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An inception cohort study of patients in a military clinic treated for lower back pain with lumbar fusion and SIGNAFUSE® with a systematic review of the literature

A B S T R A C T

Background: Use of synthetic bone graft substitutes for spinal fusion has increased sharply over the past 20 years. SIGNAFUSE® is one such synthetic graft material that provides an osteostimulatory effect for spinal fusion. Because clinical trials are not required for commercialization of synthetic bone graft substitutes in the United States, fusion rates attained using SIGNAFUSE for lumbar fusion are not well documented. The goal of the current study is to determine the rate of spinal fusion in a military clinic following lumbar fusion surgery augmented with SIGNAFUSE.
Methods: We report a retrospective chart review of 8 patients who received lumbar spinal fusion surgery augmented with SIGNAFUSE. All patients were assessed by computed tomographic (CT) imaging at least 1-year post-surgery to determine whether bony fusion had occurred. We also systematically reviewed literature sources that report fusion rate following spinal fusion surgery, for broader context.
Results: An average of 1.6 spinal levels were treated with SIGNAFUSE-loaded interbody cages. All patients had stabilization hardware via pedicle screws or integrated cage fixation. Seven of 8 patients successfully fused, for an overall fusion rate of 87.5% (95% confidence interval: 47.4% to 99.7%). Systematic review of 26 recent publications that included 1,126 patients treated with synthetic bone graft showed that the overall fusion rate in the literature is 84.4%.
Conclusions: Fusion was achieved in 87.5% of patients treated with SIGNAFUSE. This is comparable to the fusion rate in a systematic review of 1,126 patients treated with synthetic bone graft materials.

Introduction

About two-thirds of adults have lower back pain (LBP) at some point during their lifetime [1]. LBP may be even more prevalent in a military population, due to acute trauma in combat and stress injuries in training [2]. LBP caused more than 457,000 Americans to seek spinal fusion in 2011, with ~75% of fusion procedures for spondylolisthesis, spondylosis, or other painful disk disorders [3, 4].Lumbar fusion surgery is done to achieve solid fusion, restore spinal stability, and enable return to normal activities. Spinal fusion procedures use various biologic materials to promote new bone growth, with iliac crest bone graft (ICBG) considered the “gold standard” of treatment, because of its osteoconductivity, osteoinductivity, osteogenicity, and angiogenic potential [5, 6]. Though ICBG is widely used, problems such as donor site morbidity, limited supply of graft material, potential increase in surgical complication rates, and the increase in surgical times argue against use of ICBG [5, 7]. Thus, there has been an effort to develop other bone grafting options that include allograft bone (e.g., demineralized bone matrices, allograft chips), synthetic graft materials (e.g. hydroxyapatite or HA), β-tricalcium phosphate (β-TCP), bioactive glass, collagen-based matrix, or recombinant growth factors (e.g., rhBMP-2). Synthetic graft materials provide the osteoconductive element that ICBG provides but may lack the osteoinductive and osteogenic components of ICBG [6]. To circumvent these limitations, some synthetic grafts incorporate bioactive glass to provide an osteostimulatory signal and many surgeons combine synthetics with bone marrow aspirate (BMA), to provide an osteogenic component. Synthetic graft materials are attractive because of the low risk of disease transmission, minimal immunogenicity, and superior intra-operative handling capabilities [6]. Additionally, synthetics avoid the potential adverse events reported in some patients following use of rhBMP-2, including retrograde ejaculation, ectopic bone formation, and dysphagia [8, 9].

Here we report an inception cohort study of 8 patients treated in a military clinic who underwent lumbar fusion procedures to alleviate symptoms of degenerative disk disease and other spinal disorders. All patients were treated with SIGNAFUSE® Bioactive Bone Graft (Bioventus, Durham, NC), a combination synthetic graft composed of hydroxyapatite with β-tricalcium phosphate (HA/β-TCP) and bioactive glass in a resorbable polymer carrier, and all patients were evaluated for fusion by computed tomographic (CT) imaging. We also present a systematic review of publications reporting synthetic bone graft use in lumbar fusion surgery, as a point of comparison for our observed fusion results with SIGNAFUSE.

