstructural ICBG for common
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short-segment lumbar fusions, in our opinion, rests on much weaker and flawed evidence. Certainly, the older literature concerning long-segment fusions for deformity, neuromuscular disease in patients with pelvic dysplasia, or repeated harvesting for spinal nonunions noted serious, and sometimes catastrophic, graft site complications. These clinical scenarios were once common in managing the postpolio deformities after the epidemics in the 1930s, 1940s, and 1950s. The risks in these situations are well recognized. Today, most spinal fusion is performed in a much healthier group, usually with little or no pelvic dysplasia, and requires much smaller ICBG volumes. Furthermore, modified and less destructive techniques in obtaining ICBG have fewer complications and higher satisfaction rates [7]. These techniques include using a more vertically oriented incision (to reduce cluneal nerve injury) or a single incision for graft harvesting and low lumbar exposure [8,9]. Serious complications in these settings can be as low 0.7% [10] Nonetheless, the rate of ICBG use relative to commercial substitutes has sharply declined. Although data on crest graft usage are not comprehensive, the trend seems to be down, and the use of alternative methods, particularly recombinant human bone morphogenetic protein-2 (rhBMP-2), has risen dramatically. Between 2002 and 2006, the use of bone morphogenetic protein has increased from !1% of fusion procedures in the United States to 25%. rhBMP appears to be used in nearly 40% of lumbar fusions [11]. Remarkably, in 2006, 85% of the bone morphogenetic protein use was in one- or two-level fusions. Supporting this trend, the article by Kim et al. [2], entitled ‘‘Prospective study of iliac crest bone graft harvest site pain and morbidity,’’ in this issue of The Spine Journal, focuses on complications after ICBG harvesting in a cohort of 104 patients. The authors reported significant ‘‘functional limitations’’ associated with pain in the area of the ICBG harvest site. At one year after surgery, this was reported in 6% to 15% of patients depending on the activity examined. Purportedly, all of the pain and dysfunction in this region was exclusively because of the bone graft harvesting. These rates of functional limitation were noted to be higher than those previously reported [12]. Other investigators have also identified subjective complaints around the donor site area, including functional limitations in ambulation, work, and activities of daily living [13–15]. They relate all these symptoms to the donor site, per se. Also in this issue, Dimar et al. [3] report that 60% of 224 patients undergoing ICBG harvesting for single-level fusions ‘‘complained of graft site pain’’ 2 years after surgery. Closer review shows that this pain was ‘‘elicited by palpating for tenderness over both posterior iliac crests.’’ It is not clear what the pain level was with this maneuver on the contralateral side or whether this finding, a common ‘‘trigger point’’ in patients with degenerative lumbar pathology, was actually present before surgery. Despite this ‘‘provocative’’ examination, the pain level was modest. At 3 months after surgery, the pain
level was 6.3 on a 20-point scale. The rate of wound complications at the graft site was less than 1%. Despite harvesting extremely small quantities of ICBG in some patients (as little as 7 cm3) [16], the fusion rate was fairly good. Using several methods to assess intertransverse process fusion rates, 84% to 90% of the spines appeared to have solidly fused using ICBG alone. It is very important to note that in the Dimar et al. study [16], all local autologous bone graft was actually discarded by the study surgeons. In the degenerative spine, this is often a substantial quantity of good bone graft material. Also by protocol, a formal facet arthrodesis was not required, and bone graft was not impacted into a prepared joint space. The wasting of perfectly good bone graft material and the failure to perform a meticulous facet arthrodesis (although perhaps appropriate in a research study) are very dubious practices in real life. This protocol, without doubt, handicaps the fusion outcome in these study subjects compared with usual practice. We doubt if surgical outcomes in this group reflect those that would be achieved using more standard arthrodesis techniques [17].
