Applications of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) in Spinal Surgery

Applications of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) in Spinal Surgery Gerard K. Jeong, MD,* and Harvinder S. Sandhu, MD† Animal studies and clinical trials have demonstrated the efficacy of rhBMP-2 as an adjunct or substitute to autogenous bone graft in anterior lumbar interbody fusion, posterolateral fusion, and in overcoming inhibitory effects (ketolorac and nicotine) on fusion. Importantly, no serious adverse events or systemic side effects have been observed in clinical trials. Before widespread application of rhBMP-2 can be accepted, future investigations are needed to evaluate its efficacy in various spinal disorders, optimal dose and delivery system, long-term safety profile (immunogenicity, antibody formation), cost-effectiveness of therapeutic growth factors, and non-fusion application in altering the progression of degenerative disc disease. Semin Spine Surg 18:15-21 © 2006 Elsevier Inc. All rights reserved. KEYWORDS recombinant human bone morphogenetic protein, interbody fusion, posterolateral fusion, iliac crest bone graft, degenerative disc disease

I

t has been nearly 40 years since Marshall R. Urist made the seminal discovery that a specific protein, later named bone morphogenetic protein (BMP), found in the extracellular matrix of demineralized bone could induce new bone formation when implanted in extraosseous tissues in a host.1 Since Urist’s initial discovery, BMPs have been the subject of extensive basic science, animal, and clinical research as a potential therapeutic modality to induce fracture healing and to promote bone fusion. Numerous structurally related BMPs have been isolated, purified, and characterized using recombinant DNA techniques.2-6 These factors in combination with a number of cytokines and matrix components have been shown to induce a cascade of events resulting in the recruitment and differentiation of osteoprogenitor cells during bone formation and remodeling.7,8 Animal studies have demonstrated that BMPs are capable of upregulating other BMPs (BMP-4, -6) and growth factors (PDGF, VEGF, IGF, EGF, FGF) in their naturally occurring sequence.9-11 As a result of the initial preclinical, proof-of-concept studies and the subsequent prospective, randomized clinical trials, recombinant human bone morphogenetic proteins (rh*Tucson Orthopaedic Institute Spine Center, Tucson, AZ. †Hospital for Special Surgery, New York, NY. Address reprint requests to Gerard K. Jeong, MD, Tucson Orthopaedic Institute, PC, The Spine Center, 2424 North Wyatt Drive, Suite 100, Tucson, AZ 85750. E-mail: [email protected].

1040-7383/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.semss.2006.01.003

BMP) have now become commercially available as they have been shown to demonstrate equivalent or superior efficacy to autogenous ICBG in the specific treatment of certain orthopedic trauma (ie, open tibia fractures) and spinal conditions. At the time of this writing, there are only two rhBMPs that are commercially available for clinical spinal applications (Table 1). rhBMP-2 carried on an absorbable collagen sponge, trademarked as INFUSE Bone Graft (Medtronic Sofamor Danek, Memphis, TN) is commercially available and FDA-approved when used with a lumbar tapered fusion cage (LT-CAGETM) for one-level anterior lumbar interbody fusion for degenerative disc disease. rhBMP-7, trademarked as Osteogenic Protein-1 (OP-1 Putty; Stryker Biotech, Inc., Hopkinton, MA), is FDA-approved as a humanitarian device exemption (HDE) for revision posterolateral lumbar spinal fusion. The preclinical studies, clinical trials, and the current and future applications of rhBMP-2 in the clinical arena of spinal surgery will be the focus of discussion in this review.