Patients and Methods

A planned retrospective chart review was combined with prospective computed tomographic (CT) imaging at follow-up, to evaluate the primary endpoint of radiographic fusion rate in patients treated with SIGNAFUSE at William Beaumont Army Medical Center (WBAMC) in El Paso, TX. The study received full Institutional Review Board (IRB) approval in October 2016. Potentially eligible patients were contacted after surgery by research staff to assess their interest in participating in the study. Patients were eligible for inclusion in this study if they:

  • Were age 18 years of age or older;
  • Were active duty military;
  • Were a Department of Defense beneficiary;
  • Had undergone a 1-3 level lumbar spinal fusion for a degenerative spinal process at WBAMC between August 2012 and January 2016;
  • Voluntarily signed the IRB-approved informed consent document.
Patients were excluded from study if they:
  • Were pregnant;
  • Underwent lumbar spinal fusion surgery at 4 or more levels;
  • Were diagnosed with concurrent tumor;
  • Were indicated for surgery due to trauma;
  • No longer resided in the WBAMC area.

Patients interested in the study were invited for an on-site visit with a follow-up CT scan at WBAMC. A total of 19 patients were consented for study participation; 8 patients met inclusion criteria and completed a follow-up CT scan. Fusion status of the patient was assessed using CT scans and the patients were considered fused if there was evidence of bilateral continuous trabecular bone across the fusion bed.

A systematic review was also performed to compare the observed healing outcomes to healing outcomes from a range of different spinal fusion techniques that used many different commercially available synthetic bone graft substitutes. Sources were identified by several PubMed searches, augmented with sources drawn from a recent systematic review [10]. We sought to identify lumbar fusion procedures that used a range of commercially available synthetic bone grafts. Specific inclusion criteria were that studies:

  • Were identified using the search phrase “lumbar spinal fusion” or “lumbar spine fusion”;
  • Had been published within the last 20 years;
  • Were randomized controlled trials (RCTs), prospective cohorts, or retrospective cohorts;
  • Reported sufficient data to calculate fusion rate following fusion surgery;
  • Used synthetic bone graft materials, bone grafts augmented with autograft, or bone marrow aspirate during the procedure;
  • Assessed bony fusion by X-ray or CT;
  • Were published in a peer-reviewed journal.

Science Repository

Figure 1: CT image for Patient #3, acquired 1.8 years after surgery. Patient #3 was a 34-year old male with a long history of lower back pain, beginning after an injury while on active-duty military service. His pain was midline in the lower back, with bilateral lower leg numbness and pain on the posterior aspect of both legs, with subjective muscle weakness. The patient was diagnosed with L5/S1 degenerative disc disease with herniation. The patient attempted conservative management, including physical therapy, pain medications, traction, and bracing, without relief, so he underwent an ALIF at L5/S1 without complication. Three months later, X-rays demonstrated L5/S1 incorporation of the graft into the endplates with bony fusion.

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Figure 2: CT image for Patient #12, acquired 1.6 years after surgery. Patient #12 was a 25-year old male with bilateral leg pain and lower back pain of 2 years duration. Onset of pain was insidious, with no overt injury. Dorsal leg pain projected to the toes, with numbness and tingling, and patient had positional relief when leaning forward, but most other activities increased pain. Patient was diagnosed with L5/S1 spondylolisthesis with radiculopathy. The patient underwent an ALIF at L5/S1 without complication and CT scan demonstrated L5/S1 fusion of 40% of the disc at 20 months.

Exclusion criteria (for the whole study or for a particular study arm) were that:

  • Patient follow-up was less than 12 months;
  • Surgery involved the cervical spine;
  • Bone graft materials were augmented with rhBMP;
  • Fusion was reported by level, not by patient;
  • Radiographic assessment of fusion was not reported;
  • Publication was as an abstract, conference proceeding, or editorial.