Unvalidated donor site pain assessment Still, it remains unclear if the pain and functional limitations referred to the gluteal area in these studies are, in fact, because of residual donor site problems. It seems clear that pain in this region may also be because of continued preoperative gluteal pain or new gluteal pain referred from new spinal pathology (nonunion, instrumentation complications, adjacent segment pain, etc) or pain that is secondary to sacroiliac pain associated with changing gait mechanics or arthritis. As mentioned, a criticism of these studies is that neither was there an attempt to determine the preoperative level of gluteal area pain and perceived impairment nor was postoperative pain assessed for the contralateral gluteal area, which may have been the same as, or greater than, that on the harvested side. In addition, neither the patient nor the examiner appears to have been blinded to the side where the crest graft was taken. The authors also did not report the incidence of clinical or radiographic sacroiliac joint disease in these cohorts having low lumbar fusion. All these variables may be confounding factors associated with continued gluteal pain after lumbar surgery. Other authors have attempted to distinguish continued low back pain from graft site pain [18–22]. Fernyhough et al. [18] noted difficulty in differentiating donor site pain from other possible pain generators. They found that significant possible harvest site pain was less frequent in those patients undergoing fusion surgery for stenosis compared with ‘‘degenerative disc disease.’’ Delawi et al. [19] reported more than three times the rate of donor site area pain in those patients undergoing iliac crest graft for low (L3– S1) compared with high (T2–L2) spine fusions. That is, patients undergoing ‘‘high’’ fusion, with little chance of
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referred spinal pain to the harvest site area, had significantly less pain, compared with the group undergoing a ‘‘low’’ spinal fusion (14% vs. 41%). Another prospective study found that pain near the harvest site was reported more frequently after lumbar fusion compared with cervical or thoracic procedures, again underlining the difficulty in delineating pain from surgery or donor site. [20]. A recent study of 92 patients who had ICBG harvested from one posterior crest looked at pain diagrams with Visual Analog Scale measures over both crests. They found that 74 patients (80%) had no reported difference in pain between the ICBG site and the contralateral side. Of patients with more pain on one side than the other, there was no significant difference in the proportion having greater pain on the ICBG site [21]. These data suggest that the self-reported pain about the iliac crest after lumbar surgery, as described in this issue of The Spine Journal, is unlikely to be exclusively a result of ICBG harvesting. Still, suppose one was to assume the highest estimate by Kim et al., 15% impairment due to gluteal pain ipsilateral to the harvesting site, is accurate [2]. And suppose, as an estimate, that 25% to 50% of that impairment burden is due solely to the bone graft harvesting (a very generous estimate). This would mean that if an equally effective bone graft alternative were used, the number needed to treat to prevent just one significant bone graft harvesting complication would be between 14 and 28, an extremely small effect size. That is, most patients would receive no benefit from switching to the alternative method. And yet, the best evidence would suggest that even that estimate is too high.
Best evidence: randomized clinical trials The most compelling argument against a clinically important morbidity from ICBG harvesting for short-segment posterior lumbar fusions is found in multiple randomized controlled trials. The best evidence from randomized clinical trials [16,23–26] consistently show that there is little, if any, negative clinical effect from taking ICBG for posterior-lateral fusion. This has been pointed out by Kang [27] and Papakostidis et al. [28]. There have been three Food and Drug Administration– regulated, randomized, nonblinded investigational device exemption trials of rhBMP-2 matrix for posterolateral lumbar spinal fusion compared with ICBG [16,24,25] and one comparing osteogenic protein-1 (OP-1) with ICBG [29]. In no study was there any significant increase in back pain scores or functional disability at any time after surgery for those subjects undergoing the ICBG harvesting (Figs. 1–4). This is a remarkably consistent and astonishing finding for a procedure purported to be so painful and disabling. If the ICBG harvesting has any deleterious effect, it did not appear to affect postoperative pain, function, or occupational activities in the best comparative trials we
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Fig. 1. Randomized clinical trialdsmokers vs. non-smokers: (Top) the mean back pain Visual Analog Scale (VAS) and (Bottom) the mean leg pain VAS of smokers and nonsmokers undergoing fusion with iliac crest bone graft (ICBG) or recombinant human bone morphogenetic protein-2. At no point is the back or leg pain symptoms significantly worse in patients having ICBG harvesting. Note that in the ICBG group, all local autograft harvested were discarded, and facet fusions not performed. From Glassman SD, Dimar J III, Burkus K, et al. The efficacy of rhBMP-2 for posterolateral lumbar fusion in smokers. Spine 2007;32:1693–8. Copyright 2007 Lippincott Williams & Wilkins [26].