Principles of Bone Graft Biology Several factors dictate the successful incorporation of grafted bone and include (1) the type of bone graft; (2) the host site; (3) the vascularity of the graft and host– graft interface; (4) the immunocompatability between the donor and the host; (5) preservation techniques; and (6) local (cytokines, growth 15

G.K. Jeong and H.S. Sandhu

OP-1

Putty

RhBMP-7 protein on type 1 collagen carrier with CMC additive

Osteoinduction

Nonhuman primate studies Prospective, randomized clinical trials

Approved as a Humanitarian Device Exemption (HDE)

Revision posterolateral (intertransverse) fusion April 2004 Prospective, randomized clinical trials Lower animal studies Resorbable collagen scaffold

Received Premarket Approval (PMA) Nonhuman primate studies Osteoinduction

factors, etc) and systemic factors (smoking, steroids, etc). In the posterolateral spine, autogenous bone fusion matures through a series of steps including inflammation, fibrocartilage formation, enchondral ossification, and final remodeling. Osteogenesis is the synthesis of new bone by cells derived from either the graft or the host and refers to the ability of graft or host cells to directly form bone. Only autogenous bone marrow elements possess osteogenic properties with osteoinductive proteins, osteoprogenitor cells, and a local blood supply. Osteoconduction refers to the process by which an organized, microarchitectural framework is established that acts as a scaffold to support the formation of new host bone. Osteoinduction is the process by which mesenchymal stem cells at and around the host site are recruited as osteoprogenitor cells to differentiate into mature osteoblasts. Recruitment and differentiation are the two characteristic processes of osteoinduction and are tightly modulated by various graft matrix-derived growth factors and cytokines. These growth factors include BMP, platelet-derived growth factors (PDGF), fibroblast growth factors (FGF), insulin-like growth factors (IGF), vascular endothelial-derived growth factors (VEDGF), and various interleukins (IL). The majority of commercially available bone graft extenders (DBM, allograft, calcium salts, coral, hydroxyapatites, etc) serve as osteoconductive agents with limited to no osteoinductive potential.

Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) rhBMP-2 (INFUSE) is one of the earliest and most investigated rhBMPs in preclinical studies and clinical trials. INFUSE, a combination of rhBMP-2 on an absorbable collagen sponge, delivered in a lumbar tapered fusion cage (LTCAGETM), was FDA-approved in July 2002 as the first complete bone-graft substitute in spinal fusion.12 Its use is currently approved for one-level anterior lumbar interbody fusion in patients with symptomatic degenerative disc disease (DDD) from L4-S1 via an anterior open or an anterior laparoscopic approach. Animal studies and human clinical trials, which have demonstrated the efficacy of rhBMP-2 in interbody fusion and in overcoming inhibitory effects of fusion, have formed the basis for the current and future applications of rhBMP-2 as a viable bone graft substitute in spinal surgery. The exact role of rhBMP-2 in the posterolateral fusion environment remains to be determined and continues to be the subject of further investigation.

Biotech

Stryker RhBMP-7

Danek

Animal Studies (Interbody Fusion) Sofamor

Indication FDA-Approval

July 2002

Burden of Proof

Lower animal studies Bioresorbable sponge RhBMP-2 protein with absorbable collagen sponge Medtronic RhBMP-2

INFUSE

Reported Mechanism of Action Composition Product Company RhBMP

Table 1 Commercially Available rhBMPs Approved for Spinal Applications

Anterior lumbar interbody fusion (L.4-S1) for degenerative disc disease Delivered in LT-Cage via open or laparoscopic anterior approach

16

Sandhu and coworkers reported the first preclinical study of the use of an interbody cage augmented with rhBMP-2 in a sheep model.13,14 In this study, cylindrical, threaded fusion cages were filled with either autogenous ICBG or rhBMP-2 on an absorbable collagen sponge carrier. All animals in both treatments appeared to have achieved radiographic evidence of fusion at 6 months. However, only 37% of the sheep in the

rhBMP-2 in spinal surgery autograft group had histological evidence of fusion at 6 months compared with 100% in the rhBMP-2 group. It was also noted histologically that there was less fibrous tissue ingrowth in the fenestrations of the cage in the rhBMP-2 group compared with that in the autograft group. Zdeblick and coworkers reported similar findings using titanium BAK fusion cages (Sulzer Spine-Tech, Minneapolis, MN) in a goat model.15 Boden and coworkers then demonstrated the efficacy of rhBMP-2 in a nonhuman primate model.16 They utilized two different concentrations (0.75 or 1.50 mg/mL) of rhBMP-2 with the same collagen carrier packed in a titanium lumbar interbody fusion cage in rhesus monkeys. They observed a dose–response phenomenon with the higher concentration producing a faster and thicker interbody fusion mass. As a result of these findings, the 1.50 mg/mL dose was utilized for the interbody fusion implants in subsequent clinical trials. Hecht and coworkers also demonstrated similar findings in rhesus monkeys using rhBMP-2 packed in threaded cortical allograft interbody dowels.17 Interestingly, they noted at 6 months complete resorption and remodeling of the cortical allograft within the fusion mass, suggesting that rhBMP-2 may accelerate not only osteoblastic bone formation but also osteoclastic remodeling. This finding was in sharp contrast to that observed in the control autograft group, in which no remodeling was observed.