Results

Average patient age was 41.6 years (standard deviation (SD) = ± 10.6) at surgery and 2 patients had prior surgery (Table 1). Diagnoses within the cohort included 6 patients with spondylosis and 2 with spondylolisthesis. In 5 patients, SIGNAFUSE was used in combination with bioglass granules and in 1 patient SIGNAFUSE was used in combination with cancellous allograft bone. Four patients received anterior lumbar interbody fusion (ALIF), 3 received transforaminal lumbar interbody fusion (TLIF), and 1 received oblique lumbar interbody fusion (OLIF) fusion surgery. An average of 1.6 spinal levels were fused (range: 1 to 3 levels). All patients received stabilization hardware via pedicle screw instrumentation or integrated fixation built into the ALIF cages (Table 2). Average duration of surgery was 181 minutes (SD = ± 94 minutes), and operative blood loss was 164 mL (± 260 mL SD). The average hospital stay after surgery was 2.1 days, with the longest stay being 3 days. Seven of 8 patients had successful fusion, as determined by CT, for an overall fusion rate of 87.5% (95% confidence interval: 47.4% to 99.7%) (Table 2). All 2- and 3-level fusion procedures showed evidence of radiographic fusion by CT scan within 2 years post-surgery, while 3 out of 4 patients with 1-level fusion procedures showed evidence of radiographic fusion. Figures 1 and 2 show representative CT scans of successfully fused patients.

A total of 26 published studies were identified for the systematic review (11-36). The process by which these studies were identified is shown (Figure 3). Included studies were predominantly posterolateral fusions (PLF) with instrumentation and used ceramic bone grafts augmented with autograft or bone marrow aspirate. Analysis of these published studies shows that the overall weighted average fusion rate is 84.4% in 1,126 patients (Table 3). Thus, fusion results from SIGNAFUSE-treated patients (Table 2) are comparable to fusion results in the systematic review (Table 3).

Science Repository

Figure 3: PRISMA diagram, showing how the sample of 26 studies reported in Table 3 was assembled.

Table 1:  Patient demographics at surgery.  DDD = Degenerative disk disease; Spond = Spondylolisthesis; LBP = Lower back pain.

Gender

Patient age

Pre-operative diagnosis

Pre-operative symptoms

Prior surgery

Male

42

L3/L4, L4/L5 DDD

LBP, anterolateral right thigh pain, left thigh pain

None

Male

33

L5/S1 DDD, herniation

LBP for 13 years, bilateral lower leg numbness, muscle weakness

None

Male

41

L4/L5 DDD, L5/S1 Spond

LBP for 2 years, right leg numbness, right leg tingling, right leg pain

None

Male

25

L5/S1 Spond, radiculopathy

LBP for > 2 years, bilateral leg pain, bilateral leg numbness, bilateral leg tingling

None

Male

55

L4/L5, L5/S1 DDD

LBP for 30 years, right foot numbness, right lower leg numbness

None

Male

42

L4/L5 DDD, herniated disc

LBP for 5 years, bilateral lower extremity pain

None

Female

38

L5/S1 Synostosis

LBP for > 5 years, L5/S1 synchondosis, right leg pain, right foot pain

L4/L5 ALIF

Male

57

L3/L4, L4/L5, L5/S1 DDD

Back pain for > 1 year, right lower extremity tingling for > 1 year

L4/L5 microdiscectomy

Table 2: Operative characteristics and outcomes. INTERFACE = synthetic granules (45S5 bioglass) ALIF = anterior lumbar interbody fusion; TLIF = transforaminal lumbar interbody fusion; OLIF = oblique lumbar interbody fusion

 

 

Fusion levels

 

Surgical Technique

 

SIGNAFUSE graft used

 

Other graft used

Spinal levels fused

 

Operative time (min)

Operative blood loss (mL)

Hospital stay (days)

 

 

   Outcome

L3/L4, L4/L5

ALIF

15 g

INTERFACE 1 g

2

160

100

3

Fused

L5/S1

ALIF

15 g

INTERFACE 1 g

1

105

50

2

Fused

L4/5, L5/S1

ALIF

15 g

INTERFACE 1 g

2

273

75

3

Fused

L5/S1

ALIF

15 g

INTERFACE 1 g

1

104

20

2

Fused

L4/L5, L5/S1

TLIF

7.5 g

Cancellous chips 30 cc

2

232

50

2

Fused

L4/L5

TLIF

15 g

None

1

83

NA

1

Not Fused

L5/S1

TLIF

15 g

None

1

143

100

2

Fused

L3/4, L4/5, L5/S1

OLIF

30 g

INTERFACE 1 g

3

347

750

2

Fused

   

Average

 

1.6

180.9

163.6

2.1

87.5% fused

   

SD

 

0.7

94.0

260.2

0.6

35.4%

Discussion

Our results show that a fusion rate of 87.5% can be attained in a clinical setting with a range of different lumbar fusion approaches combined with SIGNAFUSE (Table 2). The fusion rates obtained with SIGNAFUSE are thus comparable to fusion rates reported with a range of other synthetic bone grafts (Table 3). The overall weighted average of fusion in the 26 publications was 84.4% (943 of 1,126 patients fused), while the fusion success of our SIGNAFUSE-treated patients was 87.5% (7 of 8 patients fused). Sub-analysis of the systematic review by graft type (HA, β-TCP, or HA/β-TCP) showed that fusion rates did not differ appreciably, with respective average fusion rates of 80%, 86%, and 88% (Table 3).

