Commentary & Perspective

Commentary & Perspective on
"Osteoinductivity of Commercially Available Demineralized Bone Matrix: Preparations in a Spine Fusion Model"
by Brett Peterson, MD, et al.

Commentary & Perspective by
Thomas A. Einhorn, MD, and Jennifer L. Fitch, BS*,
Department of Orthopaedic Surgery, Boston University Medical Center, Boston, Massachusetts

Bone graft substitutes represent a growing industry within the orthopaedic marketplace. Originally limited to calcium and phosphate-based osteoconductive materials, this grouping of products now includes demineralized bone matrix, autologous blood concentrates, platelet gels, bone-marrow cells, and recombinant human bone morphogenetic proteins. While the mechanisms of action among these materials range from providing a simple scaffold for cell attachment to inducing cellular differentiation, the results are always viewed in the same way—does the product enhance bridging of the skeletal gap? Does the product enhance fusion? Direct comparisons in performance become inevitable because everyone is looking for the same or a similar end result, despite inherent differences in the materials. As a result, the cost and simplicity of production become factors.

The ability of a recombinant human bone morphogenetic protein (rhBMP) to induce the formation of bone in parts of the body where bone would not otherwise form may indicate superior therapeutic potential in comparison to other materials. However, depending on the clinical application, it is possible that the same therapeutic result could be achieved with a purified protein, which is less expensive to produce but possibly not as active as rhBMP, or with demineralized bone matrix (DBM), which is much less expensive to produce but has unknown biological activity. For years, investigators have reported the results of animal studies that have demonstrated great potential for the use of DBM in enhancing the healing of a variety of skeletal defects and conditions. However, despite reports of small case series and anecdotal experiences, the use of DBM in patients has never been firmly established. Although the results of randomized, controlled trials have been reported regarding the use of several formulations of calcium-phosphate-based bone-graft substitutes^1,2 and BMPs^3-5, no such trials have been conducted with DBM. Hence, the levels of evidence used to assess the performance of DBM do not approach the levels available for these other bone-graft substitutes.

In an effort to promote the use of commercially available DBM, companies report so-called "bioassays" that measure the ability of the product intended for use in humans to induce bone in an animal model. We find it interesting that anybody would be impressed by the results of such an assay as there is no guarantee that something that works in an animal will necessarily result in similar efficacy in a patient.

The article by Peterson et al. assesses the osteoinductivity of three different demineralized bone matrices in an effort to determine how they compare among themselves and which has (have) the greatest potential for efficacy in a clinical setting. With use of a spinal fusion model in athymic rats, the investigators compared the radiographic, histologic, and manual mechanical testing results after treatment with Grafton Putty, DBX Putty, or Allomatrix Injectable Putty in comparison to a control group in which no material was implanted. All animals in all groups underwent decortication of the transverse processes of L4 and L5. On the basis of statistical analyses, after eight weeks, higher radiographic fusion rates were achieved in the animals treated with Grafton versus Allomatrix or control; at four weeks, manual testing revealed various fusion rates among the three different DBM implants; and at eight weeks, all of the animals treated with Grafton, half of the animals treated with DBX, and none of the animals treated with Allomatrix or no implant showed fusion. In summary, Grafton was found to be more effective than DBX, and the use of Allomatrix was found to be no better than control. The investigators concluded, "This study demonstrated differences in the osteoinductive potentials of commercially available demineralized bone matrices in this animal model."

Our only disagreement with the conclusions of this article is that, as the authors themselves noted, there is no proof that what was measured here was osteoinduction. Although DBM is known to contain osteoinductive BMPs, without a direct assay of cellular mitogenesis, the formation of bone in an in vivo setting could also be due to the osteoconductive potential of the implant. DBM contains substantial concentrations of proteins that have attachment sites for osteoprogenitor cells. This property may provide sufficient osteoconductivity to enhance healing. In support of this concept, there is evidence of substantial variability in the osteoinductive potency and content of BMPs among different DBM products, as well as within lots of the same DBM product⁶.

There are two limitations to the current study by Peterson et al., neither of which discounts the importance of the findings. The first concerns the use of an athymic rat spinal fusion model. Athymic rats are immunologically privileged. It was necessary to use them in this study because implantation of a human protein into a rat would otherwise lead to immunological rejection. However, the role of the immune system in skeletal repair has been well studied^7,8, and measurement of healing in the presence of impaired immune function may be different from what occurs in a normal setting. The other limitation concerns the use of an untreated control group. Because it is possible that the new bone formation induced by either Grafton or DBX was due to some osteoconductive capability, the use of autoclaved, inactivated DBM would have been a more appropriate control.

The clinical relevance statement assigned to this study suggested that "comparative clinical testing of demineralized bone matrices is indicated in order to determine which preparations are best suited for promoting spinal fusion in humans." We believe that this is a fair statement to make, although we are still not convinced that the findings of DBM efficacy in animal models should be extrapolated to what may be expected in humans. On the other hand, if animal studies fail to show the efficacy of a bone-graft substitute, the likelihood that it would be a successful therapy in humans is remote. This was clearly shown with respect to the failure of spinal fusion in the animals treated with Allomatrix.

Another potential application of DBM in a clinical setting would be as an extender for the use of autogenous bone. Two studies, one in canines and the other in nonhuman primates, have demonstrated that when an amount of autogenous bone that is by itself insufficient to induce fusion is combined with equal quantities of DBM, the results are comparable with those achieved with use of sufficient quantities of autogenous bone^9,10. Although this result has not been reproduced in a human clinical model, we believe that it is a reasonable hypothesis to test, perhaps through a study in a defined clinical setting with the application of an appropriate experimental design and controls.

The need to study DBM preparations in human clinical settings is great. Right now, the cost of an rhBMP implant is approximately five times the cost of a preparation of DBM. However, without a randomized, controlled trial, the efficacy of DBM or its performance in comparison to that of rhBMPs is unknown. Orthopaedic surgeons also need to understand the approaches used by the United States Food and Drug Administration to regulate and approve the marketing of products for clinical use. DBM is considered a reprocessed human tissue and is therefore not subjected to a rigorous testing of its efficacy, as is the requirement for a recombinant protein or a synthetic product. Other materials regulated in a manner similar to that of DBM include autologous blood concentrates, platelet gels, and the selective retention technologies for the concentration of human bone-marrow cells. Since companies that produce such materials are not required to pay for expensive, randomized controlled trials, those products may reach the marketplace without sufficient evidence of therapeutic efficacy.

The development of bone graft substitutes is in its infancy. Currently available materials have had varying degrees of success, and some products have unknown efficacy. To make the right choices for their patients, orthopaedic surgeons must pay careful attention to the quality of the evidence put forth with regard to increasingly more effective and powerful materials.

*The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. A commercial entity (Osteotech) paid or directed, or agreed to pay or direct, benefits to a research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

References

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Copyright © 2004 by the The Journal of Bone and Joint Surgery, Inc.