Biological Products Show Promise, but More Evidence Is Needed (NASS)
The use of biological products in spine treatments is increasing, but more reliable data about their use are needed, according to a series of presentations during the NASS Annual Meeting’s final session, Biologics: A Critical Review of the Evidence.
During the November 5 symposium, six speakers discussed the need for more evidence about biologics, reviewed the level of evidence and examined biological materials, including demineralized bone matrix (DBM) and allograft stem cells.
The Need for Evidence
About 200,000 spinal fusions requiring biologic products are performed each year in the United States. Product choices are abundant, but the information about them is not.
“The biological products to choose from are plentiful. The decision as to what to use is significantly limited by the amount of evidence we have,” said Wellington K. Hsu, MD, Assistant Professor and Director of the Spine Fellowship at Northwestern University Feinberg School of Medicine, Chicago.
An increase in spine procedures has created a shortage of cadaver allograft material and stimulated corporate interest in developing bone-graft substitutes using a variety of materials. Dr. Hsu cautioned that any materials used should be supported by preclinical and human studies in site-specific locations.
“Biologics will play a key role in the future, not only in spine surgery, but in orthopedic surgery,” Dr. Hsu said. “Scientific advances need to be made not only by independent scientists, but also by industry scientists in a collaborative effort to review the evidence and make decisions based on science.”
Levels of Evidence: Why Is It Important and How Is It Applied?
Eugene J. Carragee, MD, Professor and Vice Chairman of Orthopedic Surgery at Stanford University, Palo Alto, CA, agreed with Dr. Hsu’s calls for more evidence on biological products by reviewing five levels of evidence.
Level V is the lowest level. At its best, it presents expert opinions of conditional support, and at its worst, suggests evidence is solid despite the lack of data. Level IV is “usually, but not always, junk science,” Dr. Carragee said, because it is based on case series, with authors reporting on patient responses to interventions.
Level III evidence is based on case control studies in which results are compared to those from a control group. They can provide good quality; however, quality is poorer if the evidence is from a single center or involves a small number of patients.
Level II evidence is based on lower quality randomized control trials or prospective cohort control trials. Randomized control trials are lower in quality if they are unblended, have small numbers, have randomization failures, are controlled by industry, or if primary data are unvetted or unavailable, Dr. Carragee said.
Level I evidence is the “holy grail,” he said. “It usually will trump lower level evidence rather than conflict with lower level evidence.” Level I evidence is based on randomized clinical trials with low study errors or meta-analysis.
When looking at the level of evidence, it is important to know the trial design type and quality, Dr. Carragee added.
Demineralized Bone Matrix: What is it and How Does it Work?
Dr. Hsu returned to the podium to explain what demineralized bone matrix (DBM) is and why it works well in bone grafts.
DBM is allogenic bone crushed to a particle size of 74 to 420 um that is demineralized in .5 hydrochloric acid for three hours. Components include growth factors and collagen, and carriers are then added to make it more “user-friendly.” The most common synthetic carriers are glycerol, hyaluronic acid, gelatin and calcium sulfate.
More than 40 DBMs are available commercially, and the percentage of carriers in the various products varies from 4 percent to 85 percent. The percentage of human tissue in each product also varies, “so we are left in the dark as to what we are using,” Dr. Hsu said.
Demineralized Bone Matrix: The Evidence
The ideal bone graft has three properties — it is osteoconductive, osteoinductive and osteogenic. DBM has only two of these properties — it is osteoconductive and osteoinductive, and the differences in carriers added to the various DBM products lead to great product heterogeneity.
Tom Mroz, MD, Director of the Spine Surgery Fellow Program at the Cleveland Clinic Neurological Institute, echoed a theme discussed by his fellow presenters when he said “there is no evidence to say which (product) is best.”
Complicating the decision of which DBM works best are product studies showing variability across product lots, he said. Researchers have tested DBM in animal models, but DBM behaves differently from species to species. One common thread, though, is that fusion rates were similar across products, Dr. Mroz said.
“Considering the whole list of different carriers on the market, I’m not sure anyone is sure how these translate to the clinical situations we are using these in,” he said. “There truly is a paucity of clinical evidence available to us to make decisions.”
Allograft Cells: What Are They and How Do They Work?
An option to using DBM is an allograft transplant using mesenchymal stem cells (MSCs) that can potentially differentiate into the cells needed, said Paul Santiago, MD, Associate Professor of Neurological and Orthopaedic Surgery at Washington University, St. Louis.
Dr. Santiago reviewed the general process of transplanting MSCs. Research is lacking on how MSCs work, but it is known that the more cells transplanted, the better the rate of fusion, he said, adding that the amount of cells needed in a transplant is as yet unknown.
Allograft Cells: The Evidence
Just as researchers are working to learn more about why MSCs work, they are developing trials to measure the effectiveness of MSCs for spine treatments, but no Level I, II or III evidence is available. The only evidence gathered so far is Level IV. The largest study to date involves 23 patients who received revision foot and ankle surgery, said Michael P. Steinmetz, MD, Chairman of the Department of Neurosciences at MetroHealth Medical Center and Assistant Professor of Neurosurgery at Case Western Reserve University School of Medicine, Cleveland.
Dr. Steinmetz reviewed the use of allogenic MSCs in a rat model that show promise in reducing inflammation while providing superior fusion mass compared to mineralization products. These allogenic MSCs are available commercially, but clinical evidence is lacking to support strongly their use at this time, he said.
Multiple prospective spinal fusion studies are under way, and more than 50,000 patients have allogenic MSCs implanted without reports of adverse events. “Success is seen anecdotally and in abstracts presented but not published to date,” Dr. Steinmetz added.