Animal Studies (Posterolateral Fusion) The initial preclinical investigations of rhBMP-2 for posterolateral spinal fusion demonstrated consistently larger, thicker, and stiffer fusion masses compared with autograft controls. These studies utilized rhBMP-2 on a collagen sponge carrier in rabbit and canine models.18-22 However, success with rhBMP-2 for posterolateral fusion in lower animals did not directly translate to nonhuman primates. Martin and coworkers found that the rhBMP-2 concentrations effective in lower animals were not effective in higher species and was the result of mechanical compression of the overlying paraspinal muscles on the collagen sponge carrier, thereby impeding new bone formation.23 As a result, a porous polyethylene shield was developed and placed over the rhBMP2-soaked collagen sponge to protect the carrier from overlying muscle compression. This intervention led to successful fusion with an even lower rhBMP-2 concentration and thicker, more compact fusion masses compared with those achieved without the shield. It thus became evident that the delivery of rhBMP-2 in posterolateral fusion applications would need to be different than that found in the interbody fusion model as a result of the different anatomic characteristics in each environment. Boden and coworkers first demonstrated the preclinical efficacy of rhBMP-2 for posterolateral fusion in a nonhuman primate model.24 The investigators developed a highly porous biphasic calcium phosphate compression-resistant matrix consisting of 60% hydroxyapatite and 40% tricalcium phosphate to be used in a primate posterolateral fusion model. This specific carrier resulted in solid fusion masses

17 when used with any of three different concentrations of rhBMP-2. Different delivery systems in the posterolateral fusion model continue to be investigated. Suh and coworkers demonstrated the efficacy of a newer, easily moldable, compression-resistant biphasic calcium phosphate ceramic composite as a carrier for rhBMP-2 in primates.25 Bulking agents consisting of allograft chips or ceramic granules to provide the collagen sponge some compression resistance have also been introduced and demonstrated promising results.26,27

Animal Studies (Inhibitory Effects) The ability of rhBMP-2 to overcome inhibitory effects of nonsteroidal antiinflammatory drugs (NSAIDs) and nicotine has also been demonstrated in animal studies. Martin and coworkers established the adverse effects of ketorolac on posterolateral spinal fusion and then tested the ability of rhBMP-2 to overcome such inhibition.28 The investigators demonstrated an autograft fusion rate of 35% with an intravenous (IV) ketorolac pump infusion when compared with a 75% autograft fusion rate with an IV saline pump. Fusion rates subsequently increased to 100% in an autograft/rhBMP-2 group with IV ketorolac infusion. In a similar model, Silcox and coworkers demonstrated that rhBMP-2 can also overcome the inhibitory effect of systemic nicotine on fusion.29 The investigators administered nicotine to rabbits using mini-osmotic pumps and compared the fusion rates among three different treatments. They found a 100% fusion rate in the autograft/rhBMP-2 group, a 64% fusion rate in the DBM, rhBMP-2 group, and a 0% fusion rate in the autograft alone group.