have. Multiple randomized controlled trials, all showing the same finding of no apparent increase in clinical problems from the ICBG harvesting, is strong Level 1 evidence. Even a close examination of very early pain and function scores (6 weeks to 3 months after lumbar fusion), as reported in the rhBMP-2 versus ICBG trials (Figs. 1–4), fails to show the expected early effect of ICBG harvesting. Fig. 1 shows that the best back and leg pain scores at 6 weeks postoperation is actually in the ICBG (nonsmoker) group. Again, in Fig. 4, there is slightly greater disability in the rhBMP-2 group at 6 weeks. Unless the rhBMP has some independent early morbidity, we would expect the ICBG group to have, at the very least, worse scores for 1 or 2 months as the ICBG site heals. These findings suggest that the rhBMP may, in fact, have a clinically deleterious effect in the early postoperative period. As previously
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Fig. 2. Randomized clinical trail in subjects older than 60 years: (Top) the mean back pain Visual Analog Scale (VAS) and (Bottom) the mean leg pain VAS of the older subjects undergoing fusion with iliac crest bone graft (ICBG) or recombinant human bone morphogenetic protein-2. At no point is the back or leg pain symptoms significantly worse in patients having ICBG harvesting. Note that in the ICBG group, all local autograft harvested were discarded, and facet fusions not performed. From Glassman SD, Carreon LY, Djurasovic M, et al. RhBMP-2 versus iliac crest bone graft for lumbar spine fusion: a randomized, controlled trial in patients over sixty years of age. Spine 2008;33:2843–9. Copyright 2008 Lippincott Williams & Wilkins [24].
reported with rhBMP-2 use in other spinal surgery approaches, this early effect is possibly because of local inflammatory effects in the wound or neuroinflammatory effects at the nerve roots [11,30–34]. Finally, data regarding the purported harvest site pain in some randomized clinical trials have extremely poor face validity. Fig. 5, bottom from the randomized controlled trial by Vacarro et al. [29], comparing ICBG with OP-1, shows the prevalence of pain, supposedly a result of ICBG harvesting for lumbar fusion. These authors report a decrease in pain around the harvest site over the first 3 months followed, paradoxically, by a dramatic increase in pain at 6 and 9 months. This finding is inconsistent with expected bone and soft tissue
Fig. 3. Randomized clinical trial comparing an ‘‘optimized recombinant human bone morphogenetic protein-2 formulation’’ with iliac crest bone graft (ICBG). (Top) The Oswestry Disability Index (ODI) and (Bottom) back pain scores show no significant clinical effect of ICBG harvesting at any time point after surgery. Note that in the ICBG group, all local autograft harvested were discarded, and facet fusions not performed. From Dimar JR II, Glassman SD, Burkus JK, et al. Clinical and radiographic analysis of an optimized rhBMP-2 formulation as an autograft replacement in posterolateral lumbar spine arthrodesis. J Bone Joint Surg Am 2009;91:1377–86. Copyright owned by The Journal of Bone & Joint Surgery [16].
healing and strongly suggests that increases in pain are primarily related to the lumbar spine or other factors. Ahlmann et al. [7], reporting on complications and pain after large-volume (mean 55 ml) posterior iliac crest harvesting for limb salvage procedures, found no cases of persistent donor site pain in 42 consecutive subjects. Similarly, one of us (EJC) has closely followed subjects, without any baseline low back pain symptoms, who underwent ICBG harvesting (for nonlumbar problems) as part of a prospective study of discography in asymptomatic subjects [35,36]. Fig. 5, top shows the reported prevalence of moderate or severe iliac crest donor site pain after harvesting in subjects treated for nonlumbar conditions. Pain around the ICBG site appears to taper down to general population (moderate/severe) levels within 6 months after harvesting.
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Fig. 5. (Top) Expected and conventional decline in donor site pain in patients having iliac crest bone graft harvesting for nonlumbar spine problems (eg, C1–C2 fusion, femoral nonunion). By 6 months, pain in gluteal area approximates LBP prevalence in the general population. (Bottom) Paradoxical decrease followed by increase in ‘‘donor site pain’’ 3 months after lumbar surgery [29]. While bone graft site pain is seen to decrease to very low rates in nonspinal procedures, gluteal area pain increases with time after low back surgery.
