Use of Recombinant Human Bone Morphogenetic Protein-2 in Spinal Fusion Applications (2002)

Bone morphogenetic proteins (BMPs) have been the subject of considerable research for several decades. The academic chronicle began in 1965 with Dr. Marshall Urist’s discovery of osteoinductive activity within demineralized bone protein extracts, and continued with his later identification of the active molecules as bone morphogenetic proteins. 23,24 This was followed in 1988 by the isolation of an individual protein, BMP-2, from a purified extract and its recombinant production. 25 The long-awaited clinical use and commercial availability of BMPs have only recently approached reality. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is the only BMP for which a prospective randomized pivotal clinical trial for a spine fusion indication has been completed. It has demonstrated equivalence to autogenous iliac bone graft with regard to both fusion rate and clinical outcome. 7 On the basis of this study, the Food and Drug Administration (FDA) has advised that rhBMP-2 be approved for commercialization as the first complete bone graft substitute for spinal fusion indication. At this writing, all other FDA-cleared bone-grafting products are only osteoconductive scaffolds incapable of solely initiating bone formation under the classic definition of osteoinduction: the ability to induce de novo bone formation at a nonbony site. A significant body of data on the use of rhBMP-2 in spinal fusion surgery has been collected. Both the potential uses of rhBMP-2 and its limitations in spinal fusion applications have become clear through this extensive series of preclinical and clinical investigations. It was determined that an application-specific carrier was required to release the rhBMP-2 protein over an adequate period and at a sufficient concentration. Different fusion techniques such as intervertebral arthrodesis and posterolateral intertransverse process arthrodesis presented their own specific challenges, which required specific carrier–rhBMP-2 combinations. The relevant preclinical and clinical research that provided data regarding site-specific product configurations is presented in this article. The first part of the article reviews some of the preclinical efficacy data and lessons learned from these animal studies. The second part describes FDA-approved investigational device exempted (IDE) clinical human trials and their results involving rhBMP-2 for human spinal fusions. Product Development Considerations Early work with rhBMP-2 demonstrated that the carrier had a profound effect on the efficacy of the molecule for specific applications. It was determined that the carrier serves three very important functions: It acts as a three-dimensional space occupier and scaffolding across which de novo bone formation can occur. It maintains a critical threshold concentration of BMP at the site of implantation for the desired period. It contains the BMP at the site of application to prevent extraneous bone formation. Several carriers for rhBMP-2 have been evaluated including collagen sponges, calcium phosphate ceramics, and degradable synthetic and natural polymers. Each of these vehicles offers its own unique advantages and disadvantages. The efficacy of the carrier–growth factor composite was evaluated largely through preclinical research, which requires a long iterative trial and error process. Ideally, a carrier is a resorbable material with a resorption profile that generally matches the rate of de novo bone formation. If the carrier resorbs before adequate osteodeposition, misdirected bone formation and pseudarthrosis may be the ultimate result. If the carrier resorbs too slowly, bridging bone formation and remodeling may be impeded. Preclinical research is complicated by the fact that rhBMP-2 efficacy is species dependent (i.e., higher concentrations of the molecule are required in more evolved animals). Thus, a valid determination of the efficacy of the carrier–rhBMP-2 composite, before initiation of human clinical trials, ultimately is dependent on findings in primate studies using clinically relevant models. Two of the more common spinal fusion procedures are interbody fusion using load-bearing cages and posterolateral intertransverse process fusion. Because these two distinct spine fusion techniques involve different mechanical and biologic demands, specific carrier–rhBMP-2 composite configurations were indicated for each technique. Therefore, preclinical findings with interbody and posterolateral fusion techniques were reviewed separately. Preclinical Studies by Site of Application Interbody Spinal Fusion The intention of interbody spinal fusion is to achieve a bony arthrodesis across a degenerated and usually narrowed disc space. In the process of achieving fusion, the intervertebral space is distracted to a reasonable approximation of its original height with the intent of restoring sagittal plane alignment. At the time of this writing, no carrier material could be identified that could deliver the molecule biologically to the site of fusion while sustaining the loads for disc distraction and motion resistance. Therefore, preclinical attention was