Clinical Studies (Interbody Fusion) The first clinical study examining the use of RHBMP-2 in spinal fusion applications was conducted in 1996 as a pilot Investigational Device Exemption (IDE) study to evaluate the safety and feasibility of INFUSE for anterior lumbar interbody fusion.30 This prospective, randomized, controlled multicenter trial enrolled 14 patients for a one-level anterior interbody fusion using a lumbar tapered titanium interbody fusion cage (LT-Cage, Medtronic Sofamor Danek) using either INFUSE or iliac crest autograft. All 11 patients in the rhBMP-2 cohort achieved a successful fusion as determined by plain radiographs and fine-cut computed tomography (CT) scans interpreted by blinded, independent radiologists, whereas only two of three patients in the iliac crest autograft control group had a successful fusion. The one patient in the pseudarthrosis group required additional posterolateral fusion and instrumentation approximately 18 months following the index procedure. Although the results from this study were too small to achieve significant values, the rhBMP-2 group also had achieved a better clinical outcome as determined by the Oswestry Disability Index (ODI) scores at each follow-up. The safety and efficacy data from this initial pilot study initiated a larger pivotal trial.31,32 The study design, interventions, and outcome measurements were nearly identi-

G.K. Jeong and H.S. Sandhu

18 Table 2 Clinical and Radiographic Results of rhBMP-2 versus Iliac Crest Autograft in Anterior Lumbar Interbody Fusion Using a Lumbar Tapered Titanium Cage

Fusion rate at 2-year follow-up FDA criteria for successful result 20% Improvement in Oswestry Disability Index

RhBMP-2 (%)

Iliac Crest Autograft (%)

100 94.5

95.6 88.7

79

79

cal to the original pilot study. Approximately 280 patients in 16 investigational centers were enrolled in the study. Both operative time and blood loss were significantly less in the experimental rhBMP-2 group compared with the iliac crest autograft control group. Radiographic fusion rates were slightly greater in the rhBMP-2 cohort at 2-year follow-up (Table 2). There were no differences in (1) the clinical outcomes, measured by the ODI; (2) the presence of back pain, measured by a pain analog scale; and (3) the number of patients returning to employment between the two cohorts. However, over one-third of the patients in the autograft group still experienced some type of donor site pain 2 years following surgery. A concurrent pilot study investigating the safety and efficacy of rhBMP-2 in anterior lumbar interbody fusion using machined cortical allograft dowels was also conducted.33 This prospective, randomized, multicenter trial enrolled 47 patients for a one-level anterior interbody fusion using a allograft bone dowel packed with either INFUSE or iliac crest autograft. The investigators reported significantly less blood loss and greater improvement in Oswestry scores at 3- and 6-month follow-up in the INFUSE group. They also reported higher fusion rates at 6- and 12-month follow-up in the INFUSE group. At 1 year, all (100%) patients in the experimental group had fused compared with 90% (17/19) of the patients in the control group. At 2 years, 67% of the INFUSE group compared with 35% of the control group were able to return to employment. Furthermore, 39% (7/18) of the patients in the control group continued to report persistent donor-site pain, whereas no adverse effects were reported in the rhBMP-2 group. The role of rhBMP-2 in posterior lumbar interbody fusion (PLIF) remains to be determined. Heterotopic bone within the spinal canal was noted in patients enrolled in an rhBMP-2 PLIF trial. Although there were no neurological sequelae, the study was halted before completion due to potential safety concerns.34

Clinical Studies (Posterolateral Fusion) Clinical studies have also examined the use of rhBMP-2 in lumbar posterolateral fusion. Boden and coworkers reported the early results of a pilot study investigating the use of rhBMP-2 in single-level posterolateral fusion.35 Based on nonhuman primate studies, dose and carrier modifications were

made to accommodate the differences between the posterolateral and interbody fusion environments. Experimental groups were given a higher dose (20 mg) of rhBMP-2 and a different carrier (biphasic calcium phosphate (BCP) carrier acting as a bulking agent) compared with experimental groups in the interbody fusion studies. In this prospective, multicenter trial, 25 patients were randomized to receive one of three different interventions. Patients in the control group received an instrumented fusion with autograft. Patients in the two experimental groups received either an instrumented fusion with rhBMP-2 with a BCP carrier or an uninstrumented fusion with rhBMP-2 with a BCP carrier. At 17 months, the radiographic fusion rate was 40% (2/5) in the control group and 100% (20/20) in the two experimental groups (P ⫽ 0.004). The investigators also found a significantly greater and faster improvement in patient-derived clinical outcome measurements in the two experimental rhBMP-2 groups.