Fig. 4. Randomized clinical trial of recombinant human bone morphogenetic protein-2 (on collagen sponge) compared with iliac crest bone graft (ICBG) (control) for single-level posterior-lateral fusion. Note even at 6 weeks after surgery, there is no apparent functional effect of having ICBG harvested. Note that in the ICBG group, all local autograft harvested were discarded, and facet fusions not performed. From Dawson E, Bae HW, Burkus JK, et al. Recombinant human bone morphogenetic protein2 on an absorbable collagen sponge with an osteoconductive bulking agent in posterolateral arthrodesis with instrumentation. J Bone Joint Surg Am 2009;91:1604–13. Copyright owned by The Journal of Bone & Joint Surgery [25].
The best evidence from these rigorously controlled trials suggest strongly that the later pain after lumbar surgery reported by Vacarro et al. [29] and others [2,3,13,16] is very unlikely a result of ICBG harvesting morbidity and more likely related to primary lumbar pathology.
At-risk patients, risks and costs We certainly recognize that autograft bone does represent a finite source of graft material. This is an important clinical concern in the multiply operated spine, the patient with serious risk factors for nonunion, and in the patient undergoing a long fusion. In addition, certain individuals with inflammatory or metabolic disease or complicating pharmacologic effects may be poor candidates for obtaining autologous graft. As previously mentioned, patients with developmental or neuromuscular disease may simply have inadequate anatomy for bone graft harvesting under any circumstances. The new commercially available substitutes
represent a great advance in caring for these patients. The basic science and clinical researchers who have pursued and achieved these goals have done valuable work and should be highly commended for their efforts. However, these clinical scenarios are the exception rather than the rule. These patients constitute a small minority of patients considering spinal fusion. Certainly, most primary lumbar fusions in adults are one- or two-level fusions without contraindications to bone graft harvesting. While iliac crest bone is available in limited amounts, so is money. Cost is an important consideration in using commercial bone graft alternatives. Direct costs are far greater when using rhBMP-2 or other substitutes [37,38]. For instance, the cost of rhBMP-2 ranges from $2,500 to $4,500 per level and involves increased hospital charges of 14% to 37% per patient. Although $9,000 just for rhBMP-2 may not seem to be much in the era of AIG bailouts and $40 million executive bonuses, it may pay to reflect that this is about 20% of the median household income in the United States for a full year of work. It is also important to understand that this money takes a slice out of a finite pie available for the care of many patients. Is this the best way to spend $10,000? Our patients often get such brief rehabilitation treatments, overstressed nursing care, and sometimes nearly absent home-care resources. If the typical surgeon had an additional $5,000 to $9,000 to improve the care of a single patient having a short-segment fusion, would a dose or two of rhBMP-2 be how we would really choose to spend it? Finally, and perhaps most importantly, the long-term risks from powerful growth factors are not clear at this time [11].
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The possibilities of neuroinflammatory effects, ectopic bone formation, and malignant transformation have been a concern from the inception of these products. We note with some concern that the recent randomized clinical trial by Dimar et al. [16] reported eight new malignancies in the rhBMP-2 group and only two in the ICBG group (p5.1); not statistically significant by the authors’ standard, but not particularly comforting either. The p value indicates that the chance of this being a real, and not random, effect is 90%.
Who advocates against IBCG harvesting? Nevertheless, the recent publications advocating against ICBG for posterolateral fusion have focused on persistent severe pain and unlikely complications, such as pelvic fractures, as described above [39,40]. There has been little or no mention of the serious methodological limitations we have observed in these studies. We are concerned, as Kang has pointed out [27], that all the recent comparative data on donor site pain were derived from industry-sponsored research. Our review of the recent literature for this editorial similarly found these potential conflicts of interest from the authors in every comparative trial reporting potential benefits of commercial alternatives to IBCG in the setting of short-segment posterior lumbar fusion. Granted, in many instances commercial support is necessary in developing new tools for health care, and we have stressed the importance of this relationship in past editorials [41]. We want to assume that all authors try to avoid any bias in reporting. Given that industry-sponsored clinical trials have been clearly associated with a disproportionate reporting of outcomes favorable to the sponsor [42], we cannot preclude bias, even if it is unintended. This organic biasby-sponsor must be taken into consideration when examining the literature concerning alternatives to host grafting, all of which use commercial implantable products [42,43]. The ICBG harvesting procedure, however, has no apparent sponsor. The benefits of its use are dispersed across many patients and a foundering system of care at large. There is no one to bang the drum.