This study has several limitations. First, the number of patients in our series is small, and patients were treated with several different surgical techniques, while most published studies were PLF procedures. Second, varying amounts of SIGNAFUSE graft material were used (range: 7.5 - 30 g) in our series (Table 2). Third, the systematic review reports a range of different synthetic graft materials which may not all be comparable to one another, but the sample size of the individual graft materials is too small to analyze separately. Fourth, even within the cohort of patients who received SIGNAFUSE, some patients had SIGNAFUSE augmented with bioactive glass, some patients had SIGNAFUSE augmented with cancellous chips, and some patients did not have any supplemental grafting materials. Fifth, the volume and relative ratio of other materials (BMA, autograft, etc.) mixed with graft materials varied, so it is not possible to attribute fusion success to any specific synthetic materials. For example, one study used HA and β-TCP without other supplemental grafting materials, while all other studies in the systematic review used BMA or autograft to augment the synthetic materials [33]. Finally, few controlled trials using synthetic bone graft materials have been conducted overall, so there is a compelling need for additional research.

Conclusions

Lumbar fusion surgery has increased in the recent past and is expected to continue to increase as the population ages [4]. Stable fusion is the goal of surgery, so there is a strong impetus to identify which types of bone grafting materials or bone graft substitutes are most effective in attaining fusion. The use of a synthetic graft such as SIGNAFUSE, alone or in combination with other grafting materials, may provide an advantage in spinal fusion surgery.

Table 3:  Systematic review of previously published studies utilizing synthetic bone grafts in lumbar fusion approaches

HA = hydroxyapatite; β-TCP = beta-tricalcium phosphate; A = autograft; BMA = bone marrow aspirate; β-TCS = beta-tricalcium sulfate; C = collagen;

DBM = demineralized bone matrix; Si-CaP = silicate substituted calcium phosphate.

First Author Year Ref # Design Approach Graft FU (mos) Patients Fused Fusion rate {%}
Cavagna 1999 11 Prosp. PLF HA + 13-TCP + A + BMA 24 106 100 94
Chen 2005 12 Retro. PLF 13·TCS + A 30 39 34 87
  2005 12 Retro. PLF 13-TCS (S) + A 30 35 29 83
Hsu 2005 13 Prosp. PLF HA + A 12 38 25 66
Korovessis 2005 14 RCT PLF HA + A + BMA 12 38 38 100
Kanayama 2006 15 RCT PLF HA + 13-TCP + A 12 10 9 90
Kitchel 2006 16 Prosp. PLF + PLIF HA + C + BMA 24 25 20 80
Neen 2006 17 Prosp. PLF HA + C + BMA 24 15 14 93
  2006 17 Prosp. PLIF HA + C + BMA 24 13 11 85
  2006 17 Prosp. ALIF HA + C + BMA 24 22 17 77
Moro-Barrero 2007 18 Prosp. PLF HA + 13-TCP + A 30 35 31 89
Chang 2008 19 Retro. PLF 13-TCS + A 12 66 61 92
Dai 2008 20 RCT PLF 13-TCP + A 12 32 32 100
Epstein 2008 21 Prosp. PLF 13·TCP + A + BMA 24 60 51 85
Epstein 2009 22 Prosp. PLF 13-TCP + A + BMA 12 100 95 95
Niu 2009 23 Prosp. PLF 13-TCS + BMA 24 22 10 45
Jenis 2010 24 Retro. PLF HA + BMA 24 42 34 81
Ploumis 2010 25 RCT PLF HA + C + BMA + A 24 12 11 92
Park 2011 26 Retro. PLF 13-TCP + A 12 30 25 83
Yamada 2012 27 Prosp. PLF 13·TCP + A + BMA 24 61 57 93
Kong 2013 28 Prosp. PLF 13-TCP + A 12 42 24 57
Kunakornsawat 2013 29 Retro. PLF HA + C + BMA 24 27 8 30
Pimenta 2013 30 RCT XLIF Si-Ca P 12 13 7 54
Yoo 2015 31 Retro. TLIF HA + A 24 77 67 87
Nam 2016 32 Prosp. PLF HA + A 12 41 30 73
Parker 2016 33 Prosp. XLIF HA + 13-TCP 24 25 20 80
Epstein 2017 34 Prosp. PLF HA + C + A + BMA 37 59 57 97
Gatam 2017 35 Prosp. TLIF HA + DBM 12 17 13 76
vonderHoeh 2017 36 RCT TLIF HA + A 12 24 20 83
          Average = 20.1 1126 950 84.4

