Bone graft substitutes used in anterior lumbar interbody fusion: a contemporary systematic review of fusion rates and complications

Introduction

Background

Interbody fusion is used for spine stabilization during the management of common spine conditions causing back or radicular leg pain, such as degenerative disk disease and spondylolisthesis (1,2). Multiple factors affect the chosen surgical approach, with the anterior retroperitoneal approach for anterior lumbar interbody fusion (ALIF) permitting the use of a wide footprint cage filled with high volumes of bone graft (1,3). Bone grafts are biological materials used to provide a scaffold and promote bone growth for complete fusion (4). In an interbody fusion, the nucleus of the intervertebral disc is removed, and then a biocompatible implant, cage, or spacer that can be filled with bone graft is inserted into the disc space (4).

Autologous iliac crest bone grafts (ICBGs) have been traditionally used for ALIF, but they are associated with postoperative complications, including donor site morbidity (4). Therefore, several biological bone graft substitutes have been developed to replace or augment ICBGs. The effectiveness of bone graft substitutes is assessed by determining the fusion rate, which is the proportion of patients with successful solid fusion at a specified time. Unsuccessful fusion can lead to pseudoarthrosis, which may result in persistent pain, reduced mobility, and the need for further surgery (1).

Rationale and knowledge gap

In 2013, Mobbs et al. reported the results of their systematic review of bone graft substitutes used in ALIF and concluded that autologous ICBGs remained the gold standard (4). However, subsequent developments in bone graft substitutes during the past decade have prompted the need for further analysis and review. Furthermore, the landscape of bone graft substitutes in Australia has undergone substantial changes. Use of recombinant human bone morphogenetic protein 2 (rhBMP-2) in Medtronic’s Infuse Bone Graft/LT-Cage Lumbar Tapered Fusion Device was approved by the United States (US) Food and Drug Administration in 2002 (5) and by the Australian Therapeutic Goods Administration in 2006 for single-level ALIFs from L4 to S1 in adults (6), as fusion rates were similar to those achieved with ICBGs (7-9). However, in March 2020, rhBMP-2 was removed from the commercial market in Australia following reports that rhBMP-2 was being used “off label” without the LT-cage and because of concerns about the cost and potential complications associated with rhBMP-2 (10,11).

Objective

The objective of this systematic review was to examine recent studies on fusion rates and postoperative complications associated with bone graft substitutes used in ALIF. Although bone graft substitutes other than rhBMP-2 have been developed, there is currently no consensus on which bone graft is preferred for ALIF. The findings of this review can be used to identify gaps in research, including identifying which bone grafts require further evaluation, and to help guide the selection of bone grafts for ALIF in clinical practice. We present this article in accordance with the PRISMA reporting checklist (available at https://jss.amegroups.com/article/view/10.21037/jss-24-24/rc).

Methods

Search strategy

To identify relevant studies, we first developed search terms combining natural language and Medical Subject Headings, along with Boolean operators, as outlined in Table 1. These terms were utilized to query databases [Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, MEDLINE, and PubMed], focusing particularly on bone graft substitutes. The terms were grouped using ‘OR’ Boolean operators to widen the scope of our searches. Similarly, a broad range of key terms relating to postoperative outcomes from recent studies were grouped using ‘OR’ operators. ‘AND’ operators were then used to merge search terms related to ALIF, bone graft substitutes, and outcomes into a single comprehensive search. We restricted our searches to articles published between 1 January 2012 and 6 July 2023. This timeframe was chosen to build upon the systematic review by Mobbs et al. published in 2013 (4).

Study inclusion and exclusion criteria and selection process

We established appropriate inclusion and exclusion criteria to select studies focusing on the relevant population, types of interventions, and outcomes, as summarized in Table 2. The study selection process began with detecting and removing duplicates using Rayyan software. Following this, the abstract of each article was independently screened according to the inclusion and exclusion criteria by two reviewers (Z.A.W. and D.T.B.), who were blinded to each other’s assessments. Discrepancies between the reviewers were resolved through discussion. Full-text articles that met the inclusion/exclusion criteria were then retrieved, and the screening process was repeated. The reasons for excluding full-text articles are shown in Figure 1.

Figure 1 PRISMA diagram showing the process resulting in the 27 included studies. ALIF, anterior lumbar interbody fusion; CINAHL, Cumulative Index to Nursing and Allied Health Literature.

Data collection

Information about the study characteristics, methodology, and outcomes were independently extracted from each study included in this review by two reviewers (Z.A.W. and D.T.B.), with discrepancies being resolved through discussion. The study characteristics included the first author, year of publication, country where the study was conducted or nationality of the first author, and type of study. Information on the study populations was collected, including the size (number of patients and spinal levels) and proportion of males. Intervention details, such as the type and dose of bone graft substitutes, cage specifications, and spinal levels, were recorded. Information regarding study methodology was also collected, focusing on the imaging modality and fusion criteria, including whether these criteria were specified in the Methods section, whether fusion was considered a binary or categorical outcome, and how functional outcomes were assessed. Finally, data regarding the fusion rate and postoperative complications were extracted. This structured approach allowed us to obtain a comprehensive understanding of the methodologies and outcomes assessed in the literature on bone graft substitutes for spinal surgery.

Results

Study selection and characteristics

As shown in Figure 1, 834 articles were initially retrieved through our database searches (CINAHL, 65; Embase, 388; MEDLINE, 189; PubMed, 192). After removing duplicates, the abstracts of the remaining 408 papers were assessed, and 327 were removed based on the inclusion and exclusion criteria. Of the 81 articles that underwent full-text review, 54 studies were excluded for these reasons: ALIF outcomes could not be determined (n=15), ALIF was not performed (n=13), outcomes were not separated by graft type (n=11), no bone graft substitute was specified (n=4), outcomes of interest (fusion rate and postoperative complications) were not assessed (n=2), and the article was not a full-text version of an original human research study (n=9: 3 reviews, 3 case reports, 2 editorials, and 1 in vitro study). Thus, 27 studies remained for inclusion in this review.

The characteristics of each of the 27 included studies are shown in Table 3. The studies were most frequently conducted in the US (n=13), followed by mainland Europe (n=7) and Australia (n=5). Only one study was performed in South Korea and one in the United Kingdom. As shown in Table 4, two-thirds of studies (18/27) involved the use of rhBMP-2 alone or combined with allograft or synthetic material.

Fusion rates

Table 4 shows the final fusion rates reported for each main type of graft material used for ALIF. rhBMP-2 was associated with the highest overall final fusion rates when assessed by computed tomography (CT). Synthetics were associated with the greatest range of fusion rates across different imaging modalities (9).

Of the included studies, only nine studies assessed fusion rates using CT at 12 months after surgery. As shown in Table 5, the highest fusion rates were seen with rhBMP-2 (71–100%), whereas less CT fusion data is available for allograft, synthetics, and peptide-based grafts (9,33).

Discussion

Fusion criteria

The fusion rates in ALIF differed between studies, at least partly because of a lack of standardized imaging methods, fusion criteria, and timing of assessment. The included studies assessed fusion radiologically by CT (n=11), X-ray (n=4), or both CT and X-ray (n=5), or the method was not specified (n=7). Most studies in Australia used CT, whereas most studies in the US used X-ray only. Fusion rates assessed by CT tend to be lower than those assessed by X-ray (33). For example, Lechner et al. (24) assessed fusion rates by both CT and X-ray and noted that fusion rates were lower with CT (77.78%) than with X-ray (85.48%) when using β-tricalcium phosphate (β-TCP) plus bone marrow aspirate as bone graft material (23). However, use of CT is accompanied by distinct disadvantages, especially higher radiation exposure and cost (23). Although most studies (n=16) specified their fusion criteria in the Methods section, these criteria often differed, leading to difficulties in comparing fusion rates between studies. Furthermore, studies assessed fusion at differing times after surgery, ranging from 6 months (19,33) to a mean of 47 months (13) for CT and from 6 to 24 months (14,33) for X-ray. However, fusion was often assessed at 12 months, allowing us to use this as a reasonable assessment time for comparisons. Importantly, Malham et al. reported that CT fusion rates using rhBMP-2 were 66% at 6 months, 96% at 12 months, and 100% at 24 months, suggesting that fusion does not differ substantially between 12 and 24 months postoperatively (3). Establishing standard fusion criteria would allow for more accurate comparisons between studies.