Current and Future Applications of rhBMP-2 INFUSE is approved currently for primary anterior lumbar interbody fusion. The early results from several completed prospective, randomized clinical trials have demonstrated rhBMP-2 to be equivalent or superior to autologous iliac bone graft in both fusion rate and clinical outcome.32,33,35-38 Furthermore, no adverse effects related to the use of rhBMP-2 has been reported in contrast to the 30 to 40% incidence of persistent donor site pain related to ICBG. At longer term 10-year follow-up, Sandhu and coworkers have reported that no patients experienced adverse sequelae related to the rhBMP-2 implant.39 The future role of rhBMP-2 in spinal surgery applications remains to be determined (Table 3). Questions of rhBMP-2 with regards to (1) carrier/dose combination; (2) immunoge-

Table 3 Advantages of and Remaining Questions on the Clinical Application of rhBMP-2 Advantages

Remaining questions to be answered

1. Eliminate donor site morbidity 2. Decreased operative time and blood loss 3. Equivalent fusion rates to autogenous iliac crest bone graft 1. Improvement in clinical outcomes 2. Optimal dosage 3. Optimal delivery systems and/or carrier 4. Appropriate indications (interbody versus posteriolateral fusion setting) 5. Immunogenicity of growth factors and carrier 6. Nonfusion applications 7. Cost-effectiveness

rhBMP-2 in spinal surgery nicity; (3) cost-effectiveness; and (4) its role in nonfusion spinal applications will be the subject of future investigation. Further work is necessary to determine the optimal dosing in the interbody and posterolateral environment to improve on the preliminary results reported thus far. Preclinical studies have also demonstrated that the ideal delivery system for rhBMP depends on the anatomic location where the treatment is needed. Carriers for rhBMP are used to increase the retention of these growth factors at the fusion site while at the same time provide an osteoconductive matrix on which bone formation can occur. The study of different compressionresistant carriers, bulking agents, and easy-handling substrates in the posterolateral fusion environment are under current investigation. Moreover, percutaneous, injectable strategies to deliver rhBMP without direct exposure of the operative site are being studied. These injectable delivery systems could complement the minimally invasive approaches, techniques, and instrumentation which have now become commercially available in spinal surgery. The immunogenicity of these substrates and antibody formation to rhBMP-2 and its collagen carrier is a safety concern regarding the use of rhBMP-2. Serological testing from the previously mentioned clinical trials have demonstrated that patients do develop antibodies to rhBMP-2 and/or to their collagen carrier; these studies have shown that more patients develop antibodies to the collagen carrier rather than the rhBMP-2 itself.15,30,31 Although no adverse clinical sequelae associated with rhBMP-2 implants have been reported, the theoretical concerns regarding antibody formation and its interactions with fetal development, autoimmune disorders, and malignancies remain. The effect of maternal rhBMP antibodies on an unborn fetus through the placental barrier or a nursing child through lactation has not been studied and is unknown. Furthermore, the interaction of anti-BMP or anticollagen antibodies in patients with autoimmune disorders, collagen vascular disorders, immunodeficiency, or a history of malignancy is unknown. As a result of these potential safety concerns, rhBMP-2 is contraindicated in pregnant women, skeletally immature patients, patients with a history of malignancy, and patients with a known hypersensitivity to rhBMPs or collagen (Table 4). Critics argue that the high cost of rhBMPs preclude their routine use. The economic feasibility and allocation of health care resources to these emerging technologies will become the subject of future cost-analysis studies. Polly and coworkers developed an economic model based on clinical trial data, peer-reviewed literature, and clinical expert opinion to perform a cost analysis of rhBMP versus autogenous ICBG in a single-level anterior lumbar interbody fusion.40 They concluded that the front-end costs of rhBMP-2 (approximately $3400) would be offset to a significant extent by reductions in the use of other medical resources, particularly if costs incurred during the 2-year period following the index hospitalization are taken into account. Further study will be necessary to determine the cost effectiveness of these implants. The role of rhBMP-2 in the treatment of DDD will also be the topic of future investigation. Immunohistochemical stud-