Article Info

Article Type
Original Research and Review of Literature
Article History
Received: 30 November, 2018
Accepted: 11 December, 2018
Published: 31 December, 2018
Copyright
© 2018 R. Grant Steen. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
10.31487/j.SCR.2018.03.025

Author Info

Corresponding author
R. Grant Steen
Department of Orthopaedic Surgery, Louisiana State University Medical Center, New Orleans, LA Medical Affairs, Bioventus LLC, 4721 Emperor Blvd., Suite 100, Durham, NC 27703

Figures & Tables

Science Repository

Figure 1: CT image for Patient #3, acquired 1.8 years after surgery. Patient #3 was a 34-year old male with a long history of lower back pain, beginning after an injury while on active-duty military service. His pain was midline in the lower back, with bilateral lower leg numbness and pain on the posterior aspect of both legs, with subjective muscle weakness. The patient was diagnosed with L5/S1 degenerative disc disease with herniation. The patient attempted conservative management, including physical therapy, pain medications, traction, and bracing, without relief, so he underwent an ALIF at L5/S1 without complication. Three months later, X-rays demonstrated L5/S1 incorporation of the graft into the endplates with bony fusion.

Science Repository

Figure 2: CT image for Patient #12, acquired 1.6 years after surgery. Patient #12 was a 25-year old male with bilateral leg pain and lower back pain of 2 years duration. Onset of pain was insidious, with no overt injury. Dorsal leg pain projected to the toes, with numbness and tingling, and patient had positional relief when leaning forward, but most other activities increased pain. Patient was diagnosed with L5/S1 spondylolisthesis with radiculopathy. The patient underwent an ALIF at L5/S1 without complication and CT scan demonstrated L5/S1 fusion of 40% of the disc at 20 months.

Science Repository

Figure 3: PRISMA diagram, showing how the sample of 26 studies reported in Table 3 was assembled.

Table 1:  Patient demographics at surgery.  DDD = Degenerative disk disease; Spond = Spondylolisthesis; LBP = Lower back pain.

Gender

Patient age

Pre-operative diagnosis

Pre-operative symptoms

Prior surgery

Male

42

L3/L4, L4/L5 DDD

LBP, anterolateral right thigh pain, left thigh pain

None

Male

33

L5/S1 DDD, herniation

LBP for 13 years, bilateral lower leg numbness, muscle weakness

None

Male

41

L4/L5 DDD, L5/S1 Spond

LBP for 2 years, right leg numbness, right leg tingling, right leg pain

None

Male

25

L5/S1 Spond, radiculopathy

LBP for > 2 years, bilateral leg pain, bilateral leg numbness, bilateral leg tingling

None

Male

55

L4/L5, L5/S1 DDD

LBP for 30 years, right foot numbness, right lower leg numbness

None

Male

42

L4/L5 DDD, herniated disc

LBP for 5 years, bilateral lower extremity pain

None

Female

38

L5/S1 Synostosis

LBP for > 5 years, L5/S1 synchondosis, right leg pain, right foot pain

L4/L5 ALIF

Male

57

L3/L4, L4/L5, L5/S1 DDD

Back pain for > 1 year, right lower extremity tingling for > 1 year

L4/L5 microdiscectomy

Table 2: Operative characteristics and outcomes. INTERFACE = synthetic granules (45S5 bioglass) ALIF = anterior lumbar interbody fusion; TLIF = transforaminal lumbar interbody fusion; OLIF = oblique lumbar interbody fusion

