Bone morphogenic proteins in spinal fusion

Use of Bone Morphogenic Proteins in spinal fusion

Bone Morphogenic Proteins and Spinal Fusion:
Written By - Dr Prakash Nayak, MS Ortho
Editor - Dr Ashok Shyam, MS Ortho

Research into Bone morphogenetic protein, or BMP, has seen a flurry of events in last decade. They seem to provide a better way to achieve spinal fusion with more success and less complications. An up-to-date review of role of BMPs in spinal fusion is reported below

SPINAL FUSION.....

Spinal fusion has always been a challenge. The success of this procedure is limited by morbidity from iliac crest bone graft harvest and a non-union rate that ranges from 10% to 40% [1,2]. This is due to the high forces borne by the spine and the instability rendered by surgery. Advances in spinal instrumentation have improved spinal fusion rates but not eliminated non union or spinal pseudoarthroses which often affects final surgical outcomes in 10% to 15% [2,3]. Traditionally autografts and allografts have been the mainstay for spinal fusions. The limited availability of autograft, significant morbidity (reported to be as high as 30%) and the variability in fusion success rate remain issues [4,5]. The osteoinductive and limited osteoconductive capacity of Allograft (mineralized or demineralised) is highly variable [6,7]. Various modalities used for enhancing fusion have included electrical stimulation, low intensity ultrasound and demineralised bone matrix (DBM).These have not been effective and their viability as a good alternative is questionable [8,9]. BMPs seem to answer all these difficult questions

UNVEILING OF A NEW HORIZON

The unique ability of devitalized bone to induce a cellular response resulting in new bone was observed and researched extensively by an orthopedic surgeon, Dr. Marshall Urist in the 1960s [10,11]. He subsequently extracted these organic components of bone using chaotropic agents, and named them “bone morphogenetic protein.”

In the 1980s, the proteins were individually identified and reproduced.

After numerous animal studies using BMP, it was used for the first time in 1997 in a clinical trial of patients undergoing spinal fusion. 10 of the 11 patients enrolled in the study had successful fusions within 3 months of surgery, all without the unpleasant side effects of bone grafting.

HOW DO THEY WORK
Bone morphogenic proteins (BMPs) are a heterogenic group of transforming growth factors (TGF). Recently up to 20 subtypes have been identified, their genes sequenced and cloned. Many have significant osteogenic effects and promote both intramembranous and endochondral ossification. BMPs work by stimulating mesenchymal stem cells through a complex system of second messengers, which are yet to be identified. Bone formed by BMPs is histologically and biomechanically identical to normal bone and undergoes normal fracture healing and remodelling10. Over a range of concentrations, rhBMP-2 results in endochondral bone formation including mesenchymal cell infiltration, differentiation of the cells into chondrocytes, removal of the cartilage, formation of bone, population of the bone with bone marrow elements, and ultimately normal remodeling of the bone [12].

MODE OF APPLICATION
Presently the BMPs are commercially produced by Recombinant deoxyribonucleic acid technology offering unlimited supply and substantial control over purity and reproducible activity [13]. One important problem is to find an efficient delivery system for BMPs. The ideal carrier system will retain and release the BMP in a controlled fashion, be biocompatible, not interfere with normal bony healing, be porous to promote osteoconductivity, be biomechanically strong, be easy to apply, and be easy to manufacture. Buffer delivered factors do not work in human beings as sufficient local retention of factors does not take place [14].Current delivery systems include following
1 calcium phosphate cements have been used as both injectable and implantable formulations of delivery.
2. Demineralised bone matrix, one of the first collagen-based carriers evaluated for BMP delivery had the major disadvantages of potential immunogenicity, risk of disease transmission [15].
3.The synthetic polymers eliminate the possibility of disease transmission associated with natural polymers [16].
4.Newer Viral vector systems deliver the cDNA of BMPs for osteogenic factors to cells at the site of orthopedic repair [17,18].
The combination of polyetheretherketone (PEEK) cage and rhBMP-2 has evolved as a front runner. PEEK cages are reported to be the ideal spacers, because they share the same modulus of elasticity as bone [19,20]. They are nonresorbable and elicit minimal cellular response when placed in vitro and in vivo [21].

Commercial aspects
Two BMP products are commercially available for clinical use, BMP-2 (INFUSE,
Medtronic, Memphis, Tennessee) and BMP-7 (OP-1 Putty, Stryker, Kalamazoo,
Michigan). BMP-2 is approved for anterior lumbar interbody fusion in skeletally mature patients and BMP-7 received a humanitarian use device approval in 2003 for revision intertransverse lumbar fusion in compromised patients [22],without the need for autologous graft. Although BMP is FDA approved for use only in the lumbar spine, recent work has focused on applications at other spine levels, including use in cervical interbody fusion [23]. The decision to use BMP to increase bony-fusion rates may decrease the need for a revision fusion procedure; therefore, cost-effectiveness analyses must be include d in longitudinal outcomes analysis .The preliminary data shows that from a payer perspective, the upfront price of BMP is likely to be entirely offset by reductions in pain, complications of autograft and fusion failures. Additionally, by eliminating the need to harvest the autograft, anaesthesia time and surgeons’ fees would be offset [24]. Less obvious cost offsets include decreased blood loss and obviated treatment of donor site complications as well as potentially decreased transfusion requirements and shortened hospital length of stay.


PRESENT SCENARIO
Specific guidelines for rhBMP-2 and rhBMP-7 use are lacking because of the limited availability of randomized controlled clinical trials and its diverse use in many spinal applications. Mechanisms of delivery, carrier type, graft position, surgical location, and variations in BMP concentration may differ from one surgery to the next. Adverse events linked to either rhBMP-2 or rhBMP-7 use include ectopic bone formation, bone resorption or remodelling at the graft site, hematoma, neck swelling, and painful seroma [25]. The cascade of major phases involved in the healing of bone include an initial acute inflammatory response, a resorptive phase, subperiosteal and endosteal proliferation, bone formation, consolidation, and finally remodeling by osteoclast and osteoblast activity. In the process of fusion, rhBMP-2 causes a phase of increased resorption. During this period the cage is prone to migration and subsidence may occur [26].Neck swelling and hematoma have been significantly associated with the off label use of BMP in cervical spine surgeries. Other potential theoretical concerns include carcinogenicity and teratogenic effects.

 HOW SAFE ARE THEY
FDA Public Health Notification- issued July 2008 [27]

Regulatory Status of rhBMP
FDA has approved the use of two rhBMPs for well-defined medical conditions in limited patient
populations: