Effectiveness and safety of recombinant human bone morphogenetic protein-2 for adults with lumbar spine pseudarthrosis following spinal fusion surgery

Design

We conducted a systematic review of the published literature performed using a priori protocol.

Literature search

Clinical studies of any design type that investigated the safety and efficacy of BMP in revision spinal fusion surgery via any surgical approach at the lumbar region only were eligible for inclusion. We performed a systematic literature search using the following databases: Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2) which contains the Back Group, Bone, Joint and Muscle Trauma Group, and Musculoskeletal Group specialised register; MEDLINE (via PubMED) (1950 to September 2014); and EMBASE (1980 to September 2014), adopting PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) recommendations.¹⁵ We supplemented the database search by a hand search of the reference list of the identified studies (Fig. 1). The search terms and limits are provided in the supplementary material (Tables S1 and S2).

Fig. 1

Flow diagram showing the systematic review.

Article selection

We included studies if they investigated BMP for revision spinal fusion surgery secondary to pseudarthrosis. Comparative treatments included ABG, allograft and bone graft products. Trials were required to have been conducted in human subjects ⩾ 18 years of age without restriction of gender or surgical approach used except that the location of spine surgery be within the lumbar region. Due to the nature of the intervention and subsequent assessment, it was agreed that studies of open-label and single-blind design should be included in addition to the double-blind design, as well as studies of both prospective and retrospective design.

Data from previous reviews were not used to enable collection of data from original sources, however, any such publications identified served as a comparator to ensure that all relevant studies had been included within this review.

We excluded all studies which were not published as full-text articles and: where BMP was not used (e.g. use of synthetic material other than BMP); which reported on non-spinal fusion (e.g. long-bone); which reported BMP use only in patients undergoing primary spinal fusion surgery; where the location of BMP applied was not clearly reported within the outcome data; where the reason for revision surgery was other than for pseudarthrosis or not clearly stated; and where follow-up data covered less than 24 months.

Outcome measures - effectiveness analysis

Our pre-specified outcomes were those likely to be important for patients and healthcare providers. The primary outcome measure was spinal fusion, assessed as success or failure in accordance with radiograph, MRI or CT scan review at 24-month follow-up. This outcome was chosen on the basis that an assessment of fusion success was the most commonly reported endpoint. The secondary outcome measure was time to fusion. The third outcome measure was the change from baseline to month six in the Oswestry Disability Index (a validated ten-domain index derived from the Oswestry Low Back Pain Questionnaire to quantify disability for low back pain, ranging from 0% (minimal disability) to 100% (bedbound)).¹⁶

Outcome measures - safety analysis

We extracted data on the number of adverse events from the published studies included for both the BMP and autograft arms.

Quality assessment and data extraction

Two investigators reviewed abstracts and full-text articles retrieved by the search and selected potentially relevant publications against the pre-specified inclusion and exclusion criteria. To ensure consistency of data abstraction for each study a structured form was used. To define the quality of evidence, each article was assigned a level of evidence (LOE) as described by Sackett.¹⁷ Any discrepancies or lack of agreement between the two reviewers were referred to a third independent investigator for arbitration. In accordance with the Cochrane Handbook for Systematic Reviews and Interventions, and the Centre for Reviews and Dissemination (CRD) guidance for undertaking reviews in health care, the assessment of risk of bias for eligible studies was undertaken using the TREND statement.^18-20 Where analyses were not directly reported as intention-to-treat this value was calculated.

Study selection

A total of six studies met the inclusion criteria representing 530 patients, of which 203 underwent revision surgery due to pseudarthrosis (Fig. 1).^21-26 Of the six studies, four provided a comparison of recombinant human (rh) BMP2 and bone graft whereas the other two solely investigated the use of BMP2. No studies investigating the use of BMP-7 met the inclusion criteria. Within the pseudarthrosis population, 117 patients received BMP2 as part of revision surgery while bone graft alone was used in 68 patients (the remaining 18 patients received bone marrow aspirates and are therefore excluded from analyses). All studies were published as full journal articles with a follow-up of 24 months.

Study characteristics

The main characteristics of the studies included are given in Table I. Of the six studies, two were single-arm assessments of BMP2 alone (one retrospective study and one prospective study,^24,25 and four were comparative assessments of BMP2 and bone graft (two retrospective studies and one prospective study).^21-23,26 Reasons for exclusion from the systematic review are provided in Figure 1.

Quality assessment

A common theme across eligible studies was an absence of sample size calculation and the availability of a protocol detailing trial design or planned outcomes. In two of the eligible studies, the authors declare receipt of royalties from the manufacturer of BMP2, although this does relate to involvement in the study design, analysis or publication. Due to study design and differing methods of surgical technique used which increases the potential for methodological diversity, all six studies included were noted as having a moderate risk of bias in accordance with the TREND Statement Checklist, a tool recommended for systematic reviews which include non-randomised studies.