 

 

Fusion levels

 

Surgical Technique

 

SIGNAFUSE graft used

 

Other graft used

Spinal levels fused

 

Operative time (min)

Operative blood loss (mL)

Hospital stay (days)

 

 

   Outcome

L3/L4, L4/L5

ALIF

15 g

INTERFACE 1 g

2

160

100

3

Fused

L5/S1

ALIF

15 g

INTERFACE 1 g

1

105

50

2

Fused

L4/5, L5/S1

ALIF

15 g

INTERFACE 1 g

2

273

75

3

Fused

L5/S1

ALIF

15 g

INTERFACE 1 g

1

104

20

2

Fused

L4/L5, L5/S1

TLIF

7.5 g

Cancellous chips 30 cc

2

232

50

2

Fused

L4/L5

TLIF

15 g

None

1

83

NA

1

Not Fused

L5/S1

TLIF

15 g

None

1

143

100

2

Fused

L3/4, L4/5, L5/S1

OLIF

30 g

INTERFACE 1 g

3

347

750

2

Fused

   

Average

 

1.6

180.9

163.6

2.1

87.5% fused

   

SD

 

0.7

94.0

260.2

0.6

35.4%

Table 3:  Systematic review of previously published studies utilizing synthetic bone grafts in lumbar fusion approaches

HA = hydroxyapatite; β-TCP = beta-tricalcium phosphate; A = autograft; BMA = bone marrow aspirate; β-TCS = beta-tricalcium sulfate; C = collagen;

DBM = demineralized bone matrix; Si-CaP = silicate substituted calcium phosphate.

First Author Year Ref # Design Approach Graft FU (mos) Patients Fused Fusion rate {%}
Cavagna 1999 11 Prosp. PLF HA + 13-TCP + A + BMA 24 106 100 94
Chen 2005 12 Retro. PLF 13·TCS + A 30 39 34 87
  2005 12 Retro. PLF 13-TCS (S) + A 30 35 29 83
Hsu 2005 13 Prosp. PLF HA + A 12 38 25 66
Korovessis 2005 14 RCT PLF HA + A + BMA 12 38 38 100
Kanayama 2006 15 RCT PLF HA + 13-TCP + A 12 10 9 90
Kitchel 2006 16 Prosp. PLF + PLIF HA + C + BMA 24 25 20 80
Neen 2006 17 Prosp. PLF HA + C + BMA 24 15 14 93
  2006 17 Prosp. PLIF HA + C + BMA 24 13 11 85
  2006 17 Prosp. ALIF HA + C + BMA 24 22 17 77
Moro-Barrero 2007 18 Prosp. PLF HA + 13-TCP + A 30 35 31 89
Chang 2008 19 Retro. PLF 13-TCS + A 12 66 61 92
Dai 2008 20 RCT PLF 13-TCP + A 12 32 32 100
Epstein 2008 21 Prosp. PLF 13·TCP + A + BMA 24 60 51 85
Epstein 2009 22 Prosp. PLF 13-TCP + A + BMA 12 100 95 95
Niu 2009 23 Prosp. PLF 13-TCS + BMA 24 22 10 45
Jenis 2010 24 Retro. PLF HA + BMA 24 42 34 81
Ploumis 2010 25 RCT PLF HA + C + BMA + A 24 12 11 92
Park 2011 26 Retro. PLF 13-TCP + A 12 30 25 83
Yamada 2012 27 Prosp. PLF 13·TCP + A + BMA 24 61 57 93
Kong 2013 28 Prosp. PLF 13-TCP + A 12 42 24 57
Kunakornsawat 2013 29 Retro. PLF HA + C + BMA 24 27 8 30
Pimenta 2013 30 RCT XLIF Si-Ca P 12 13 7 54
Yoo 2015 31 Retro. TLIF HA + A 24 77 67 87
Nam 2016 32 Prosp. PLF HA + A 12 41 30 73
Parker 2016 33 Prosp. XLIF HA + 13-TCP 24 25 20 80
Epstein 2017 34 Prosp. PLF HA + C + A + BMA 37 59 57 97
Gatam 2017 35 Prosp. TLIF HA + DBM 12 17 13 76
vonderHoeh 2017 36 RCT TLIF HA + A 12 24 20 83
          Average = 20.1 1126 950 84.4

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