Bone Morphogenic Protein: Current State of Field and the Road Ahead

*Dr. Vaibhav Bagaria. MBBS, MS, DO, FCPS.      #Dr V Prasada. Phd

*Fellow, Spine, Medical College of Wisconsin, Milwaukee, USA
#Post doctorate Fellow, Medical College of Wisconsin, Milwaukee, USA.
 

Address for Correspondence:
Dr. Vaibhav Bagaria
Department Of Orthopaedic, Medical College of Wisconsin,
9200 W Wisconsin Avenue, Milwaukee, WI 53213, USA
E-mail address: vaibhavbagaria@rediffmail.com
 

ABSTRACT

Bone morphogenic proteins (BMP) have shown significant potential in enhancing spinal fusions and bone formation at non-union sites. Animal studies and limited human studies have proven their efficacy as an alternative or enhancer of autologus bone graft in bone regeneration. Optimal dose and carrier especially in complex scenarios like recalcitrant non unions posterolateral spinal fusion still remain an important issue where the use of BMP has not been entirely successful. Their use in fields like articular regeneration, joint replacement and chronic renal failure is also being aggressively investigated. This review article intends to give brief information on the biology and basic science behind BMPs and provide an update on the current research data on various clinical applications of BMPs.

Key Words: Bone morphogenic protein, Spine fusion, Fracture healing, Bone regeneration, rh BMP 2, OP –1

J.Orthopaedics 2005;2(4)e3

Introduction

Use of biofactors for bone regeneration has revolutionized the management of fracture and spinal fusion. Various biological factors, such as bone morphogenic proteins (BMP), fibroblast growth factors (FGF), platelet-derived growth factor (PDGF), insulin like growth factors (IGFs) and LIM mineralization protein-1, have been investigated for application in bone regeneration and skeletal repair. Despite remaining the gold standard for most orthopaedic procedures, autologus bone graft suffers from significant disadvantages (Table 1). Different approaches are being tried to achieve sound bone regeneration (Table 2) and the look out for idea bone graft continues (Table 3).  

Table 1:Disadvantages of autogenous bone graft 
 

Table 2: Current approach towards Bone regeneration: 
Osteogenic Methods:
            Autogenous Bone grafts.
            Allogenic bone grafting.
            Autogenous bone marrow grafting.

 Osteoinductive Method:
            Bone Morphogenic proteins.
            Platelet rich plasma containing growth factors like PDGF, IGF I and II, TGF beta.

 Osteoconductive methods:
            Calcium based ceramic grafts.
            Calcium based collagen substitutes.
            Synthetic polymers.
            Bioactive ceramics and glasess.

 Systemic agents:
            Prostaglandins.
            Osteogenic proteins present in systemic circulation.

Bone Morphogenic proteins or BMP as a viable substitute to autologus bone graft has been subject of intense research in last few decades and has followed a long and iterative process to provide a burden of proof for clinical use at present time (Fig 1). They are by far the most extensively studied orthobiologic product in history and over 2000 peer-reviewed publications in worldwide literature have studied their application. The long awaited approvals for the clinical use and commercial availability have only recently been granted. The research in field of BMP is being pursued relentlessly and studies on their mechanism of action, optimal formulations, and alternative uses continue. This review article intends to give brief information on the biology and basic science behind BMPs and provides a latest update on the research data on various applications of BMPs for clinical use.

Figure 1: Burden of proof assessment for rh BMP 2

Table 3: Features of an ideal bone graft substitute 

History

Dr Marshall Urist in 1965 pioneered the concept of presence of a substance that is naturally present in the bone and is responsible for regeneration and repair activity in the bone, he called this substance bone morphogenic protein (BMP), later also known as osteogenic protein or OP. Since then the path breaking research provided newer insights into the nature of bone biology and the break through in the recombinant technology made commercial availability of BMP products a reality (Table 4).  

Table 4:History of evolution of Bone Morphogenic protein: 

These proteins have been isolated from the bones of a variety of mammals - mouse, rats, bovine, monkey and man and also from clonal osteogenic sarcoma lines. In 1979, Urist et al showed that BMP can be extracted from animal cortical bones by digesting the demineralized bone matrix with bacterial collagenase and solubilization of the digest in a neutral ethylene glycol and a salt mixture. The extracted BMP was found to induce bone formation in not only the same species but also in other species. The human BMP was later extracted by Bauer and Urist using a 4M guanidine hydrochloride solution, this extracted substance was shown to induce bone formation in thigh muscles of athymic nude mice. 

