Authors

1. Kornelis Poelstra MD – Nevada Spine Clinic
2. With acknowledgement to Katherine Sage, DO

Abstract

Study Design: Retrospective Level IV Study

Background: Limited availability of autologous bone graft has led to a vast array of alternative bone graft options including allograft, demineralized bone matrices, bone morphogenetic proteins, and synthetic bone grafts. In this retrospective review, a novel synthetic biphasic calcium phosphate (BCP<µm) bone graft was utilized for cervical and lumbar spinal arthrodesis.

Materials and Methods: Seventy-seven patients divided into two cohorts (25 cervical and 52 lumbar) underwent interbody reconstruction arthrodesis surgery, using a combination of allograft and a novel BCP<µm with a unique submicron surface topography. Fusion outcomes were assessed via flexion-extension radiographs and Computed Tomography (CT), and clinical outcomes were assessed via modified Prolo scores.

Results: Successful lumbar fusion rates determined by radiographs or CT were achieved in 94 of 97 levels (96.9%), or 49 of 52 patients (94.2%).  Successful cervical fusion rates were achieved in 75 of 80 levels (93.8%), or 21 of 25 patients (84%). All pseudarthroses were observed in three or more level reconstructions, with 100% fusion rates in all one- and two-level cases. Modified Prolo scores showed significant differences in 74/77 patients with 46.3% and 48.1% improvements in the lumbar and cervical cohorts, respectively.

Conclusions: This novel submicron surface topography BCP<µm offers a promising bone graft substitute for reliable augmentation of cervical and lumbar arthrodesis.

Keywords: Bone graft, spine fusion, spine arthrodesis, osteoimmunology

Introduction

Spinal arthrodesis surgeries have increased in the United States, with the number of cases expected to reach 876,000 in the United States (US) by 2022.¹ One challenging complication is pseudarthrosis of an operated segment. Recent literature approximates a pseudarthrosis rate of 17%, resulting in 149,000 non-unions in the US per year.² Approximately 10% of these non-unions are revised at the index level, leading to 92,000 revisions per year.³ Non-unions are challenging for the surgeon and patient alike, and can lead to poorer clinical outcomes, continued spinal instability at the affected level, and the need for revision surgery.

One important factor in obtaining a solid fusion is the bone graft chosen for the procedure. Autograft bone in the form of Iliac Crest Bone Graft (ICBG) is the gold standard, but there is limited supply and co-morbidities with harvesting, such as pain at the donor site.⁴ Additionally, evidence suggests significant variability in autograft bone due to age, metabolic disease, or other co-morbidities.⁵ As a result, multiple products have entered the market as an alternative or adjunct to bone graft.

Allograft, or cadaver donor bone, is a cost-effective and readily available alternative to autograft. The donor cancellous bone provides a scaffolding onto which the patient’s own bone cells can grow. Drawbacks to allograft include the risk of disease transmission from the graft to the patient.^6-7

Another category of bone graft is Deminineralized Bone Matrices (DBMs). These are processed allografts in which the inorganic material of bone and biological contaminants have been removed. Published data on DBMs have shown tremendous variation in composition and efficacy. Sterilization protocols may inactivate the osteoinductive properties, while still maintaining a chance of disease transmission.^{6, 8-9}

Cell based allografts or matrices (CBMs) are allografts that contain native bone cells. The cells are kept alive by freezing and undergo a specific dethawing process requiring an optimized infrastructure. As a result, this category of bone grafts is more expensive than allografts. Early level III and IV data on reported fusion rates with CBMs was noteworthy,^10-11 however recently published data reports significantly lower fusion rates.^12-13 Additionally, the safety profile of CBMs is concerning, and in 2021 a well-known CBM contaminated with Tuberculosis was implanted into spinal fusion patients, prompting an FDA recall.¹⁴

Beyond allografts, Bone Morphogenetic Proteins (BMPs) are laboratory manufactured growth factors used to induce bone formation. Reports of on-label and off-label complications include undesired bone formation in adjacent tissues, bone resorption, and inflammation.¹⁵

Synthetic bone grafts can be used to augment autograft or used as a standalone graft. Multiple synthetic materials have entered the market including Calcium Sulfate, Hydroxyapatite (HA), β-Tri Calcium Phosphate (β-TCP), Biphasic Calcium Phosphate (BCP), Bioglass, and Silicated – Calcium Phosphate (Si-CaP). As a group, synthetic bone grafts have proved an efficacious and cost-effective alternative to the gold standard ICBG. However, because there is no standard research protocol for synthetic bone graft products, there is significant variability in the quality and quantity of research.¹⁶

Biphasic Calcium Phosphate

In recent years, research on biphasic calcium phosphates has led to increased utilization in spine surgery, owing to BCPs ability to support bone formation and reduce the need to harvest large amounts of autologous bone.^17-18  This class of bone graft material is cost effective, has been proven to have an appropriate safety profile, and has a low incidence of reaction or material-related complications.¹⁹ Additionally,  BCP bone graft has the ability to resorb equally to anatomic bone, due to the ratio of HA and 𝛽-TCP. ²⁰

Objective

The purpose of this retrospective cohort study is the evaluation of safety and efficacy of a novel biphasic calcium phosphate with needle-shaped submicron surface topography  (BCP<µm; MagnetOs™, Kuros Biosciences, B.V.) in 77 lumbar and cervical reconstruction patients.  

