The opening symposium at the 2019 Global Spine Congress (15–18 May, Toronto, Canada) focused on cutting edge updates in spine surgery. Scott Boden addressed the topic of biologics in spine surgery, detailing state of the art evidence and novel developments in the field. Here, for Spinal News International, he gives a summary of his talk.
Since the 1990s, there has been a recognition that rigid internal fixation alone without favorable biologic healing is not sufficient to generate consistent spine fusions. This realisation is especially true in the posterolateral spine which is one of the body’s most challenging healing environments. Around 1990 demineralised bone matrix products emerged on the market with variable osteoinductive activity. There was a brief phase of platelet rich plasma which did not produce consistent results. In 2002, recombinant human bone morphogenetic protein-2 (rhBMP-2) was approved by the US Food and Drug Administration (FDA) for specific applications in the lumbar spine and this sparked an even greater focus on biologics for spine fusion. This approval came 37 years after Marshall R Urist’s seminal hypothesis that demineralised bone contained a protein capable of modulating bone regeneration from scratch and 14 years after the cDNA for BMPs was cloned and sequenced.
After approval, rhBMP-2 physician directed usage expanded substantially but ultimately was limited by cost, local side effects, and limited regulatory approval. Those limitations opened the door for increased interest in bone marrow concentrates which did not produce reliable enhancements to spine fusion. In the last decade, a number of allograft products processed to enhance mesenchymal stem cell preservation have become popular, but again with limited evidence in humans that the active ingredient (the mesenchymal stem cells) are providing any additive biologic value over the carrier which is often demineralised bone matrix. The challenge with mesenchymal stem cells is that the available number is much less than some preclinical studies have suggested are needed to produce bone and the lack of specific growth factors and other environmental stimuli needed to drive these pluripotent cells down the osteogenic pathway.
At present, recombinant or purified BMPs when delivered in the proper concentration on the proper carrier have the highest demonstrated osteoinductive potential as measured by the ability to generate bone from scratch in a non-bone environment, like the posterolateral spine. Local side effects may include seroma formation, local nerve inflammation, ectopic bone formation, and local cancellous bone resorption. These local side effects are often, but not always, related to a higher concentration than needed of BMP for a given healing environment. Although there were concerns raised about whether rhBMP-2 increased the risk of cancer in patients based on the original relatively small clinical trials, larger database studies have failed to document any increased risk of cancer, and in fact may suggest a slightly lower risk, with the exception of pancreatic cancer.
Given the relatively high cost of rhBMP-2, it is critical to determine which clinical scenarios can justify the increased cost. Based on the “delta” of increased fusion success when rhBMP-2 is added, studies support it adding value in multilevel anterior cervical fusions, posterolateral fusions, and potentially in biologically challenged hosts (diabetes, chemotherapy, steroids, smokers, etc). There are some development efforts around second generation designer recombinant BMPs that might be less resistant to BMP inhibitors and thus require lower doses, but it is not known if the safety profile will be any different, and the current manufacturing cost of a recombinant protein is still higher than desired for routine use in orthopaedics.
In recent years, several proteins (Nell-1) and small peptides (P-15), while not osteoinductive are still being investigated as to whether they can enhance spine fusion healing. LMP-1 was an intracellular protein discovered in 1998 that was osteoinductive, but required a gene therapy delivery technique which presented unnecessary clinical risks for the spine fusion population. Subsequent study of the mechanism of action of LMP-1 showed that it resulted in increased responsiveness of human MSCs to BMPs and led to the development of small molecules that could potentially mimic the activity of BMP without the extraordinary high cost associated with manufacturing a recombinant human protein. The LMP-1 derived small molecules have demonstrated the possibility for a small molecule to possess osteoinductive properties and may open the door in the future for safer and more cost effective strategies to activate the BMP pathway.
Scott Boden is a professor of orthopaedic surgery at Emory University School of Medicine, director of the Emory Orthopaedics & Spine Center, and chief medical officer/chief quality officer at Emory University Orthopaedics & Spine Hospital (Atlanta, USA).