In 1980’s bone inductive preparations were purified from bovine bone in sufficient quantity and purity to provide amino acid sequence data. Using these sequences, nucleic acid probes were generated and used for the identification and characterization of DNA sequence encoding these proteins. With advent of better isolation techniques and the research leading to recombinant cloning techniques, a large number of molecules that form part of the BMP family have been described and have provided a vital impetus to research in this field (Table 5).  

Table 5: BMP and their alternative names: 

The availability of recombinant human BMP (rh BMP) created an opportunity to assess the material properties devoid of impurities and without the potential risk of xenograft reaction during human use. All except BMP 3 have shown to be osteoinductive. BMP 3 has in fact shown to be an inhibitor of osteoinductive activity in the rat assay, this is interesting given the fact that the BMP 3 is the most abundant BMP in bone.

Bone Morphogenic Protein Classification, Character and Properties

BMPs are members of the TGF – beta super family. The super family compromises of proteins that are coded for by a 45-gene sequence that has a highly characteristic conserved 7 Cysteine motifs in their mature domain.  This super family of proteins contains: five isoforms of TGF –Beta (TGF beta 1 through TGF beta 5), the BMPs, growth differentiation factors (GDFs), activins, inhibins and Mullerian inhibiting substance. The superfamily has impact on a wide array of cellular activities including growth, differentiation and extracellular matrix formation. 

 BMP is the largest sub group belonging to the TGF beta superfamily. They are synthesized and stored as large dimeric proteins in the cytoplasm and cleaved by proteases during secretion. The structure of BMPs that has been most extensively studied in OP 1 is one of a polypeptide containing 431 amino acids. The crystal structure described for OP1 and BMP 2 consists of a “hand shaped structure” comprising two fingers of anti parallel beta strand and an alpha helical region at the heel of the palm. 

Signaling pathway: BMP exert their effect through activation of transmembrane heteromeric receptor complex formed by types I and type II serine /threonine kinase polypeptides, also known as the BMP receptor (BMPR) type I A and I B and BMPR Type II.  The activated receptor kinases in turn phosphorylate the transcription factors Smad 1, 5, and 8. The phosphorylated Smads then forms a heterodimeric complex with Smad 4 in the nucleus and activate the expression of target genes in concert with co activators. 

BMP localization: Traditionally BMP were considered localized to bone but subsequent studies have shown that BMPs are expressed in most other tissues and throughout the embryonic development. Some of these members of BMP family have also been mapped to different chromosomes loci’s: BMP 2 (Chromosome 20), BMP 3 (Chromosome 4), BMP 4 (Chromosome 14), BMP 6 (Chromosome 6), BMP 7 (Chromosome 20), BMP 8 (Chromosome 1), BMP 15 (chromosome X). 

Biological Activity: BMP are pleiotropic regulators orchestrating various sequential cellular response: chemo taxis of cells, mitosis and proliferation of progenitor cells, differentiation into chondroblasts, cartilage calcification, vascular invasion, bone formation, remodeling and bone marrow differentiation. BMP also stimulates extra cellular matrix formation and besides its osteogenic potential the BMPs have also shown to have an effect of the development of other organ and tissues particularly those form through the mesenchymal-epithelial interactions.  

Implantation of purified recombinant BMP with bone collagen matrix in subcutaneous sites in rats has shown to induce a sequence of cellular event leading to formation of new bone with all its elements (Table 6). The BMP stimulates the stem cells to proliferate and differentiate into chondrocytes. This transformation takes 5 to 7 days, following which the capillary invasion takes place. The chondrocytes subsequently hypertrophies and becomes calcified, and the osteoblasts appear at the implant site. The new bone formation is seen at 9-12 days and subsequent remodeling and formation of ossicles and bone formation takes place in next 14 –21 days. This process is identical to the physiologically occurring enchondral ossification. A process similar to intramebranous ossification in which stem cells directly differentiate into the osteoblasts has also been seen with BMP in some in vitro studies. However this effect may be seen only at a higher concentration of BMP.

