The spine surgery community has a large variety of fusion adjuncts and bone graft options available, including iliac crest bone graft, local bone graft, allograft, demineralized bone matrix, mesenchymal stem cells, calcium phosphate ceramics, and BMP-2. They all have risks and benefits, with the most effective options (i.e. iliac crest bone graft and BMP-2) also having the highest risk of complications. BMP-2 is also extremely expensive. The other lower cost, lower risk options are also less effective. As such, investigators have been in search of an effective, low complication, low cost fusion adjunct. One option that has been evaluated in the fracture healing literature is the cholesterol lowering agent simvastatin. This medication has been shown to stimulate bone formation through similar pathways as BMP-2 and also prevent osteoblast apoptosis. In order to assess simvastatin as a spinal fusion adjunct, Dr. Iyer and colleagues from the Hospital for Special Surgery developed simvastatin eluting nanoparticles (SimNP) and evaluated their effectiveness in both cell culture and a rat fusion model. In cell culture, SimNP treated osteoblasts had greater alkaline phosphatase activity and generated more mRNA for multiple markers of bone formation compared to controls. They also performed uninstrumented, intertransverse fusions at L4-L5 using iliac crest bone graft in 40 rats. The rats were treated with SimNP, blank nanoparticles (BlankNP), or simvastatin alone (Sim). The SimNP rats had higher x-ray fusion scores at 4 weeks and 9 weeks and at 9 weeks had a significantly higher fusion rate compared to the BlankNP rates based on manual inspection of the fusion (43% vs. 0%). The Sim rats had an intermediate fusion rate (22%). Based on these findings, the authors concluded that simvastatin was an effective adjunct to lumbar fusion in a rat model.
Rarely do basic science articles generate much attention, so the authors should be congratulated for performing such a promising rat study. While there is a long way to go from the basic science lab and small animal operating room to use in humans, the data are promising. It seems clear from this and other papers that simvastatin is an osteoinductive agent. Additionally it is low cost, and it seems to have a good safety profile. Whether it turns out to be effective in humans remains to be seen, and much work needs to be done on dosing and delivery methods. However, there is a major unmet need in the bone graft substitute/fusion adjunct market, despite the plethora of products currently available. Other than BMP-2, no other synthetic agent or allograft product has been shown to be effective. Unfortunately, BMP-2 is bordering on prohibitively expensive and has an undesirable side-effect profile. The only studies currently listed on ClinicalTrials.gov evaluating locally applied simvastatin as an osteoinductive agent are looking at dentistry applications. Hopefully orthopaedic and spine investigators will continue to work on simvastatin and evaluate it in human studies looking at fracture healing and spinal fusion in the future. Maybe in ten years we will all be adding simvastatin to our bone graft.
Please read Dr. Iyer's article on this topic in the August 1 issue. What do you think of simvastatin as a fusion adjunct? Let us know by leaving a comment on The Spine Blog.
Adam Pearson, MD, MS
Associate Web Editor