Fracture nonunions of long bones continue to represent a significant clinical challenge and socioeconomic burden, associated with high complication rates and the potential for poor long-term outcomes [1–5]. Autologous bone grafting has received a negative reputation in the past, mainly due to the high risk of postoperative complications related to the harvesting procedure [6]. However, more recent innovative and minimally invasive harvesting techniques have mitigated the historic issue of donor site morbidity and renewed the interest in autologous bone as a preferred source for bone grafting [7–9].

The introduction of new generation bone substitutes and recombinant molecules with osteoinductive properties has recently challenged the role of autologous bone grafting as the ‘gold standard’ for the surgical treatment of nonunions [10–12]. In light of the immense market potential for bone graft substitutes and related products, estimated to be US$1 billion in the USA alone, the push for new ‘osteobiologicals’ may in large part be industry-driven, rather than based on objective patient safety and quality data [13–15]. In fact, well-publicized concerns have recently been raised regarding the safety of the uncritical application of recombinant bone morphogenetic protein (BMP)-2 for a variety of indications, including its off-label use [14, 16–18].

The present study was designed to determine the ‘ideal’ modality of adjunctive bone grafting in the management of long bone fracture nonunions. We hypothesized that the use of autograft is equivalent to other bone grafting options with regard to healing times and complication rates.

The present study was designed to analyze the efficacy of distinct adjunctive bone grafting modalities for surgical revisions of long bone fracture nonunions. Our data revealed that in this particular patient population, the use of autograft had a significantly shorter time to union when compared to allograft, the lowest incidence of surgical revision rates and revision bone grafting, and the lowest postoperative infection rates, compared to the allograft alone, allograft/autograft or rhBMP-2 comparative cohorts. There was a statistically nonsignificant trend towards earlier time to union in autograft patients compared to autograft/allograft or rhBMP-2 cohorts. These findings support the notion that autograft remains the gold standard for bone grafting of nonunions [22], despite the emerging availability of a multiplicity of novel osteobiologicals that have recently received considerable attention as bone grafting adjuncts [23]. The indication spectrum of human recombinant rhBMP-2 remains highly controversial, particularly in light of some recent concerns regarding its questionable safety and efficiency profile [14, 16–18]. The historic ‘rhBMP-2 Evaluation in Surgery for Tibial Trauma (BESTT)’ multicenter prospective randomized trial on 450 patients with open tibial fractures managed by unreamed interlocking nail fixation revealed that the local application of rhBMP-2 resulted in a significant reduction of nonunion rates [24]. Jones et al. reported the results from a randomized, controlled clinical trial on 30 patients, which revealed that rhBMP-2 in combination with allograft had similar times to union and outcomes compared to autograft in tibial shaft fractures with cortical defects [25]. A more recent prospective, randomized trial failed to demonstrate accelerated healing in open tibia fractures treated by reamed intramedullary nailing and rhBMP-2, confirming the notion that reaming represents a more crucial parameter for successful fracture healing, rather than the adjunctive use of rhBMP-2 [26].

Our present study supports the notion that autograft remains at least as effective as rhBMP-2, with similar time to union and decreased incidence of postoperative complications and requirement for surgical revisions. These findings are challenged by a different recent publications, which compared rhBMP-2 with cancellous allograft and iliac crest autograft in a retrospective study of 89 patients with long bone nonunions [27].The authors failed to find a difference in union rates between the treatment groups and reported an increased incidence of postoperative infections in the autologous iliac crest bone grafting group, compared to the rhBMP-2/allograft cohort [27]. In addition, iliac crest autograft was associated with longer operative procedures and a higher amount of intraoperative blood loss. The authors concluded that rhBMP-2 may provide a viable alternative to autologous iliac bone grafting in the management of long bone nonunions [27].

The lack of long-term safety and efficiency data on the use of BMPs as bone grafting adjuncts, in conjunction with realistic concerns that BMPs may be associated with the long-term induction of bone tumors [28, 29], substantiates the ongoing discussion against liberal application of BMPs until long-term data are available [16, 30]. Ritting et al. recently published a pediatric case report describing a massive local inflammatory reaction after use of rhBMP-2 for repair of a symptomatic forearm nonunion in a child [31]. Such serious complications question the standard use of rhBMP-2 as routine bone grafting adjuncts in nonunion surgery.