Table 6: Biological action of BMP: 

Development and production: The extracted BMP from bone was not a commercially viable option and this prevented the exploitation of BMP technologies in 80’s and 90’s, but with the evolution of recombinant technology the commercial development of BMP took the center stage of the mainstream research in orthopedics. The recombinant methodology results in extreme pure solutions of a single BMP. The recombinant technology used to develop and manufacture BMP involves two steps:

• Identifying and cloning the human gene for BMP.
   

• Production of rh BMP.

The Specific genes responsible for carrying code for making BMP in humans were identified at Genetics institute.  Once this gene was identified and isolated, it was spliced and recombined into the DNA of a commonly used production cell. This insertion or ‘recombination’ of gene results in formation of a “recombinant”. The recombinant cell grows and multiplies by a process known as ‘cloning’. This results in development of a homogenous population of cells producing a recombinant human bone Morphogenic protein. Batches of recombinant cells are preserved in several small vials for future production also known as cell banking. The cell bank is maintained at –135 degree centigrade for future production of BMP. The recombinant cells when cultured in optimal media produce the BMP that after appropriate purification process is available for commercial use. 

 The commercially available BMPs approved currently by US FDA are:  rh BMP 2- Infuse (Medtronics Sofamor Danek, Memphis, Tenesse) and OP1 (Stryker Biotech, Hopkinton, MA). Other BMP products that are being currently evaluated for commercial use include BMP –X (Sulzer Biologics, Wheat Ridge, Colarado), BMP –9 and combinations of animal and human BMP implant. 

Delivery Material: Carrier for BMP needs to perform a three-fold function:

1. Maintaining a critical threshold concentration of BMP at implantation site for the required period (Temporal Distribution)

2. Act as scaffold over which bone growth can occur.

3. Contain the BMP at the localized site and prevent extraneous bone formation. (Spatial containment).

The delivery material in addition to these, should be biocompatible and biodegradable, and allow a rapid neo angiogenesis and invasion by mesenchymal cells. It should resorb over time as the new bone forms and remodels. Application specific carrier are being tested that will enable release of BMP over an adequate period in adequate concentration. Various materials have been evaluated for local delivery of BMPs for new bone formation (Table 7). An absorbable collagen sponge (ACS), reconstituted from bovine tendon, and a collagen based matrix, derived from demineralized/guanidine – extracted bovine bone, are two most common delivery materials currently being used for rh BMP-2 and rh BMP-7 respectively. The collagen in these delivery materials is a natural component of the bone and preclinical studies have indicated that they may also play a role in pharmacological stimulation of local bone by both proteins. Several recent studies have led to enthusiasm about injectable solution in a buffered media as an alternative to solid phase matrix carriers. 

Table 7: Various carrier materials available for BMP: 

Dosage Related Toxicity: There have been many preclinical toxicity studies to evaluated acute and systemic toxicity, bio distribution, reproductive toxicity and carcinogenity of BMPs. BMP has demonstrated excellent safety profile in most studies. Studies have even used up to 1000 times the dose that are used clinically and did not find any adverse drug reaction. The preclinical toxicity study have shown that direct injection of high doses of rh BMP 2 (5.3mg/kg) into the blood stream did not have significant adverse effects. The possible reason behind the lack of adverse drug effect with high doses of BMP may be its extremely short half-life that has been found to be less than 1 min. After orthotopic injection the maximum blood level that rh BMP 2 achieves is only 0.1% of the implanted amount, this amount also disappears very rapidly from the circulation. Another study that investigated the adverse effect of BMP after direct application to nervous tissue, found no adverse physiologic or permanent histologic effects on these tissues. This is encouraging in view of the fact that certain application of BMP in spine surgery may involve such a scenario. 

Carcinogenicity: There is no evidence that the BMP is carcinogenic. Conversely, it has shown anti proliferative effect in vitro on human breast, ovary, lung and prostate cells. Pre clinical safety studies have shown to have inhibitory effect on the human osteosarcoma, prostate, lung, breast and tongue carcinoma line.  