directed at rhBMP-2 with a nonstructural carrier housed in an intervertebral fusion construct such as a cylindrical metallic cage or in cylindrical allograft bone dowels. Normally, these hollow-chamber constructs are packed with autogenous bone graft and provide the osteoinductive stimulus for intervertebral fusion. Because the loads are borne by the construct itself, the autogenous bone graft or any other filling material is not subject to normal physiologic load. One of the most effective nonstructural carriers for rhBMP-2 proved to be the Type I bovine absorbable collagen sponge (ACS). The cohesive ACS is hydrated with rhBMP-2 solution at the time of surgery. The collagen sponge, which efficiently binds the rhBMP-2, then is packed into the fusion construct (Figure 1). This particular collagen sponge has been used commercially over the past 20 years as a hemostatic agent (Helistat). The ACS is a fibular collagen with a slow resorption profile well suited for the delivery of the growth factor. The minimum intraoperative soak time at surgery for adequate binding of the molecule to the sponge before its implantation has been determined to be 15 minutes. After implantation, the ACS undergoes resorption over a 2- to 4-week period via cell-mediated degradation. The collagen also provides a favorable surface for cell attachment during early osteoid formation. The half-life for local delivery of rhBMP-2 is approximately 2 to 3 days. The molecule then is undetectable beyond 4 weeks after implantation.Figure 1: Collagen sponge carrier is soaked with recombinant human bone morphogenetic protein-2 solution at the time of surgery (A), then rolled and placed into an interbody fusion cage (B).The first preclinical interbody cage study using rhBMP-2 was reported by Sandhu et al. 5,16 In this study, interbody were in the using the and fusion cages were with autogenous iliac bone graft or rhBMP-2 on a collagen sponge The were after surgery. was determined and to all the had fusion by the were both and the with fusion after the with had fusion at the in In the by rhBMP-2 had the of the cage the by autogenous bone graft (Figure In to the efficacy of rhBMP-2 in this fusion this study also demonstrated the of to the of spinal fusion through metallic intervertebral and and and of interbody cages with iliac and or recombinant human bone morphogenetic protein-2 (rhBMP-2) on a collagen sponge and was the of cages more other preclinical interbody fusion studies using cages and rhBMP-2 demonstrated et used a fusion cage in a was with the use of rhBMP-2 on a collagen The findings that of the cages with were with spinal fusion, as with of the cages with the of the fusion not with the of the fusion. On the basis of the results in these animal intervertebral were in the primate et 2 the use of rhBMP-2 on the collagen sponge in a interbody fusion cage in The cages were with two concentrations of rhBMP-2 and and with a The implantation of a collagen sponge growth factor and a fusion of the with the spinal fusion after the with concentration of the rhBMP-2 on to fusion. The higher concentration was with a and bone formation the concentration any (Figure On the basis of these the concentration was as the for the human clinical of collagen (A), concentration of recombinant human bone morphogenetic protein-2 (rhBMP-2) and concentration of rhBMP-2 study using allograft bone of cages also was with the et reported that after interbody fusion, all with allograft bone with rhBMP-2 on a collagen sponge fusion. of three with allograft bone with autogenous bone graft fusion. the allograft bone in the of recombinant rhBMP-2 had complete resorption and remodeling during the study period. This was distinct from the in which the of the allograft was after (Figure This study that the of rhBMP-2 not only bone also was no of intervertebral or early of the bone in investigational all of the preclinical studies of sponge in interbody fusion and and and of allograft bone with iliac and or recombinant human bone morphogenetic protein-2 on a collagen sponge and 1: of Interbody Fusion Preclinical Studies Fusion The mechanical and biologic for posterolateral spine fusion is more that for interbody spinal fusion. The of rhBMP-2 for posterolateral applications was more Preclinical studies in higher indicated that the Type collagen sponge was an carrier for rhBMP-2 in a posterolateral fusion In this such as that provided by an interbody fusion cage not be several animal studies with and demonstrated the ability of the collagen sponge to deliver rhBMP-2 in an intertransverse process fusion, this was not the in higher such as et reported a fusion rate for rhBMP-2 in a posterolateral fusion 4 weeks after In this only of the both and rhBMP-2 and more bone and remodeling autogenous bone Fusion with rhBMP-2 was and (Figure the of to and of at 4 as with recombinant human bone morphogenetic protein-2 and collagen carrier at the time et 15 reported a fusion rate of in a posterolateral fusion within weeks after the implantation of rhBMP-2 on a collagen In this of the In a trial in which the were not the were to induce process fusion in the of et evaluated the use of rhBMP-2 as an for autogenous bone by to the