Do Bone Graft Substitutes Cause an Allergic Response?

Have you ever heard of therapeutic proteins? You probably have without knowing it because insulin is a therapeutic protein. People who are missing important proteins like insulin develop problems like diabetes. They can be treated with exogenous (coming from outside the person's own body) proteins such as insulin made from animal (or human) sources.

Another example of therapeutic proteins are bone morphogenetic proteins (BMPs) used in spinal fusions. BMPs as a bone graft substitute are a fairly new development. Unlike the diabetic who doesn't have enough insulin, the bone-making proteins aren't deficient in adults who have one or more spinal segments fused. In other words, it's not that the body isn't making its own bone cells. But rather, in the case of spinal fusion (or bone fracture), the patient needs extra bone-generating proteins to speed up regeneration and repair.

Scientists have developed something called recombinant human bone morphogenetic proteins (rhBMPs). They have used modern DNA technology to create highly purified protein products to enhance spinal fusion and fracture healing.

That all sounds great, so what's the problem? Just one word: immunogenicity. That's the body's immune (allergic) response to anything introduced exogenously (outside the body). The natural response is for the immune system to mount a defense against what it sees as a foreign invader. It creates antibodies to fight against rhBMPs. So the challenge is to find a way to create an rhBMP that does not create an allergic reaction.

The use of rhBMP is still in its experimental or investigational phase. It's not routinely used yet because no one knows for sure if the body really does mount a defense against locally administered proteins. And if it does, what effect does it have? We say locally administered because the bone protein is placed in the spine at the time of the fusion -- not given systemically by pill or intravenously into the bloodstream.

The next dilemma is finding ways to measure the immune reaction. Right now, we have a blood test (called bioassay) to show antibodies in the blood. But we don't have a reference standard -- a consistent way to measure what is normal from study to study.

Studies so far on the immunogenicity (strong immune reaction) to rhBMP have been done mostly in animals. Results of the first studies in humans were published in the early 21st century (year: 2000). Blood tests from those studies did not shown antibodies to a specific therapeutic bone-producing protein (rhBMP-2) made from cows and used in spinal fusions.

Later studies did report a very low number of cases in which antibody formation against rhBMP-2 occurred, but there were no apparent adverse effects or any change in clinical outcomes as a result of those antibodies. In other words, the fusion didn't fail because of rejection of the bone. The next step was to compare the responses and results using different amounts of rh-BMP-2. Assays for antibodies showed only a small number of patients developed antibodies and no one had any signs of an allergic response.

The lack of immunogenicity of rhBMP is encouraging. The hope is that these therapeutic proteins can be used instead of bone taken from some other part of the patient's body. Using your own bone from one place in the body to help create new bone in another part of the body is called autogenous transplantation. It works well but often leaves the patient with problems at the donor site. Using bone-stimulating protein like rhBMP could make it possible to speed up bone healing with no adverse side effects.

Right now, the focus is on improving the assay testing so that it is sensitive enough to screen for antibodies and give the same results no matter who uses the test. This would make it possible to compare studies done in one lab with other similar studies elsewhere. And long-term results are needed.

Just because antibody production is not evident at first, doesn't mean there couldn't be delayed reactions much later. The belief is that bone formation fostered by rhBMP occurs rapidly with new bone developing long before antibodies develop. So when and if antibodies are formed, there's nothing for them to do. They just circulate in the blood and remain inactive. All indications are that even if the body produces these antibodies, they don't interfere with bone formation or cause any adverse effects.

In summary, with recombinant DNA technology, it's possible to produce almost identical (to human) bone-forming proteins, thus eliminating any hypersensitivity reactions. But there are still some antibodies produced. New subclasses of BMPs are being developed and tested to eliminate antibody formation.

Slight structural differences between the rhBMPs might result in a product that is more effective (produce stronger bone faster) without antibody formation. Studies will be done to see if someone has one bone graft using rhBMP for spinal fusion or bone fracture and then has another one later, does the added exposure to these therapeutic proteins increase the risk of an immune reaction? Safety and effectiveness are the primary concerns right now. These products are not considered safe for use in pregnant women (or women who could get pregnant).

Chang Ju Hwang, MD, et al. Immunogenicity of Bone Morphogenetic Proteins. In Journal of Neurosurgery: Spine. May 2009. Vol. 10. No. 5. Pp. 443-451.

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