Many authors have highlighted the inadequacies of X-rays for assessing spinal fusion postoperatively. While both X-rays and CT scans are commonly used for this purpose, the limitations of X-rays, including inferior soft tissue visualization, resolution, and accuracy of detecting early fusion, render CT scans more dependable in many ways. CT excels in offering an intricate evaluation of mineralized bone structures and accurately identifying hardware-related complications, such as pseudarthrosis and infection. Despite their widespread use because of easy accessibility and cost-effectiveness, X-rays do not provide the comprehensive view essential for assessing spinal fusion progression and hardware complications. In our review, many authors firmly recommended using ‘focused’ CT (involving only the operative level/s to reduce radiation exposure) for more accurate, up-to-date fusion assessment, superseding the outdated and less precise X-ray methods.

Urologic complications of rhBMP

Recent studies have focused on the possible association between rhBMP-2 and urologic complications, but their results are conflicting. Comer et al. (15) found that rhBMP-2 was associated with a higher incidence of retrograde ejaculation (RE), but Lubelski et al. (27) detected no association between rhBMP-2 and urologic complications, including RE, erectile dysfunction, and persistent retention. Lammi et al. (23) and Malham et al. (3) likewise reported no urologic complications with rhBMP-2 use. Although RE is a potential complication of ALIF itself because of mechanical and inflammatory damage, rhBMP-2 has been associated with inflammatory adverse effects, which may contribute to an increased risk of RE (15). However, most studies assessing urologic complications were retrospective and contained no comparison group. Only Tepper et al. (36) evaluated urologic complications diagnosed via laboratory analysis of semen and urine. They found that RE was overreported in questionnaires, as 15 patients reported RE in these questionnaires, whereas only four had true RE based on laboratory analysis. This suggests that the method of assessing RE can significantly affect the reported incidence. The authors also found no significant difference in RE incidence between patients who received rhBMP-2 plus femoral ring allografts (FRA) (9.5%) versus ICBG (10%). In both groups, RE resolved spontaneously, indicating that RE may be a short-term complication, as suggested in other studies (26).

In a number of studies, patients were not specifically asked about postoperative urologic complications. However, in two studies by Malham et al. (3,28), an independent physician assessed specific complications and found that only one patient (1.5%) developed RE. Furthermore, most studies focusing on urologic complications did not report fusion rates, preventing more comprehensive comparisons between bone graft substitutes. The differing complication rates between studies were likely affected by variances in postoperative protocols between surgeons and hospitals. Further studies are required to specifically evaluate the potential association between rhBMP-2 and urologic complications.

Nonurologic complications of rhBMP-2

The studies included in this review assessed several nonurologic complications potentially associated with rhBMP-2 use, including pseudoarthrosis, subsidence, radiculopathy, and dysesthesia. The study with the largest sample size showed that the incidence of complications (including reoperation and radiculopathy) within 12 months after surgery was not significantly different between patients receiving rhBMP-2 and those not receiving rhBMP-2 (17). Heterotrophic ossification was also detected in a small number of patients, indicating that further studies should also assess this potential complication (17). However, Khalid et al. (21) recently reported that the rate of pseudoarthrosis was higher in patients treated with rhBMP-2 than in those without rhBMP-2 (21). Although subsidence was reported in some studies, it can be affected by the type of cage (38). Behrbalk et al. (14) found that 15.6% of patients treated with rhBMP-2 in PEEK cages had implant subsidence, and Kolcun et al. (22) reported that the mean disc height subsidence was 1.8 mm when rhBMP-2 was used in an OptiMesh device. However, Lee and Kim (25) detected no implant subsidence in patients receiving rhBMP-2. Therefore, future studies should account for the type of cage when evaluating the association between bone graft substitutes and implant subsidence.

Higher incidences of neurologic complications were found in patients who received rhBMP-2. In one study, postoperative radiculitis occurred in eight patients (38%) receiving rhBMP-2 and only two patients (10%) treated with map3 cellular allogenic bone grafts (25). Malham et al. (3) reported that among 50 patients receiving rhBMP-2 for ALIF, three (6%) developed radiculopathy and three (6%) experienced dysesthesia. Only one study, Malham et al. (28) assessed cancer and found no increased risk of cancer in patients who received rhBMP-2 or rhBMP-7 for lumbar interbody fusion, including ALIF, with a minimum 1.8-year follow-up. Further studies should assess the incidences of cancers specifically following ALIF. Only one study (34) reported in-hospital mortality after ALIF with rhBMP-2 but did not specify whether the deaths were related to rhBMP-2. Overall, the methods for detecting and diagnosing complications differed between studies, which likely affected the reported incidences and highlighted the need for further studies to compare rates of complications between bone graft substitutes based on the same methodology.

