The bone graft product market is flooded with more than 300 available products, but not all are equal in terms of the level of scientific and clinical evidence supporting their use. Consequently, healthcare professionals must bridge this gap as they make decisions about the products they choose for their patients.
During a Cerapedics-sponsored webinar on April 20, Michael E. Janssen, DO, founder of Thornton, Colo.-based Center for Spine and Orthopedics, and Scott Johnson, PhD, director of clinical marketing and education at Cerapedics, discussed the importance of choosing a bone grafting material based on evidence.
Bone graft basics
A bone graft is a synthetic, inorganic or biologically organic combination intended to treat a bone defect in place of, or in combination with, autogenous or allogenous bone. "Despite the number of bone graft substitutes available on the market today, there are various mechanisms of actions and only the bone cells themselves — which we refer to as osteoblasts — produce, manufacture and grow bone," said Dr. Janssen.
Clinicians tend to possess the following expectations of bone graft substitutes:
• Enhances natural process, encouraging the body to repair itself
• Only healthy bone is present at the end of the process
• Bone healing occurs within a physiologically acceptable time
• The product is safe and predicable with evidence of efficacy
Dr. Janssen notes the real gap is in safety and predictability of bone graft substitutes, as most of the technologies on the market don't possess proven efficacy. As a result, autograft continues to serve as the "gold standard" in bone healing, as it features the three key properties of incorporating biological bone:
• Osteogenesis: Synthesis of new bone by donor cells from host or graft donor, such as autograft or stem cells
• Osteoinductivity: Growth factors that encourage differentiation of host mesenchymal stem cells to bone-forming cells, such as bone morphogenetic proteins
• Osteoconductivity: Implanted scaffold that permits ingrowth of host vasculature, cells and tissue, such as resorption of calcium phosphates
"Not only is autograft the gold standard for the efficacy, we're using the patient's own bone stock so there's really no risk of transmittable issues or histocompatibility," explained Dr. Janssen.
Autograft is not free from disadvantages, however. A limited supply; risk of second site morbidity; increased operating room time; longer hospital stay; and potential increased costs are all barriers to use.
"There are disadvantages, and we weigh these disadvantages against some of the synthetic properties of new technologies that may be more equivalent and to some extent, may have an increase in clinical efficacy or safety, compared to our gold standard," said Dr. Janssen.
While autograft encompasses all three key biological mechanisms, the majority of bone graft substitutes on the market only possess the osteoconductive property, meaning they offer only a scaffolding to create an environment for biological incorporation.
Choosing the right bone graft
Clinicians should select bone graft materials based on a reasonable burden of proof, recommended by peer-review articles. Providers must also consider costs and coverage, due to an increased burden of proof. Payers are limiting coverage for bone graft substitutes, due to beliefs that the technology is experimental or unnecessary.
Dr. Janssen emphasized a single solution will not meet every patient's unique needs, and clinicians must consider a multitude of factors before selecting a bone graft substitute. Clinicians should understand the mechanics and biology of different healing environments as well as the clinical factors impacting the healing process.
"As clinicians, we have to be inspired by the evidence, and I think there's sometimes a gap between the usage and the real evidence," Dr. Janssen said. Most studies on the technology provide only Level III or Level IV evidence.
Dr. Janssen encourages clinicians to always inquire about the strength of the evidence for an osteobiologic. "The Level I evidence versus the current gold standard of autograft is really important for us to make good informed decisions on what we want to [use]," said Dr. Janssen.
He outlines the benefits and drawbacks of four bone graft materials for clinicians to consider.
Synthetic bone grafts: The largest bone graft market, synthetic bone grafts account for more than 200 FDA-cleared products. The majority of these products entered the market via the FDA 510(k) clearance, implying they are similar to existing technologies.
An osteoconductive scaffold, synthetics resemble Styrofoam with a particular pore size. They take on a passive construct, working toward a gradual cellular population. "In my experience, I've used many of these different synthetics and there is a huge variation in clinical performance between them," Dr. Janssen said.
In the cervical spine, Level I evidence exists for synthetic material. However, the 2016 International Journal of Spine Surgery study demonstrates that Coralline Ha results proved inferior to autograft control.
The most evidence for synthetic bone grafts exists in Level IV studies. "So, there is some data available for synthetics, however, we must also remember that there's a large number of different types of synthetic chemistries that probably have an impact on what we're actually using as clinicians," adds Dr. Janssen.
Allograft cancellous bone chips: Used in approximately one-third of bone graft procedures, allograft cancellous bone graft is popular among clinicians. Allograft is a critical component for osteoconductive scaffolding. The material is fairly inexpensive and available in a variety of preparations and forms. Some disadvantages, however, include the possible transfer of infectious agents, potential unreliable sourcing and inconsistent quality.
Allograft evidence also includes a Level I study, but it tested allograft preparation methods and did not use a control.