the as the or by on a collagen sponge that then was to the autogenous fusion were with in which rhBMP-2 was to the autogenous bone The fusion were with rhBMP-2 on the collagen sponge to autogenous bone et also evaluated rhBMP-2 as an in the posterolateral fusion demonstrated that the fusion in the of rhBMP-2 after surgery (Figure of with or and recombinant human bone morphogenetic protein-2 (rhBMP-2) the in the fusion from that of at weeks with and rhBMP-2 at the time This was significant findings in were not in the primate In a series of by et rhBMP-2 concentrations to be effective in were not effective in posterolateral in It was that mechanical of the collagen sponge was the sponge and bone formation. In a a was and placed over the collagen sponge carrier across the to from (Figure this a rhBMP-2 concentration a fusion. fusion also were the On the basis of these is that a carrier had to be for the posterolateral fusion of a spine with across used to the recombinant human bone morphogenetic collagen of a spine after surgery of bone formation the with use of a and to no bone the use of a et reported on of the first carriers to achieve posterolateral fusion with in this The carrier was a calcium phosphate of and phosphate Both and have a long of clinical undergoes very slow and undergoes The calcium phosphate was to for a part of the composite to resorption while a of was for the of phosphate are well to This carrier requires only a intraoperative soak time to adequate rhBMP-2 binding before The of rhBMP-2 release from the has been in a posterolateral fusion The half-life was to be approximately days. et reported that all three rhBMP-2 concentrations evaluated in this primate study and in of the with autogenous bone graft a fusion (Figure This trial was the first preclinical of rhBMP-2 efficacy for posterolateral spinal fusion in a primate and of fusion from weeks after arthrodesis with and phosphate and and with recombinant human bone morphogenetic protein-2 (rhBMP-2) and bone and are in the fusion with bone in the fusion with and carriers with have been for use in the posterolateral fusion A composite of and into the collagen The of these the provides to by in the posterolateral fusion (Figure This as the can be and into the desired and before with rhBMP-2 solution using an The rhBMP-2 solution then is the using a to that used with the ACS The soak time in this is a minimum of minutes. The of to was to resorption of the carrier and of bone formation. It was that resorbs too to bone formation. A with a of undergoes significant resorption in approximately 3 to 4 and is by bone that is after the carrier is via cell-mediated and The of rhBMP-2 release from the carrier was in a posterolateral fusion The half-life was approximately to that of the The composite sponge is of resorbable calcium phosphate in a collagen This sponge is to in a posterolateral fusion as is across the their et demonstrated that all with as with the fusion rate in iliac autogenous bone graft of fusion and that these were and in and to with carriers such as the ACS collagen sponge and the with rhBMP-2 (Figure the of to of at as with using recombinant human bone morphogenetic protein-2 (rhBMP-2) and collagen sponge carrier and rhBMP-2 on the carrier at the time carrier then was evaluated in the primate In all the with posterolateral fusion et to the effect of delivery in the posterolateral the effect of to the ACS collagen Two such of allograft or resorbable to the ACS collagen sponge some resistance. The allograft or resorbable of ACS collagen or in the collagen sponge (Figure of such as allograft or to the collagen sponge used in the primate study, and both of these posterolateral of the time in the In only of three with autogenous bone graft in this had fusion, and that fusion was by bone (Figure of the posterolateral fusion with and that with recombinant human bone morphogenetic absorbable collagen sponge, and resorbable or allograft at 2 all the preclinical studies of sponge and carriers in posterolateral fusion models. On the basis of these preclinical in the results of primate several human clinical trials were under Food and Drug Administration investigational device The describes the clinical results to from the use of rhBMP-2 in some of these spinal fusion of Fusion Preclinical Studies the of rhBMP-2 for Spinal At this writing, more have in clinical trials human spinal fusion. In more have been in these studies for The composite device of rhBMP-2 by the absorbable collagen sponge has been Bone The studies and in a study on the use of Bone in a cage for interbody fusion, a pivotal study on the use of Bone in a cylindrical cage for interbody fusion, a study on the use of Bone in a cylindrical allograft bone for interbody fusion, a pivotal study on the of a cage with Bone for interbody fusion, a study on intervertebral with a cylindrical fusion cage with Bone a study on the use of Bone within a allograft for and and fusion, and a study on the use of an composite for posterolateral spinal fusion. The the clinical data at this for these clinical studies. of Bone Fusion On an investigational device (IDE) was with the to study the use of rhBMP-2 in with disc The rhBMP-2 was with the absorbable collagen sponge as the This composite then was placed into a interbody fusion device The application was approved in and the first surgery was in the approved and by investigational were with rhBMP-2, and 3 were in the The were with a cage with autogenous bone graft from the iliac was in On the basis of the results from the primate study in which the sponge composite also was in a cage for interbody fusion, a of rhBMP-2 at on the collagen sponge was for the The of the study were to the investigational and for fusion efficacy on the basis of and to the of rhBMP-2 in The was to a of with attention to and The study was as a prospective randomized of the investigational and all three of the were using an to the spinal of the investigational the fusion through a the in the study were 3 and after surgery. The and were by at the time with rhBMP-2 on to fusion, as determined by Two of the three also on to fusion. One with pseudarthrosis required a and fusion approximately after the surgery. and as by the are for each of the time in Bone clinical investigational at each of the time Because of the the were not was on each of the before then weeks and 3 after surgery. were for the of specific to rhBMP-2 and bovine collagen Type I the collagen sponge is from bovine of the study had rhBMP-2 after implantation of the had collagen Type I The clinical not to be by the of collagen Type I three these were determined to have had spinal fusions. of at and after surgery the are in of at the time the with Bone are in for 7 and Bone for and of Bone The and efficacy data from the clinical study Bone placed within a for interbody fusion was used to the initiation of a pivotal 7 The pivotal clinical trial from the on and on began on and the study had surgery on A of investigational and were in this the in the study an to the spinal with this study, the also to a to this The results of the are reported in the This pivotal clinical study was as a randomized The investigational the with Bone for interbody fusion. The the cage with autogenous bone which was from the iliac The study investigational of the with (Figure the two were The data are indicated in Bone pivotal clinical Bone Bone time and were in the investigational Bone The of site was determined in the at each of the time The of such is indicated in the of iliac some of site 2 years after surgery. were no in the investigational and at each of the time (Figure The of as on an also was not different the two (Figure a of to work in both (Figure Bone pivotal clinical of site for Bone pivotal clinical Bone pivotal clinical Bone pivotal clinical for fusion in this trial were on of and fusion required the of bridging bone or to 3 of sagittal with the of more of of the two metallic was an indication of pseudarthrosis and of The fusion results are indicated in was to this The of equivalence the investigational and the was the of for the investigational was at after surgery. and a in was used as the for On the basis of this the rate after surgery for the investigational was as with for the of this data that the of equivalence the investigational and the was Bone pivotal clinical Fusion was on each of the before surgery and 3 after surgery. The were for the of specific to rhBMP-2 and bovine Type I The results were for investigational and in this clinical investigational and had that were for to One investigational had a and was not to have an The of an to rhBMP-2 was in the investigational and in the to bovine Type I collagen was in these were in the investigational and were in the The was the investigational and the of the with results for bovine Type I collagen had a for human Type I was no the of and the of of Bone and the for Interbody Fusion with the pivotal study, the to an a for of the Bone and The for this of the study was to that for the that was no randomized and the was A of from investigational were in this The first had surgery on and the had surgery on At this writing, all the have their the of disc and all were with intent to the to the The were evaluated before surgery and at and after surgery. At this writing, of the in the study have been evaluated at the time are in and data are presented in The time was 2 and the was days. This with the of 3 reported in a clinical study of interbody using with Bone Bone and is presented in the of to of the with Bone and through a had a and Bone pivotal clinical and as on an are in in for both of these was at each of the time Bone pivotal clinical and fusion results to the are reported in The fusion data are with from a study of of the with iliac autogenous bone The fusion in both the Bone and at both and after surgery. to the fusion were that the of equivalence investigational and was Bone pivotal clinical Fusion is presented in a of in both the investigational and to a of in the investigational to work in the Bone pivotal clinical was on the investigational 3 after surgery. One had a for to This an of in this In the investigational were to have an to bovine Type I This an of in this could be with these of the investigational had a to bovine Type I collagen also had a to human Type I of Bone and Bone for Interbody Fusion The primate study the