Radiological outcomes - fusion

Successful fusion was observed in 92.3% (108/117) of patients following surgery with BMP2. None of the four studies which compared BMP2 with bone graft showed superiority, however, BMP2 was equally effective. Fusion success was determined using radiographs in all but one study where CT grading was used. With the exception of one study where method of fusion assessment by the surgeon was not stated, fusion status was reviewed by the surgeon initially and subsequently confirmed by a radiologist. In three of the studies, radiological review was performed in an unblinded fashion by both surgeon and radiologist; in the remaining two studies, both surgeon and radiologist were blinded (Table II). It is interesting to note that in the one comparator study where both surgeon and radiologist were unblinded, the rate of fusion was lower for subjects who received BMP2 compared with those who received bone graft. However, in the two comparative studies in which the surgeon and radiologist were blinded, a fusion rate of 100% was recorded for subjects within the BMP2 and bone graft arms.

Radiological outcomes - time to fusion

Neither of the single-arm studies collected data for reporting time to fusion analysis. In three of the four comparative studies, subjects who received BMP2 as part of their surgery exhibited a statistically quicker time to achieving fusion (Table II). In the two studies where surgeon and radiologist blinding was used, although there was no difference in fusion rate, the time to fusion was statistically significantly faster in subjects who received BMP2.

Clinical outcomes - pain score

An assessment of BMP2 use on pain was not collected in either of the single-arm studies and in only three of the four comparative studies. Despite the Oswestry Disability Index (ODI) being regarded as the principal condition-specific outcome measure in the management of spinal disorders for measuring degree of disability and quality of life factors in a person with low back pain, this was used in one study only, with the 11-point Visual Analogue Scale (VAS) being used in two studies. Overall, despite a significant reduction in pain from baseline in both the BMP2 and bone graft arms, at no point over the two-year follow-up period was there a significant difference between the two. For studies that recruited patients not exclusively undergoing revision surgery secondary to pseudarthrosis, unlike radiological outcomes, pain scores were not reported separately for this subgroup.

Clinical outcomes - safety and tolerability

Across the six studies, the use of BMP2 was not associated with an increase in the risk of complications over bone graft. The only complication reported was in the study by Mulconrey et al²⁴ where one patient treated with BMP2 developed a tense subfacial haematoma on post-operative day four, requiring surgical drainage. Reporting of adverse events and complications was poorly described.

Investigation by surgical approach

Spinal fusion surgery via the posterior approach (posterolateral fusion; PLF) appeared to be the most commonly implemented, accounting for 86.7% (176/203) of patients undergoing revision surgery secondary to pseudarthrosis. The remaining 27 patients (13.3%) underwent surgery via the anterior approach (anterior lumbar interbody fusion; ALIF) or transverse approach (transforaminal interbody lumbar fusion; TLIF).

How does this compare with the published literature?

This is the first systematic review to be conducted focusing solely on the use of BMP in patients with pseudarthrosis following primary lumbar spinal fusion surgery. We identified the relevant studies by explicit systematic review, and the analysis conformed to PRISMA recommendations. The primary efficacy outcome we selected is established from a surgeon’s perspective within the revision setting as a clinically acceptable and informative measure, as well as being of relevance to patients and healthcare providers. Although we acknowledge that other measures of success, such as improvements in disability or pain are also of relevance, the goal of revision spinal surgery is to realise the aim of the primary surgery, which is fusion.

This review differs from others available within the published literature in that it specifically addresses the efficacy and safety profile associated with BMP use within a defined population of patients, i.e. adults undergoing lumbar spinal fusion surgery secondary to pseudarthrosis, where prior use of the considered benchmark, ABG, has failed to result in union.

Of interest, however, is a non-clinical overview of the physical and biological properties of osteoconductive and osteoinductive bone replacement materials and their use in spinal fusion surgery.³⁴ The authors of this overview included an assessment of ABG, allograft, graft extenders, and BMP, concluding that while satisfactory fusion rates may be obtained with the use of non-autologous material, in comparison with ABG, the vascularisation and remodelling of a fusion mass are delayed using allografts as they possess limited osteoinductive properties. As such, genuine bone replacement is only currently feasible with BMP. The authors further suggest that their use should be restricted to specific indications, such as complex revision surgery and pseudarthrosis.

A limitation of this systematic review is that the data acquired from the published literature are derived from a mixed population, for example different pathological backgrounds, cause of pseudarthrosis, age, number of levels, and particulars of previous surgery (type, technique, and operating surgeon) as well as varying quantity and type of BMP used. On this basis, it was considered inappropriate to subject the data to meta-analysis.

Lastly, based on the studies identified which reported on BMP2 use within the context of revision spinal surgery secondary to pseudarthrosis, it was not possible to comment on any impact on duration of operating time, duration of hospital stay, time to return to work, or changes in related pharmacotherapy.

Despite the above limitations, the use of BMP was associated with a consistently high fusion rate and demonstrated comparable results with use of bone graft in patients where such alternative intervention was possible. In the absence of a prospectively conducted randomised control trial, the above examples of heterogeneity will continue to be present in published reports.

In conclusion, of the bone grafts available, ABG remains the benchmark by which spinal fusion surgery is performed. The use of BMP2 in revision lumbar spinal fusion surgery provides comparable fusion results at 24 months compared with bone graft, but with a quicker time to fusion and without the potential donor site complications of ABG. This review supports the recommendations of NASS and the Complex Spinal Surgery Clinical Reference Group (NHS England), that BMP2 may be the most suitable bone graft option for adults with lumbar pseudarthrosis requiring revision spinal fusion surgery where ABG is not available, however, future studies, ideally of prospective randomised design, are needed to further clarify its clinical advantages and cost effectiveness.