Conclusion The advent of new alternatives to avoid structural autograft harvesting (for anterior cervical or thoracolumbar reconstruction) or morselized graft in at-risk patients has brought important and welcome options for those challenging and difficult cases. However, we are not convinced that autologous iliac crest grafting should be abandoned in any large proportion of our patients. We are also not convinced that the autologous harvesting for one- and two-level posterolateral fusions has much morbidity. In our opinion, when available, ICBG in experienced hands remains a reasonable and safe procedure for most clinical situations.
For the most common one- or two-level lumbar fusions, there appears to be a lack of convincing evidence of frequent and serious donor site pain. Instead, we find that there is strong Level 1 evidence from four randomized clinical trials that early clinical outcomes are equivalent when commercially available products are used compared with iliac crest graft in this clinical situation. There are potential near-term risks to exposing many patients to these potent growth factors in routine practice. At this point, it is impossible to appreciate the long-term risk of this exposure, especially in younger patients. And some early data cause concern. We recognized the high cost of these growth factors in a time of dwindling resources. We are concerned that a large shift in practice is occurring without sufficient consideration of the facts or discussion of the costs and consequences. References [1] Nassr A, Khan MH, Ali MH, et al. Donor-site complications of autogenous nonvascularized fibula strut-graft harvest for anterior cervical corpectomy and fusion surgery-experience with 163 consecutive cases. Spine J 2009;9:893–8. [2] Kim DH, Rhim R, Li L, et al. Prospective study of iliac crest bone graft harvest site pain and morbidity. Spine J 2009;9:886–92. [3] Dimar JR II, Glassman SD, Burkus JK, et al. Two-year fusion and clinical outcomes in 224 patients treated with a single-level instrumented posterolateral fusion with iliac crest bone graft. Spine J 2009;9:880–5. [4] Tang CL, Mahoney JL, McKee MD, et al. Donor site morbidity following vascularized fibular grafting. Microsurgery 1998;18:383–6. [5] Buttermann GR, Glazer PA, Bradford DS. The use of bone allografts in the spine. Clin Orthop Relat Res 1996;24(3):75–85. [6] Fernyhough JC, White JI, LaRocca H. Fusion rates in multilevel cervical spondylosis comparing allograft fibula with autograft fibula in 126 patients. Spine 1991;16(Suppl):S561–4. [7] Ahlmann E, Patzakis M, Roidis N, et al. Comparison of anterior and posterior iliac crest bone grafts in terms of harvest-site morbidity and functional outcomes. J Bone Joint Surg Am 2002;84:716–20. [8] Hutchinson MR, Dall BE. Midline fascial splitting approach to the iliac crest for bone graft: a new approach. Spine 1994;19:62–6. [9] Banawat JC, Asher MA, Hassanein RS. Iliac crest bone graft harvest donor site morbidity: a statistical evaluation. Spine 1995;20:1055–60. [10] Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma 1989;3:192–5. [11] Cahill KS, Chi J, Day A, Claus E. Prevalence, complications and hospital charges associated with use of bone-morphogenetic proteins in spinal fusion procedures. JAMA 2009;302:58–66. [12] Glassman SD, Carreon LY, Djurasovic M, et al. RhBMP-2 versus iliac crest bone graft for lumbar spine fusion in patients over 60 years of age: a cost-utility study. Spine 2009;34:238–43. [13] Dimar J, Glassman S, Burkus K, Carreon LY. Clinical outcomes and fusion success at 2 years of single-level instrumented posterolateral fusions with recombinant human bone morphogenetic protein-2/compression resistant matrix versus iliac crest bone graft. Spine 2006;31: 2534–9. [14] Ackerman SJ, Mafilios MS, Polly DW Jr. Economic evaluation of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusion: an evidence-based modeling approach. Spine (Phila Pa 1976) 2002;27(Suppl 1):S94–9. [15] Silber JS, Anderson DG, Daffner SD, et al. Donor site morbidity after anterior iliac crest bone harvest for single-level anterior cervical discectomy and fusion. Spine 2003;28:134–9.
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