The decreasing trend in the use of grafted iliac bone blocks and the increasing trend in the use of bone substitute materials have continued in 2012. Recombinant Osteoconductive Protein Since 2012, there has been widespread concern about the local adverse events caused by recombinant osteoconductive protein, and in June 2011, a series of articles and studies emerged regarding the potential high risk of human recombinant osteoconductive protein. The articles in this category focused on the following three points: 1) The use of human recombinant osteoinducible protein in anterior lumbar fusion increased the risk of retrograde ejaculation and premature ejaculation. 2) Human recombinant osteoinducible protein increased the incidence of radiculitis, infection and hematoma. 3) The use of human recombinant osteoinducible protein correlated with an increased incidence of cancer. Subsequent studies have shown that the occurrence of many complications possess access specificity, if not related to the access itself. Whether the application of human recombinant osteoinducible protein increases the chance of retrograde ejaculation remains poorly understood. In a 10-year retrospective study from Stanford University, human recombinant osteoinducible protein-2 increased the incidence of retrograde ejaculation by a factor of 2, similar to the results of previous FDA clinical trials on human recombinant osteoinducible protein-2. Another study from the University of Denver showed no significant difference in the potential risk of retrograde ejaculation when comparing anterior disc replacement to anterior interbody fusion with human recombinant osteoinducible protein. Another interpretation suggests that retrograde ejaculation is associated with surgical revealing (peritoneal and retroperitoneal) techniques, which would suggest that the application of human recombinant osteoinductive protein is not associated with the occurrence of retrograde ejaculation. This adds further confusion regarding the precise definition of retrograde ejaculation and how to measure it. The issue of radiculitis was probably raised in some basic studies and gradually rose to a number of clinical trials based on relatively small reanalysis. Most recent clinical studies have shown that application of human recombinant osteoinducible protein in the posterior-lateral approach does not present an increased risk of developing secondary radiculitis. A recent clinical trial based on 1400 patients showed that the application of human recombinant osteoinducible protein was slightly more likely to cause seroma (3.2%) than the application of decalcified bone matrix (2%) versus autograft bone (1.4%), but these differences were not significant. The same study showed an overall infection rate of 3.1%, which was not significantly higher in the human recombinant osteoinducible protein group. These data are also supported by the results of nearly 55,000 patients in the SRS and 16,000 patients in the Medicare database, with no increase in overall infection, seroma, or other complication rates due to BMP. All of these studies showed a significant increase in medical costs, but few patients were dissatisfied because of the skilled nursing practices. Probably of most interest is the potential relevance of osteoinducible proteins to cancer. Data from the manufacturer indicate that there is no increased risk of cancer with approved marketed 6-12 mg formulations applied to gelatin sponges, and the FDA has not warned about this. However, data from some relatively small external analyses have reached a different conclusion. A retrospective study of 93,000 lumbar fusion patients based on medical data showed no increase in the incidence of pancreatic cancer, and another Wisconsin group provided a 6.2% decrease (not an increase) in the incidence of cancer among patients with 467,000 Medicare data who had BMP applied during spinal fusion. Work continues in the search for a more effective carrier for the osteoinducible protein. Such studies hope to find a carrier that avoids the early and massive release of osteoinducible proteins. Of course early release is important for the healing process, but if too much is released, it leads to excessive vascular permeability and the local side effects described above. Other Bone Replacement Materials Although more attention has been placed on osteoinductive proteins, their relatively high cost continues to encourage research into other bone replacement materials. An animal study showed that platelet-rich plasma, with or without a bone marrow component, did not promote postero-lateral fusion of the spine. Silicate substituted calcium phosphate, various bone marrow/ceramic combinations, and bioactive glass all continue to be investigated in the field of spinal implant fusion. Most studies have shown that these studies, including mesenchymal stem cells, still fail to achieve the potency of human recombinant osteoinducible proteins.