Optimal rhBMP-2 dose

Studies have used a range of rhBMP-2 doses to achieve high fusion rates with ALIF while minimizing complications. The dose of 6 mg/level rhBMP-2 was associated with a fusion rate of 90.6% at 6 months and no subsidence (14). However, when rhBMP-2 and ICBG were used in different chambers of a cage in the same individuals, the 12-month fusion rate was 71% with 6 mg of rhBMP-2 and 88.7% with ICBG, and three patients (4.8%) experienced pseudoarthrosis (30). In a study of rhBMP use during ALIF by Malham et al. (28), patients received mean doses of 10.2 mg (range, 2.5–48.0 mg) for rhBMP-2 and 3.3 mg (range, 1.7–6.6 mg) for rhBMP-7 in ALIFs, but only the overall fusion rate was reported (94.7%), so the effectiveness of each dose could not be determined. Future studies are required to determine the optimal dose of rhBMP-2.

New combinations of rhBMP-2 with other bone graft substitutes have been developed. A 100% fusion rate and no associated complications were recently reported in 18 patients receiving Escherichia coli-derived rhBMP-2 plus β-TCP (18). These promising results justify conducting further studies with larger sample sizes and longer follow-ups to assess long-term complications of this treatment strategy (18). rhBMP-2 with bone matrix was also reported to have a 100% rate of fusion on X-ray at 12 months (32), but the fusion rate was not assessed by CT, preventing accurate comparisons with other bone graft substitutes. rhBMP-2 plus supercritical carbon dioxide (SCCO₂)-processed allograft for ALIF resulted in a fusion rate of 95%, with only one patient (6.7%) experiencing temporary erectile issues and three patients (20%) developing graft subsidence (30). However, rhBMP-2 with FRA resulted in discordant levels in nine patients with double-level ALIFs, which was only detected in this study. As fusion rates associated with combining rhBMP-2 plus other bone graft substitutes are promising, future studies should be performed to compare fusion rates and assess for long-term complications. However, since rhBMP-2 is currently off the market in Australia, further studies of the material from this country will be limited to retrospective studies, and other bone graft substitutes will need to be considered.

Allografts

A variety of allografts continue to be developed. Recently, Kasis et al. (19) developed the Northumbria technique combining femoral head allograft with ICBG and reported a 94% CT fusion rate after 5–6 months (19). Only one patient (1%) developed temporary donor-site pain, a known complication of autografts (4). However, further studies by other surgeons are required to assess the technique’s reproducibility, and this combined technique involved the use of autografts. The map3 cellular allogenic bone graft had a 91% fusion rate, with no statistical difference in fusion rates compared to rhBMP-2 (25). Furthermore, the rate of radiculitis was lower with this allograft (n=2; 10%) than with rhBMP-2 (n=8; 38%) (27). SCCO₂-processed bone allografts were associated with a fusion rate of 90.5% at 47 months on CT and no reported complications, but the fusion rate at 12 months was not available, preventing comparisons to other materials (13). FRA had the lowest fusion rate (79%) on X-ray at 12 months, with no complications detected, but CT assessment of fusion rates was not performed (34). FRA used in combination with rhBMP-2 showed a 74% CT fusion rate at 12 months (20). Overall, SCCO₂-processed bone allografts appear promising, but further studies are required to compare fusion rates with other bone grafts and assess for a range of complications.

Calcium phosphate compounds

Ceramics are synthetic grafts containing calcium phosphate combined with hydroxyapatite or silicate. β-TCP with bone marrow aspirate had a fusion rate of 85.48% on X-ray and 77.78% on CT at 12 months (24). Silicate-substituted calcium phosphate [SiCaP (Actifuse)] has been used, but we identified its use in only two patients undergoing ALIF (36). Although fusion was successful in both patients, a larger sample size is required. However, a meta-analysis comparing SiCaP with rhBMP-2 for posterolateral fusion found no difference in fusion rates between the two materials (9). However, no studies used the same type of calcium phosphate compound, so it was not possible to determine the components potentially contributing to improved fusion and complication rates. Overall, these studies regarding calcium phosphate compounds have had small sample sizes and no comparison groups, but their results were promising and warrant future larger studies, including randomized controlled trials.