Materials and Methods

Following Clinical Investigation Review Board approval #1470264-2, a comprehensive retrospective review was completed. Patients who had cervical or lumbar spinal arthrodesis from November, 2018 to May, 2019 with the use of BCP<µm were included in the study. All surgeries were performed by one board-certified fellowship-trained orthopedic spine surgeon at one institution (KP).

Radiographic outcomes for fusion were assessed using static upright and lateral flexion-extension radiographs at 3 months and/or at 6 months postoperatively. Patients experiencing predictable postoperative recovery with resolution of preoperative symptoms and fusion on flexion-extension radiographs were not subjected to additional radiation at later timepoints. Computed Tomography (CT) reconstructions were performed based on concerning clinical symptoms or radiographic imaging findings after 3 months postoperatively.

Clinical outcomes were assessed using a modified Prolo scale (Figure 1). The Prolo scale is a widely accepted evaluation tool for lumbar spinal fusion surgery. The status of the patient before and after treatment are measured, with a lower score equating to more severe deficits.^21-22

Lumbar Technique

Standard technique for a posterior, lateral or anterior approach was used. After preparation of the segment, bone graft was prepared using a ratio of 1:4 BCP<µm to compressible acellular cortical allograft shavings (Vesuvius, LifeNet Health, Virginia Beach, VA – USA). Autologous bone marrow aspiration from the vertebral bodies adjacent to the treated level was added to the bone graft mixture prior to insertion into the cage. Posterior bone grafting was performed through decorticated facet clefts using direct visualization adjacent to pedicle screw insertion points using the same mixture of BCP<µm and compressible cortical shavings. Interbody reconstructions were performed with 3D-printed titanium cages (Acuity Surgical, Dallas, TX – USA) with or without integrated fixation (Cascadia AL, K2M, Leesburg, VA – USA).

Cervical Technique

Standard technique for anterior or posterior approach to the cervical spine was utilized. After preparation of the segment, patients underwent ACDF with 3D printed titanium cages (Cascadia, K2M, Leesburg, VA – USA), posterior fusions, or anterior-posterior combined reconstructions.  These were stabilized using plate and screw fixation with segmental or multilevel plate and screw fixation constructs (Pyronees Segmental, K2M, Leesburg, VA – USA). The BCP<µm was placed either inside of the interbody cages or placed posterolateral, adjacent to the lateral mass- and pedicle screws (Yukon, K2M, Leesburg, VA – USA). For both the interbody grafting procedure and posteriorly, a 1:2 ratio of BCP<µm to local autograft was used.

Results

Lumbar

There were 24 females and 28 males, for a total of 52 patients. The mean age was 60.9 years (28-83 years), with a mean BMI of 29.6 (20.6-46.5). The average duration of follow-up was 7.5 months (6-11.8 months), and one patient did not complete full follow up. Patient demographic data are summarized in Table 1.

This cohort included posterior, lateral, or anterior lumbar interbody fusions with or without posterior instrumentation. The procedures included 22 one-level (42.3%), 19 two- level (36.5%), 7 three-level (13.5%), and 4 four-level (7.7%) procedures for a total of 97 treated levels.

Fusion status was confirmed using flexion/extension films and CT reconstructions between 3 and 12 months post-operatively. CT was ordered when radiographs were insufficient to verify solid fusion. Successful circumferential fusion using radiographs was confirmed at 6 months postoperatively in 42/52 patients (80%), and at 12 months in 49/52 patients (94.2%).  Radiographic evidence of successful fusion was seen at 12 months in 94/97 levels (96.9%). Pseudarthrosis was observed in 3/97 levels (3.1%). Figures 2A and 2B are CT images showing the typical solid fusion across two adjacent levels (Figure 2A) as well as a solid fusion adjacent to a stable, incomplete fusion, rated as one the three pseudarthroses (Figure 2B). Radiographic results are summarized in Table 2.