efficacy of the within a allograft was used as the basis for a clinical In this the allograft were from the of and to cylindrical were with with Bone for intervertebral fusion, and were with with autogenous bone from the iliac The study was as a randomized The application was approved by the in The first surgery was in and was in A of investigational and were in the the a and fusion through an were 3 and after surgery. of the the The were generally A higher of were investigational were more to have a and to have surgery. data are in The was with Bone iliac bone the of site 2 years after surgery was (Figure Bone Bone Bone pivotal clinical of site for and are indicated in The with Bone had in 3 and after and after surgery the the Bone had more a in by the The fusion are presented in the investigational had fusion by and all had fusion by after surgery. In the had fusion by and had fusion after A of investigational were to to work (Figure Bone pivotal clinical Bone pivotal clinical Fusion Bone pivotal clinical of Bone and the Fusion for Interbody Fusion randomized trial was the only to use intervertebral fusion via a The were cages to graft material and to the intervertebral through a The cages were placed as and were used only for fusion. The a and weeks and and after surgery. were in investigational these the procedures with implantation of the device with autogenous bone and the with implantation of the device with Bone The of the and investigational were generally of the in both were The data indicated a in the investigational and and were in both and The fusion rate was in the Bone at the time (Figure Bone Bone Bone pivotal clinical Bone pivotal clinical Bone pivotal clinical Fusion several bone was in the spinal to the and in the of their At this writing, the of this bone has not been with clinical It is not clear the formation of this bone is of this and the of the clinical this study has been of Bone and the for and Fusion The only spine clinical study the efficacy of Bone for spinal fusion the implantation of fibular with or Bone This study at study The or and fusion and were evaluated at the time indicated in the other studies. the in the Bone of the study, fusion and fusion. the 15 in the and with the fibular with from the iliac fusion and 7 fusion. The were not different the of the study The data that was in the Bone fusion In the site was by 3 after as on the (Figure in the was in the fusion of the study in the other (Figure the fusion by after Bone Bone Bone in Bone from the clinical trials have been to provide more and regarding rhBMP-2 and the composite Bone The and pivotal studies Bone in with the a of in the investigational and a of in the for to rhBMP-2 and to Type bovine collagen were on investigational and before surgery and 3 after surgery. Two with Bone had an to rhBMP-2 and had an to rhBMP-2 In investigational had an to the Type bovine collagen and had a of Recombinant Bone and for Fusion This was a randomized clinical trial the use of rhBMP-2 with a calcium phosphate carrier in posterolateral fusion for The study, in two of In an of rhBMP-2 to 7 of The intertransverse process space was with autogenous bone In of rhBMP-2 to of no autogenous bone The for both a and and after surgery. At this writing, all the have had a at a minimum of after surgery. In of were by after as with of In fusion was at by the a of at 15 in and a in The data from this study the efficacy of the composite as a substitute for autogenous bone graft for posterolateral intertransverse process fusion. This the preclinical and clinical at this regarding the use of rhBMP-2 for spinal fusion. The preclinical studies were important for the and limitations of rhBMP-2 used with different spine fusion only from preclinical animal that higher fusion in interbody fusion cages with bone use of the ACS in a posterolateral application required the of to adequate space for bone formation. rhBMP-2 carriers such as the and the sponge were to be to autogenous bone graft in posterolateral At this writing, the primate studies also to into results in human clinical trials, in animal models. Therefore, such studies are a to the initiation of human The clinical data the in several of rhBMP-2 in spinal arthrodesis in In some as the growth factor is used with for interbody fusion, the of Bone bone graft is with fusion in and and of to In with a to the spinal the use of Bone may be with a the trials of intervertebral fusion with Bone demonstrated autogenous bone was not The of iliac in bone graft was to at 2 years after surgery. bone within the spinal was identified in some procedures in with Bone no in clinical the investigational and was the clinical of this is in this is The of the efficacy of rhBMP-2 to induce spinal fusion in has demonstrated the of this molecule in the of spinal fusion surgery. of the data from clinical studies its of applications for the use of this factor is and Preclinical of specific BMP concentrations and carrier in higher species are a to initiating human clinical rhBMP-2 on a collagen carrier Bone has demonstrated equivalence to the use of autogenous bone graft in a pivotal prospective randomized clinical study with the uses of Bone are under