February 2003 Bulletin

Osteoinductive bone graft substitutes: Burden of proof

Essential principles for the practicing orthopaedic surgeon

By Scott D. Boden, MD
Biological Implants Committee

It is estimated that more than 500,000 bone-grafting procedures are performed annually in the United States, with just under half of those procedures related to spine fusion. Donor site morbidity, limited supply, and the imperfect success rate of autogenous bone graft, which can necessitate repeat procedures, have led to the commercialization of a variety of bone graft substitutes.

These graft alternatives have varying degrees of regulatory oversight depending on product composition, and thus safety and effectiveness for a specific clinical application may not be known prior to availability for use by orthopaedic surgeons. Moreover, given the different categories of bone graft substitutes and the seemingly similar products within each category, product differentiation has become increasingly difficult for the practicing orthopaedic surgeon. Moreover, there is at least one example of an osteoinductive product that has been marketed and implanted in humans that has failed to demonstrate bone induction in rats.

This article is intended to help suggest a framework of principles for considering the burden of proof necessary to allow clinicians to make reasonable choices when deciding on bone graft substitutes.

Osteoconductive substitutes are scaffolds or materials that are permissive for bone formation, but do not contain growth factors that can attract osteoblast precursors and initiate osteoblastic differentiation and bone formation. Examples of osteoconductive materials include collagen, ceramics or other inorganic materials, organic polymers, and coral.

Osteoinductive substitutes contain one or more growth factors such as bone morphogenetic proteins (BMPs) capable of independently attracting precursor cells and inducing new bone formation. While numerous growth factors may be involved with new bone formation, including platelet derived growth factor (PDGF), transforming growth factor beta (TGF-b), vascular endothelial growth factor (VEGF), insulin like growth factors (IGFs), and fibroblast growth factors (FGFs), evidence suggests that only BMPs are capable of initiating the entire process of new bone formation.

BMPs, along with other growth factors, are contained in low amounts in demineralized bone matrix or can be found in larger amounts as purified extracts of bone, and are also available as genetically engineered recombinant proteins. BMPs are currently available for selected clinical applications. Efficacy for bone induction is heavily dependent on finding the optimal BMP dose and carrier matrix for each specific clinical application.

First principle

The first principle to consider for understanding the burden of proof is that different healing environments (e.g. metaphyseal defect, long bone fracture, segmental diaphyseal defect, interbody spine fusion, posterolateral spine fusion) may have increasing levels of difficulty in forming new bone. In addition, different mechanisms of healing are found in different anatomic locations. For example, a metaphyseal defect will permit the successful use of many purely osteoconductive materials. In contrast, a posterolateral spine fusion or segmental long bone defect environment will not tolerate the use of purely osteoconductive materials as a bone graft substitute alone, and only in some circumstances will their use as a bone graft extender result in success. Thus, validation of any bone graft substitute in one clinical anatomic site may not be predictive of its performance in another location. Accordingly, the surgeon must exercise caution in using graft substitutes that have not been clinically tested in the particular healing environment.

The quality of the fracture healing bed (vascular vs. relatively avascular) is an important consideration for certain fracture healing problems, such as acute fractures compared to early atrophic nonunions. There are difficult fracture healing situations where autologous bone or osteoinductive bone substitutes are preferable to an osteoconductive bone scaffold.

Second principle

The second principle to consider is the burden of proof required from preclinical studies to justify the use of an osteoinductive graft material or the choice of one brand over another. Although not commonly recognized, evidence suggests that it is more difficult to induce bone formation in humans than in cell culture or rodent models. Only human clinical trials can ultimately determine efficacy of a specific product in a particular clinical application in patients.

However, a hierarchy of testing credibility exists ranging from cell culture assays of bone markers and the rat ectopic bone induction assay, which are perhaps the least stringent assays, to rabbit ulnar defect, rabbit spine fusion, and large animal long bone defect and spine fusion models, which are of greater stringency. Nonhuman primate long bone, interbody spine and posterolateral spine fusion models probably offer the highest challenge and may therefore more likely correlate with success in similar human applications. The failure of an osteoinductive graft material in a less challenging healing environment or model may predict failure in more challenging situations. In addition to bone induction potency, mechanical requirements at different sites can also affect the success or failure of a graft material.

Unfortunately, successful bone induction at any level does not ensure success at a more stringent level—only testing in that specific situation can determine efficacy. Even efficacy in humans in one clinical application (e.g., interbody spine fusion) does not ensure success in other applications (e.g., posterolateral spine fusion). Furthermore, osteoinductive potency may be altered based on host issues such as local or age-related changes in prevalence of responding cells, diabetes, or drugs (e.g., steroids, chemotherapeutic agents, and nicotine)

Although there are actually minimal safety concerns, off-label use of osteoinductive devices may not result in consistent bone formation. Thus when differentiating between brands of similar osteoinductive products that have not been validated in human clinical trials for the specific intended application, consideration should be given to choosing the product with the highest possible burden of proof satisfied in preclinical studies, i.e., success in the most challenging bone healing model or environment similar to the intended use. Appropriate testing and communication of successful and unsuccessful results will be important to minimize the risk of inadequate bone formation in patients.

Third principle

The third principle involving the burden of proof specifically pertains to products that are currently subject to varying levels of regulatory oversight such as demineralized bone matrix (DBM) and platelet gels containing "autologous growth factors."

In March 2002, the Center for Devices and Radiological Health (CDRH) of the Food and Drug Administration sent a letter to manufacturers of demineralized bone products. In the letter, CDRH clarified that demineralized bone matrix with additive ingredients for purposes other than sterilization, preservation, or storage would be regulated as a device and therefore subject to premarket notification provisions. This includes any substance added to demineralized bone with the intention of affecting the structure or function of the body.

Some demineralized bone products may not be proven to produce the desired healing effects in humans in theabsence of preclinical testing in stringent healing models or environments. With the known variability of bone induction in various demineralized matrix bone products, minimal standards are needed to assure osteoinductivity of many such products.

This information on bone induction performance should be disseminated to the orthopaedic community for decisions to be made on product choices. Only through continued testing and validation in specific settings and increasingly stringent models can the efficacy of bone graft substitutes in humans be ensured.

Scott D. Boden, MD, is Professor of Orthopaedics and Director, The Emory Spine Center, Emory University School of Medicine. He is also a member of the Biological Implants Committee.

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