Antibodies formation against BMP: Studies have documented presence of antibodies to rh BMP 2 in patients treated with rh bmp 2 collagen sponge in tapered cages for anterior spinal fusions to extent of 0.7%, raising the possibility that its use may not be effective in all group of patients. However this is still not an issue yet with its use in clinical practice. 

Ectopic Bone Formation: The formation of ectopic bone outside the desired field is also a potential concern that is aggressively being investigated. Paramore et al evaluated the toxicity of OP-1 by placing OP-1 into the epidural space after laminectomy and posterolateral fusion in a dog model. They found that animals with OP –1 implantation demonstrated bone formation adjacent to spinal cord that caused mild spinal cord compression. The spinal cord histology however, showed no evidence of spinal cord inflammation or neuron cell death. Some other animal studies however did not find any bony encroachment on the exposed thecal sac after laminectomy and intertransverse arthrodesis with the use of rh BMP 2 in non-human primate model. 

In a pilot human clinical study in which cages filled with rh BMP 2 in a collagen carrier were inserted through a posterior laminectomy approach, several patients demonstrated formation of heterotopic bone in the spinal canal posterior to the fixation device and tract of their insertion. There were no clinical implications resulting from these ectopic site bone formation but in view of these findings the study was halted before completion. These findings of ectopic bone formations was also corroborated in a similar dog study. The present consensus based on these limited available information has not suggested limitation of BMP use after repair of dural tears or open laminectomy defects. 

Dose and Concentration: The dose and concentration of BMP required varies from species to species (Table 8) and from fusion site to fusion site. In humans, for anterior interbody fusion a total dose of 4.2 –12 mg of rh BMP 2 at concentration of 1.5mg/ml is recommended. The recommended total dose of OP 1 as humanitarian device exemption for recalcitrant posterolateral fusion non union is 7 mg for both sides. For inter transverse arthrodesis, the suggested dose of rh BMP 2as based on pilot clinical trials is 20mg on each side at a concentration of 2.0mg/ml used on a carrier containing 60% hydroxyapatite and 40% tricalcium phosphate granules. The recommended dose of OP1 for recalcitrant long bone non-unions is 7mg or two vials (each containing 3.5 mg reconstituted with 1gm of type I bovine collagen resulting in a net 4 ml volume) for implantation at the non-union site. 

Table 8: Rh BMP 2 Concentration in different species 

Clinical application 

The development of BMP followed a long iterative trial and error process in the preclinical models. First studied as implants in subcutaneous sites in rabbit that produced ectopic bones, the early surgical studies for evaluation of the osteoinductive properties were done on large critical sized diaphyseal segmental defects in rats, rabbits, dogs, sheep and non-human primates. These studies showed that implantation of the BMPs carrier matrices in these defect led to bone formation that was biomechanically and biologically sound. BMP was also shown to accelerate bone formation and repair process in non critical size defects in closed fracture models that showed an early return of strength and stiffness. Various clinical scenarios where BMP are currently approved or are being aggressively being are described below:

Anterior interbody Fusion:
Preclinical studies: The first pre clinical interbody cage study was done by Sandhu et al  who compared single level anterior lumbar interbody fusion rates at 6 months in sheep models using cylindrical threaded titanium cages filled either with iliac crest graft or rh BMP 2 on collagen sponge. Out come were determined using radiographs, biomechanical tests and histologic analysis. Radiographically all animals achieved fusion, but the groups differed on the quantity and quality of bone formation histologically. Compared to 37% histologic fusion rates at 6 months in autograft filled cage group, 100% fusion rates were seen with cages filled with rh BMP 2 on collagen sponges. In addition the rh BMP 2 group fusion masses had less fibrous in growth. 

Other animal studies showed a similar results: Zdeblick et al used a titanium (BAK) cage in a goat model and demonstrated a fusion rates of 95% when the cages were filed with rh BMP 2 in contrast to 48% fusion rates when the cages were filled with autograft.. Boden et al later performed the study using rh BMP 2 on the collagen sponge in a titanium lumbar interbody cages at varying dose in rhesus monkey and it was based on his results that a dose of 1.5mg/ml was selected for subsequent human trials.  