Demineralized bone matrix (DBM) represents the most commonly used bone substitute with osteoinductive properties [32]. With the use of DBM, however, an adjunctive scaffold is needed to add osteoconductive properties [32]. Comparison of combined osteogenic products have demonstrated significant differences in osteogenic potential, depending on processing techniques, carriers, sterilization methods, and storage conditions [33, 34]. Such variations result in considerable inconsistency in product safety and efficiency. Bae and colleagues recently reported substantial ‘lot-to-lot’ variability in terms of BMP concentrations and in vivo fusion rates in DBM/BMP products, challenging the reliability of such adjuncts in bone grafting [35, 36].

Autograft possesses the combined osteogenic properties of osteoinduction and osteoconduction, thus representing superior mechanical and biologic properties than any allogeneic or synthetic bone substitutes [37]. Traditionally, autograft was harvested from the iliac crest, providing sizeable quantities of autograft and the possibility of a tricortical structural grafting [38]. However, disadvantages of using the iliac crest as a donor site are well established in the literature and include persistent pain, infections, and the induction of iatrogenic pelvic fractures and nonunions [6, 39, 40].

An emerging alternative to iliac crest harvesting is represented by the Reamer-Irrigator-Aspirator (RIA) system, which allows the harvest of significant amounts of autograft from the intramedullary femoral canal [7, 41].

Compared to iliac crest harvest, the RIA produces comparable volumes of bone graft and comparable harvesting times, but with a markedly reduced incidence of postoperative pain and lower rates of postoperative complications [42]. The grafting material obtained by RIA possesses osteogenic properties and, although morselized, appears to provide three-dimensional properties similar to trabecular bone and offers the presence of osteoinductive BMPs and growth factors in the grafting material [43, 44].

Our study has several limitations. First, the retrospective nature of the study design is associated with the known pitfalls of any retrospective analysis and thus limits the scientific value of the conclusions. Secondly, our study includes data from two different level 1 trauma centers, adding not only increased surgeon variability, but also resulting in significant differences in the modality of data acquisition between the study sites. On the other hand, this weakness may, at the same time, represent a strength, since the inclusion of two different study sites may adjust for confounding variables specific to a single institution, and thus make the findings more generally applicable. Another drawback of our study is the combined analysis of three different long bones with unequal biomechanical and biological properties with regard to the exposure to axial loading (femur, tibia) vs. rotational forces (humerus), quality of the surrounding soft tissue envelope and blood flow to the fracture site, etc. However, when attempting a subanalysis for individual long bones (humerus vs. femur vs. tibia), the sample sizes and power became too small to make reasonable statistical assumptions without the risk of a type-II error. In line, while differences exist between gender distribution and age between cohorts, subanalyses rendered patient numbers and power too small to extract meaningful statistical data without significant risk for a type-II error. Moreover, the incidence of surgical revision in the autograft group may have been reduced as these patients have received the current gold standard treatment. Finally, there is the possibility of selection bias in the present study. As bone grafting modality was left to the treating surgeon’s discretion, it is possible that patients were treated differently based upon various pre-existing patient factors. As this is a nonrandomized retrospective study, it is difficult to address these factors. In an attempt to shed light on possible differences in demographics and pre-existing social factors, patients in all groups were analyzed for gender and social factors, such as smoking status, intravenous drug use, and alcohol abuse. There were statistically significant differences (P < 0.05) between autograft cohort vs. allograft, autograft/allograft, and BMP-2 cohorts with regards to age and gender. In addition, a statistically significant difference (P < 0.05) was found between the illicit drug use status in the autograft/allograft group and remaining cohorts. All other demographics (smoking and alcohol abuse) failed to demonstrate any statistically significant differences.

Nevertheless, our study provides valuable insights into the efficacy of different bone grafting adjuncts in nonunion surgery of long bones, implying that the use of autograft as a grafting adjunct may continue to represent the best practice until higher quality data are available.

Autograft appears to represent the most efficacious bone grafting adjunct for nonunion surgery of long bones. Time to union, need for revision surgery, and revision bone grafting, as well as new onset or continuing postoperative infection rates were most favorable when autograft was used, compared to allograft, combined autograft/allograft, or rhBMP-2. In light of the growing critical reviews related to the safety and efficacy of rhBMP-2 in other indications, namely in spine surgery, the use of this product should be critically evaluated prior to surgical revision of long bone fracture nonunions.