Bioactive glass contains biodegradable granules that are osteoconductive, not osteoinductive. In 2022, Szadkowski et al. (35) reported fusion rates of 89–100% with bioactive glass, which were not significantly different from the rates achieved with autografts. Notably, the fusion rates in this study were assessed within the same patients, as one chamber of the cage contained bioactive glass and the other chamber contained ICBG. Although this methodology is useful for comparing fusion rates between bone graft substitutes, it leads to difficulties in determining which type of graft is responsible for complications. Bioactive glass also has unique properties, including antibacterial and anti-inflammatory properties, that may improve overall outcomes of ALIF (39,40). Therefore, further research is required to evaluate the effectiveness and safety of bioactive glass grafts for ALIF.

Peptide-based grafts

iFACTOR is the only peptide-based graft currently available. It is a bone graft substitute matrix containing P-15 osteogenic cell binding peptide combined with an organic bone matrix material suspended in a hydrogel carrier. Overall, iFACTOR appears to be a promising substitute, producing high fusion rates with minimal complications. However, only one study has been published using iFACTOR for ALIF. In this prospective study of 110 patients, the fusion rate assessed by CT was 94% at 2 years (31). Of note, this study was partially funded by Cerapedics, the company that manufactures iFACTOR. Overall, investigations of bone graft substitutes are industry led, with studies often funded by manufacturers. Early studies on rhBMP-2 in ALIF were widely supported financially by industry, and later independent studies reported more complications associated with this agent (41). Future independently funded studies are encouraged to reduce potential bias.

Review limitations

One limitation of this review was that outcomes for specific bone graft substitutes were often difficult to extract from studies because of combined outcomes from different bone graft substitutes or types of lumbar interbody fusions. Previous studies and meta-analyses (42) identified factors that could affect differing fusion and complication rates between approaches. This highlights the need for randomized controlled trials (RCTs) with larger sample sizes to achieve sufficient statistical power to detect significant differences in outcomes between different bone graft substitutes for ALIF.

Another limitation was that the methods used to measure functional outcomes after ALIF were patient-reported outcome measurements. Although some studies reported Oswestry Disability Index and visual analog scale scores for back or leg pain, many factors unrelated to bone graft material affect these scores. Future studies should control for factors affecting functional outcomes other than type of bone graft substitute.

A third limitation was that we did not search the grey literature, so very recently developed bone graft substitutes may not have been included. However, early studies are likely to be funded by companies that developed these substitutes, leading to a substantial risk of bias. Independently funded RCTs are required to more accurately compare fusion rates and assess complications.

Conclusions

This systematic review examined 27 studies published over the past decade regarding various bone graft substitutes used for ALIF and focused on their rates of fusion and postoperative complications. The majority of studies evaluated rhBMP-2 and reported robust fusion rates. Nonetheless, the association between rhBMP-2 and increased risk of postoperative complications remains a contentious subject, with divergent findings reported. Of note, the methodologies for quantifying spinal fusion were heterogeneous, with only one-third of studies using CT to assess spinal fusion at 12 months postoperatively, thereby underscoring the need for a uniform set of fusion criteria to enable more accurate comparative analyses. The criteria for diagnosing and identifying postoperative complications also varied significantly across studies, influencing the reported complication rates. Consequently, there is a need for further research into bone graft alternatives, particularly to ascertain and evaluate potential long-term dangers through extended postoperative surveillance. The findings from this narrative review can be used to guide future research to determine how bone graft substitutes used in ALIFs should be selected in clinical practice. Future scholarly efforts should endeavor to formulate clinical protocols delineating the optimal selection criteria for bone graft substitutes in the setting of ALIF surgery.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jss.amegroups.com/article/view/10.21037/jss-24-24/rc

Peer Review File: Available at https://jss.amegroups.com/article/view/10.21037/jss-24-24/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-24-24/coif). R.J.M. serves as the current Editor-in-Chief and G.M.M. serves as an unpaid editorial board member of Journal of Spine Surgery. R.J.M. is a consultant for Australian Biotechnologies, A-Spine, LifeHealthcare, and Medacta. G.M.M. is a consultant for Australian Biotechnologies, Globus, and LifeHealthcare. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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