Human studies: A prospective, multi center, randomized trial in humans was done to evaluate the efficacy of rh BMP 2 on collagen sponge in a lumbar tapered cage (INFUSE / LT cage, Medtronic Sofamor Danek, Memphis, USA) for a single level interbody fusion. A total of 143 patients were enrolled in the study group and 136 patients were enrolled in the control group for this study. The experimental group was treated with LT cage with INFUSE and the control group was treated with same cage filled with iliac crest auto graft. At six months 99.2% (128/129) patients showed successful radiographic fusion compared to 96.7% (119/123) patients in the control autogenous graft. At 2 years all patients (117/117) treated with INFUSE showed a successful radiographic fusion compared to 97.2% (99/102) in the control autogenous group. The clinical improvement that was defined by a 15-point improvement in Oswestry score also followed a similar trend. While 76.9% of patients in the experimental group had successful clinical out come, 75.2% had a positive clinical outcome in the control group. 

Another prospective, multicentered randomized trial using allograft bone dowel instead of the lumbar tapered cage, studied the efficacy of rh BMP 2 (INFUSE). A total of twenty-three patients were enrolled in the control group and twenty-four patients were enrolled in the experimental group. All patients under went a single level anterior discectomy and fusion via an open approach. At one year, 83% of patients treated with INFUSE had more than a 15 point improvement in their Oswestry scores compared with only 58% in the control group. Both group had 90% fusion rates at one year. The blood loss was significantly less (p=0.026) in the experimental group than in the control group.

Posterior Lumbar Interbody Fusion (PLIF):
Preclinical Studies: Magin and Delling performed a posterior interbody fusion and supplemental transpedicular instrumentation study in 30 sheep interbody fusion model. They compared OP-1 (3.5 mg of rh OP1 to 1g of bovine collagen), an osteoconductive HA bone graft substitute and autograft. The sheep fusion was assessed using CT, radiographs, mechanical testing and histology. The amount of bone formed using OP-1 was statistically higher in OP-1 group as compared to autograft and HA treated group. Mechanical testing and histology also confirmed that the maturity and stiffness of the fusion in OP-1 treated group was higher than HA group.  

Chirossel at al compared fusion rates with OP1 and autograft in a sheep model using either a polyethereketone (PEEK) cages or a titanium cage. 22 sheeps were evaluated for fusion using radiographs, Histomorphometry, flurochrome labeling, CT imaging and histology. At 24 weeks, solid boney fusion was seen in three of four titanium cage/autograft animals, three of five-titanium cage/rh OP 1animals, two of four PEEK/autograft animals and four of five PEEK/OP-1 animals. These numbers were too small for statistical significance but histology showed a more mature trabecular bone within fusion site in the group of animal treated with OP-1. 

Human studies:  A prospective, randomized controlled trial was done to compare the efficacy of rh BMP 2 (INFUSE) and autologus graft when used with cylindrical, threaded cages (INTERFIX, Medtronic Sofamor Danek). These devices were used for single level posterior lumbar interbody fusion, performed via a posterior laminectomy approach. Sixty-seven patients were enrolled at 14 investigational centers, thirty-three under went PLIF with INTERFIX and autogenous bone graft, while thirty-four under went PLIF with INTER FIX and rh BMP2.

At twenty four months follow-up period, The fusion rates in the experimental rh BMP 2 group was 92.3% compared to 77.8% in the control autogenous group. Interestingly both groups had a high number of tobacco users: 52.9% of the thirty-four in the experimental group and 45.5% in the control group. Another FDA approved study is under way to study the use of rh BMP 2 with impacted interbody devices stabilized with posterior instrumentation. 

Anterior Cervical discectomy and Fusion: rh BMP 2 (INFUSE) has also been studied for application in cervical spine interbody fusion. The prospective, randomized controlled study enrolled thirty three patients from four different centers. The study involved the implantation of machined fibular ring allograft (Cornerstone; Medtronic Sofamor Danek) filled either with auto graft or rh BMP 2. Eighteen patients in the experimental group received the rh BMP 2 and fifteen in the control group were treated with autograft. All patients had fused radiographically at six months; however the mean blood loss in rh BMP 2 group was less (91.4 ml) compared to the control group (123.3 ml). 

Posterolateral fusions: In contrast to the interbody spinal fusions, the posterolateral fusion poses a far more complex challenge. With the structural containment that the interbody cages provide gone, the pre clinical studies found that the collagen sponge did not serve an adequate delivery medium for BMPs in higher primate animals.  