19 Table 4 Contraindications and Unknown Indications to the Use of rhBMP-2 Contraindications

1. Pregnancy 2. Hypersensitivity/allergy to rhBMP-2 or bovine type 1 collagen (carrier) 3. Infection 4. Malignancy 5. Skeletal immaturity Unknown indications 1. Autoimmune disorders (systemic lupus erythematous) 2. Immunodeficiency (HIV/AIDS, radiation therapy, chemotherapy, steroid therapy) 3. Renal disease 4. Hepatic/liver disease

ies have demonstrated that BMPs and their receptors may play roles in the development of DDD.41,42 BMP-2 has been shown to increase proteoglycan, aggrecan, and type II collagen mRNA expression, which would be beneficial in maintaining an extracellular matrix of a healthy disc.41-43 BMP expression has also been shown to be downregulated in degenerative discs.44 Furthermore, BMP and its receptors have been shown to move from the hyaline cartilage of the vertebral endplate in healthy discs to the calcified cartilage at the site of enthesis in degenerative discs.45 Future studies will continue to investigate the exact role of BMP expression in DDD and may begin to explore techniques such as gene transfer to augment BMP production to possibly alter the progressive course of disc degeneration.

Conclusions Animal studies and clinical trials have demonstrated the efficacy of rhBMP-2 as an adjunct or substitute to autogenous bone graft in (1) posterolateral fusion; (2) anterior lumbar interbody fusion; and (3) overcoming inhibitory effects (ketolorac and nicotine) of fusion. Importantly, no serious adverse events or systemic side effects have been observed in these trials. The current FDA-approved application of rhBMP-2 is limited to one-level anterior lumbar interbody fusions with the use of a threaded, tapered, titanium fusion cage. The future role of rhBMP-2 in spinal surgery applications remains to be determined. The prospect of predictable and reliable osteogenesis without the need for secondary bone grafting to treat a wide spectrum of spinal disorders is tremendously appealing. However, the dose and delivery of rhBMP-2 has been shown to be site-specific and speciesspecific. Results for a specific condition or a specific region cannot necessarily be extrapolated to another condition or another region. Before there can be widespread acceptance of rhBMP-2 in spinal fusion applications, future investigations are needed to evaluate (1) the efficacy in variety of spinal conditions; (2) the optimal dose and delivery system; (3) the long-term safety profile (immunogenicity, antibody forma-

20 tion); and (4) the cost effectiveness of these therapeutic growth factors. Furthermore, the role of rhBMP-2 in nonfusion applications such as altering the progression of DDD is the topic of future investigation and remains to be determined.

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rhBMP-2 in spinal surgery 39. Sandhu HS, Kanim LE, Dawson ED. The safety and efficacy of purified native human bone morphogenic protein for spinal fusion. A ten-year follow-up study. Read at the Annual Meeting of the American Academy of Orthopaedic Surgeons; 1997 Feb 13-17; San Francisco, CA 40. Polly DW Jr, Ackerman SJ, Shaffrey CI, et al: A cost analysis of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusion. Orthopedics 26(10):1027-1037, 2003 41. Tim Yoon S, Su Kim K, Li J, et al: The effect of bone morphogenetic protein-2 on rat intervertebral disc cells in vitro. Spine 28(16):17731780, 2003 42. Li J, Yoon ST, Hutton WC: Effect of bone morphogenetic protein-2

21 (BMP-2) on matrix production, other BMPs, and BMP receptors in rat intervertebral disc cells. J Spinal Disord Tech 17(5):423-428, 2004 43. Kim DJ, Moon SH, Kim H, et al: Bone morphogenetic protein-2 facilitates expression of chondrogenic, not osteogenic, phenotype of human intervertebral disc cells. Spine 28(24):2679-2684, 2003 44. Sobajima S, Shimer AL, Chadderdon RC, et al: Quantitative analysis of gene expression in a rabbit model of intervertebral disc degeneration by real-time polymerase chain reaction. Spine J 5(1):14-23, 2005 45. Takae R, Matsunaga S, Origuchi N, et al: Immunolocalization of bone morphogenetic protein and its receptors in degeneration of intervertebral disc. Spine 24(14):1397-1401, 1999