Demineralized Bone Matrix: Demineralized bone matrix accounts for a great portion of the osteoconductive scaffold market. DBM is allograft bone with the mineral component removed leaving collagen and non-collagenous proteins.
While the composition may offer some level of osteoinductivity, the material lacks Level I comparative data and has variable processing techniques. A 2005 Spine study revealed significant variations in the concentrations of BMP-2 and BMP-7 among popular DBM brands. A variation among the three lots of the same products also proved worrisome.
"We don't have a good standardization due to the regulatory process of what the true dosage in each of these really are," explains Dr. Janssen.
INFUSE rhBMP-2: rhBMP is an engineered growth factor offered in concentrations over 1 million times higher than the naturally occurring protein found in the body. This material possesses published efficacy for lumbar fusion, but there are substantial disadvantages.
BMP is costly and is not suitable for some patients or indications. Additionally, BMP has been associated with significant safety issues including swelling/dysphagia in anterior cervical discectomy and fusion; postop late radiculitis; ectopic bone formation; and osteoclastic hyperactivity.
"The bone graft market is very complex. There are a lot of options, and we as clinicians have to make informed decisions," concludes Dr. Janssen. "So, what we're really looking for going forward, to really mind the gap, is something that's safe, predictable and proven as an alternative to autogenous bone graft."
i-FACTOR™ Peptide Enhanced Bone Graft
Due to the lack of strong evidence in the bone graft industry, Cerapedics entered the game with i-FACTOR Peptide Enhanced Bone Graft.
As the only Peptide Enhanced Bone Graft, i-FACTOR Bone Graft creates a new category of bone graft biomaterial with a novel mechanism of action. The bone graft features a synthetic peptide, P-15, which serves as an attachment factor for cells, and Anorganic Bone Mineral, which offers an osteoconductive scaffold.
The attachment sites boost the number of viable osteogenic cells to encourage the natural bone healing process. Peptides help promote cell adhesion, proliferation and differentiation.
"The small size [of peptides] also means you can pack a higher density of molecules onto the biomaterial surface to enhance the biological activity further," added Dr. Johnson.
The P-15 peptide is derived from type one collagen, and has undergone intense evaluation in bone tissue engineering. It is a naturally occurring sequence of the alpha one chain in the type I collagen triple helix, which is an important site for cell attachment.
"The cells use this attachment site as a focal adhesion point, which is crucial for the cells to receive information about the mechanical environment that surrounds them, and also enable them to move throughout the collagen network," said Dr. Johnson. The P-15 peptides sequence is 4,500 more potent when competing with other peptides for cell attachment.
Following implantation, i-FACTOR Bone Graft attracts osteogenic precursor cells via the P-15 attachment sites. The cell attachments activate natural mechanical and chemical signaling pathways to promote the release of growth factors, cytokines and BMPs.
"i-FACTOR Bone Graft is simply making use of, and amplifying, the natural bone forming process," explained Dr. Johnson.
The "attract, attach, activate" mechanism of action promises safety, as it maximizes the potential for native biology to heal. The material is not osteoinductive nor morphogenetic. Additionally, i-FACTOR Bone Graft is not chemotactic so it will not yield ectopic bone formation.
Substantial evidence backs the mechanism of action, with proof of P-15 increasing the number of adhered cells; leading to cell differentiation; increasing growth factors; and enhancing cell viability.
Equipped with a long clinical track record, the P-15/ABM technology first came about in dentistry in the 1990s. Since 2008, clinicians have used the technology for orthopedic and spine cases, with more then 25,000 performed cases to date. In November 2015, i-FACTOR Putty became the first to receive U.S. premarket approval for biologic bone graft in the cervical spine. i-FACTOR Bone Graft is one of two FDA-approved drug-device combination products available in the U.S. for use in the spine, and the only one for cervical spine.
A study tested the material for single-level anterior cervical discectomy and fusion with an allograft ring, including 319 patients at 24 clinical sties in the United States and Canada. The study compared the allograft ring filled with i-FACTOR Bone Graft to the allograft ring filled with autologous bone.
At 12 months follow-up, researchers found an 88.97 percent rate of fusion for i-FACTOR Bone Graft patients compared to 85.82 percent for autograft patients. Additionally, researchers discovered i-FACTOR Bone Graft was as successful as autograft in terms of neck disability index improvement and neurological success.
"The study demonstrated that i-FACTOR Bone Graft was statistically superior to autograft in overall success," stated Dr. Johnson. Overall success, as measured by success in all four primary endpoints, for i-FACTOR Bone Graft was 69 percent compared to 57 percent for the control group at one year, a difference that is statistically significant.
"Now we have Level I evidence that demonstrates the ability to provide a proven efficacy equivalent to our gold standard of autogenous bone graft," concluded Dr. Janssen.
To view the webinar recording, click here.