Animal studies: Schimandel et al compared autogenous bone graft and rh BMP 2 in a rabbit posterolateral fusion model. Inspection, manual palpation, radiography, histology, and biomechanics testing were used to assess the fusion. All rabbits implanted with recombinant human bone morphogenetic protein-2 achieved solid spinal fusion as confirmed by manual palpation and on radiographs, whereas only 42% of the autograft control fusions were solid. Fusions achieved with recombinant human bone morphogenetic protein-2 were found to be biomechanically stronger and stiffer than fusions achieved using autogenous bone graft. Sandhu et al performed a similar fusion study in a dog posterolateral fusion model and demonstrated 100% fusion rates with use of rh BMP 2 on collagen sponge as compared to 0 % fusion rates in the autograft group. These results were replicated in a subsequent trial where BMP induced fusion even in absence of decortication. 

Cook et al compared the fusion rates using either OP 1 (2.8 mg of rh OP 1 to 800 mg of bovine collagen) or auto graft in a dog model. All OP1 treated levels showed a stable fusion mass by 6 weeks and complete fusion by 12 weeks as demonstrated using CT Imaging, MRI Imaging, non-destructive manual testing and histology. The autologus treated levels achieved similar fusion rates but demonstrated a slower progression taking upto 26 weeks. 

However this success in lower animals did not translate as such in the higher animals. Martin et al demonstrated that the rh BMP 2 in a concentration of 0.43 mg/ml that was effective in lower animals was not effective in Rhesus monkey. It was hypothesized that overlying muscle mass may have been the cause of mechanical compression of the collagen sponge resulting in its splaying. This reduced the local concentration of BMP at the site, consequently impeding the bone formation. 

In order to avoid the problems associated with mechanical compression and splaying of the collagen sponge alternative carriers were investigated. These carriers unlike collagen sponge (that has a wet tissue paper like consistency on getting soaked) were more compression resistant and maintained higher concentration of BMP at the local site. Boden et al  developed a highly porous biphasic calcium phosphate (BCP) ceramic carrier consisting of 60% hydroxyl apatite and 40% tri calcium phosphate for use in posterolateral fusions in primate. They were able to demonstrate fusion was achieved at different rh BMP 2 concentrations (1.4, 2.1 and 2.8mg/ml) but was not achieved in any animal in which auto graft was implanted.  

Human studies: In view of the findings obtained from the non-human primate studies, different concentration and carrier media were investigated for use in humans. Boden et al followed their primate study with a pilot prospective randomized study in human subjects suffering from a single level degenerative disc pathology and showed 100% fusion rates with rh BMP2 in biphasic calcium phosphate (BCP) carrier media as compared to only 40% fusion rates in the auto grafted group.  

 In another human study, Patel et al did a safety and efficacy study for use of OP-1 in posterolateral spinal fusion. Sixteen patients suffering with degenerative lumbar spondylolisthesis were randomized in to two groups of autograft without instrumentation and autograft and OP-1 without instrumentation. At 6 months, the autograft and OP-1 showed a 75% fusion rate as compared to only 50% in the autograft group alone. Clinical success as defined by improvement of 20% or more of Oswestry score was seen in 83% of auto grafted and OP-1 patients compared to only 50% in the auto grafted patients. 

At time of writing this paper the BMP is still not approved for routine use in posterolateral fusion. The use of OP 1 for revision fusion surgeries is however allowed. 

Non-Unions:  Delayed and non-unions have always remained a challenge for orthopedic surgeons. The earliest use of BMP was done in femoral non-union in 1988. Johnson et al. treated twelve patients with an intractable femoral non-union and an average of 4.3 previous attempts at surgical union, with internal fixation and partially purified BMP extract. Eight of the twelve patients also received either an autogenous or an allogenic bone graft. Eleven of the twelve patients healed after this single intervention. The same researchers later reproduced their results in tibial non unions where in six of the patients with 3 –17 cm of tibial segmental defect non union successfully healed after a single implantation of purified BMP and autograft.

In 1992 the first FDA approved investigational human clinical trial for evaluation of OP 1 in treatment of tibial non union was started. 122 patients with 124 established tibial non unions were randomized in two groups, one group of 61 patients (61 non unions) were treated with intramedullary rod and fresh autogenous bone graft, the other group of 61 patients (63 non unions) was treated with intramedullary rod and OP1.  The patients were assessed at 3, 6, 9, 12 and 24 months for severity of pain at the fracture site, ability to walk full weight bearing, need for second intervention, and radiographic evaluation of bony union. Clinically satisfactory outcome was observed in 81% of population treated with OP 1 as compared to 85% of the auto graft treated group. The OP1 group had significantly less blood loss, a shorter hospital stay and a decreased operative time. The radiographic evidence of union was established in 75% of OP 1 treated case as compared to 84% cases, the difference was considered statistically insignificant (p=0.218). 

Other clinical experiences have confirmed the above evidence, In a study of 31 patients with 6 tibial, 9 clavarial, 10 humeral, 2 ulnar and 4 femoral non unions who under went standard internal fixation supplemented with OP 1, McKee et al found abundant new bone formation in all 31 patients and fracture healing at a mean of 13 weeks without any adverse clinical event in response to OP1. A retrospective study of 12 humeral non unions treated with OP 1 Implant ™ by Susarala et al showed clinical and radiographic evidence of union in 11 of the twelve patient at an average of 162 days.  

Open Tibial Fractures: In a randomized prospective study  investigators who organized themselves under BMP– 2 evaluation in surgery for tibial trauma (BESTT) study group, reported the results of a study in 450 patients with open tibial fractures. 450 patients were randomized into two groups: One group received a standard care in form of initial irrigation and debridement followed by a statically locked intramedullary nail. The second group received either 0.75 or 1.50 mg/kg rh BMP 2 on an absorbable collagen sponge at the time of wound closure. 

58% patients treated with 1.50mg/kg rh BMP-2 healed compared to only 38% patients healed in the group, treated with standard care (p=0.0008). Moreover the patients who received rh BMP 2 had fewer hardware failures, fewer infections and demonstrated faster wound healing. 

At present times, the indications of BMP use in fracture cases include: use of BMP 7 or OP1 in cases of recalcitrant non unions and BMP 2 in cases of acute open tibial fractures.

Potential application (still in investigational stage):

Intervertebral disc repair: The use of BMP in affecting the intervertebral repair had some encouraging results in animal models. Disc defect models were created in rabbit- either using a lysis model that involved injection of chondroitnase to disrupt the extra cellular matrix or a needle puncture model. Aqueous rh BMP -7 (OP1) was injected in disc spaces four weeks after creation of the defect. The animal were then followed over a period of three months. A control disc defect group, which did not receive OP 1, was followed for same period.  After 3 months, while the disc that received the OP –1 demonstrated a recovery of disc height almost equivalent to original disc height, the control group showed an approximate 40% reduction in the disc height. The above findings suggested the possible etiopathologic and therapeutic role of BMPs in disc degeneration and repair. 

Role in total joint arthroplasty: Cortical perforations, bone loss, acetabular defects, and periprosthetic fractures are some of the challenges that total joint replacement surgeons encounter today. Auto grafts or in some instances allograft are currently used to tackle these complex issues. Studies have shown that healing of cortical strut graft to femur is significantly increased with addition of OP 1. These findings are significant in view of the fact that autograft when used alone, although leads to healing of the defects does not necessarily leads to boney in growth. The use of allograft that appears to be an attractive alternative suffers form lack of the osteoinductive properties of auto graft or BMP. 

Osseo integration of prosthetic devices: The studies that have investigated the effect of BMP as direct coating on implants or in conjunction with carrier material have shown that BMP can promote Osseo integration at the implant bone interface.

 Distraction Histogenesis: Nature of regenerate in Illizarov technique for treating non unions have a significant bearing on the final out come. The use of BMP 2 and OP 1 (BMP7) as injection at the distraction site prior to distraction and during consolidation phase is being currently evaluated.  

Osteonecrosis of femoral head: Present treatment of avascular necrosis or osteonecrosis of femoral head includes core decompression, bone grafting and in later stages hip arthroplasty. Ongoing research is studying the possible role of implantation of BMP after removal of the necrotic core, either alone or in combination with other growth factors.

 Repair of articular cartilage with OP 1: Articular cartilages have a limited potential for repair and following injury or degeneration, secondary procedures like arthroplasty are required to maintain joint congruity. BMP 7 and BMP 2 have shown promise in repair of full thick osteochondral cartilage defects in animal models. A study designed to evaluate the effect of OP-1 on full thickness osteochondral defects in sixty five mongrel dogs demonstrated that implantation of rh BMP 7 into full thickness articular cartilages improved the histologic appearance of the repair tissue compared with that of both untreated and collagen carrier control defects. 

Beyond bones - effect of BMP on joint development, articular cartilage, kidney development, neural tissues, and cancer:  

BMP name can at best be considered misleading for this group of molecules that have shown to regulate biological processes as diverse as cell proliferation, apoptosis, cell differentiation, cell fate determination and morphogenesis. BMPs have effect on development of all three germ layers, and thus the development of nearly all organs and tissues. It helps orchestrating a well-executed basic embryonic body plan.

 BMPs are potent morphogens, capable of inducing mesenchymal cells into chondrocytes. The earliest studies involving the rabbit knee to study regeneration of artificially created osteochondral defect have shown an accelerated formation of subchondral bone and improved cartilage formation82. In view of its multipotent role in nearly all the aspects of development and regeneration, its role is aggressively being tested for clinical application in multitude of fields beyond orthopaedics. One of the most interesting fields where their use has potential of revolutionizing the management is its use in management of nephropathies. BMP 7 has shown to partially reverse diabetic-induced kidney hypertrophy, restore GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression has been shown to be associated with a successful repair reaction and a reversal of the ill-fated injury response. Another recent study on role of BMP in reversing renal damage has suggested that adult renal fibroblasts might retain parts of their original embryonic imprint and plasticity, which can be re-engaged by systemic administration of BMP-7 to mediate repair of tubular injury in a fibrotic kidney.

Conclusions 

After decades of intense research BMPs have finally moved from the realm of in vitro to in vivo. BMPs have demonstrated beyond doubt their role as a superior alternative of autogenous bone graft. Recent research has instilled renewed hopes of its use in varied musculoskeltal conditions including disc regeneration, cartilage repair, osteonecrosis and hip arthroplasties. Progress in delivery materials and techniques may further its use in minimally invasive procedures which will decrease not only the operative time, but also decrease the overall morbidity and recovery time.  

Amidst this enthusiasm of use of BMP in varied clinical situations, some studies however sound words of caution. Much of the data in BMP research has been derived from animal studies which are important as far as providing base line data for further clinical studies is concerned, but it would be prudent not extrapolate data as it is to humans. The rate of bone repair is inversely related to the position of a species on the phylogenetic scale so that there is decreased potential of bone formation in humans and higher primates when compared to lower animals like mice and rabbits, moreover the quadrepeds have different biomechanics compared to upright humans.  A host of other factors including smoking, age, steroid use, osteoporosis, malnutrition, disease severity play a role in determining the physiology of bone regeneration in humans. Thus the true efficacy and safety of these agents for different scenarios must be established in carefully designed prospective randomized clinical trials before they are approved for use.  

On the sunny side, the impact of the discovery and progress in this field can be gauged by the fact that its use as bone graft substitute alone has potential to replace the autogenous bone graft in 1 million procedures that are performed world wide every year. The potential for its use in other sectors is still untapped and the actual impact of discovery will be fully known only after some years. A disconcerting issue however is the cost of BMP. Currently the estimated cost of BMP at 3000$ to 5000$ limit their clinical use to selected clinical scenarios like recalcitrant non-union and revision fusion surgeries, it is however hoped that the cost drops and BMP eventually becomes as affordable as other recombinant products like recombinant insulin or recombinant vaccine, enabling its use in majority of indicated patient population. 

In a nutshell it is time for orthopedic surgeons to look beyond just the bone and metals and embrace newer technologies that involve manipulation of cellular environment to achieve the desired bone formation and BMP may just be the road ahead.

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 This is a peer reviewed paper 

Please cite as :Nasser Janmohammadi:Vaibhav Bagaria:Bone Morphogenic protein: Current state of field and the road ahead.

J.Orthopaedics 2005;2(5)e2

URL: http://www.jortho.org/2005/2/5/e2

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