The Modified Prolo Scores improved significantly overall from an average of 11.0 preoperatively to 16.1 postoperatively (46.3% improvement) in 51/52 patients. Prolo scores were reported as excellent (47.1%), good (49.0%), or fair (3.9%) with each reporting ≥ 3 points in the post-operative score compared to baseline scores.

There were no instances of infection, product-related adverse events, or hardware failures. Complications requiring revision surgery included the 3 pseudarthrosis cases, each involving known smokers with multiple comorbidities, as well as one additional decompression that was required because the bone graft dislodged from an L5/S1 interbody cage.

Cervical

There were 9 males and 16 females, for a total of 25 patients.  The mean age was 61.2 years (33-80 years), with a mean BMI of 29.5 (18.7-46.4). Among these 25 patients, a total of 80 levels were treated. The most common diagnoses were spondylotic myelopathy, degenerative radiculopathy and progressive cervical kyphosis. The average duration for follow up was 6.4 months (3-12 months), and two patients did not complete full follow up. Patient demographic data are summarized in Table 1.

A total of 56 Anterior Cervical Discectomy and Fusions (ACDFs) were performed. Nineteen ACDF only procedures were performed (67.5%). Two single-level ACDF plus single level disc arthroplasty hybrid cases were performed (2.5%). In this cohort of 21 patients with ACDFs and ACDF + disc arthroplasty, surgery was performed on 56 levels: 4 one-level (7.1%), 5 two-level (17.8%), 6 three- level (32.1%) and 6 four-level (42.9%) procedures.  

The cohort also included two single-level anterior corpectomies for 4 fusion levels (5%); two anterior-posterior complex revision reconstructions for 14 levels (17.5%); and one posterior-only trauma reconstruction for 6 fusion levels (7.5%). Anteriorly and posteriorly treated levels were not counted twice.

Fusion status was confirmed using flexion/extension films and CT reconstructions between 3 and 12 months post-operatively. CT was ordered when radiographs were insufficient to verify solid fusion. Overall, radiographic evidence of successful fusion was achieved by 6 months in 53/80 levels (66.3%) and in 75/80 levels (93.8%) at 12 months. Figure 3 includes CT Images of successful cervical fusions. Radiographic results are summarized in Table 2.

Fusion was achieved in 18/18 (100%) posterior cervical fusion (PCF) levels, 4/4 (100%) of corpectomy surfaces, and in 51/56 (91%) of ACDF stand-alone procedure levels.

For ACDF, all single and two-level ACDFs fused (14/14 or 100%). In the 3-level ACDF cases, 17/18 levels fused (94.4%). In the four-level ACDF cases, 20/24 levels fused (83.3%).  

There were 5 pseudarthroses in 4 patients. These occurred in one 3-level and three 4-level anterior stand-alone reconstructions fitted with titanium 3D printed cages and static locking plates. The confirmed pseudarthrosis cases remained clinically asymptomatic at greater than 12 months from the time of surgery. Each of these 4 patients involved 1 or more comorbidities known to negatively affect fusion success, including 2 smokers. None of them required additional surgical procedures.

The Modified Prolo Scores improved overall from 10.8 preoperatively to 16.0 postoperatively (48.1% improvement) in 23/25 patients. Prolo scores were reported as excellent (61%), good (35%), or fair (4%) with each reporting at least 3 points in the post-operative score compared to baseline scores.

There were no reported infections, device-related adverse events, hardware failures, or need for further surgeries. One patient had mild dysphagia post operatively which improved with time. Additionally, one healed posterior incision dehisced due to aggressive soft tissue manipulation via massage 8 weeks postoperatively.

Discussion

Fusion rates in the lumbar spine vary based on several factors including approach, instrumentation, patient co-morbidities, levels of arthrodesis, and bone graft. Several studies have sought to elucidate how much each of these factors affect the pseudarthrosis rate in cervical and lumbar arthrodesis.^23,24

Regarding approach, a recent meta review by Manzur et al analyzing Anterior Lumbar Interbody Fusion (ALIF) as a standalone, ALIF with anterior fixation, and ALIF with interbody implants reported fusion rates of 88.6%, 94.2%, and 89.2%, respectively.²³ A second meta-review aiming to report outcome differences between Posterolateral Fusion (PLF) and Transforaminal Lumbar Interbody Fusion (TLIF) reported 84.7% and 94.3% fusion, respectively.²⁴  

Studies comparing bone graft categories in lumbar fusion models demonstrate that using allograft as a standalone graft obtains fusion rates of 40% in PLF; of 52% when used in interbody fusions; and of 79% when used in combination with autograft.^{16, 25, 26}  Publications examining DBMs report fusion rates of 81% in PLF when used as an extender to autograft and 77-98% for interbody fusions.²⁷ For CBMs, early reported fusion rates were 90-96% in lumbar fusion, 87-94% in cervical fusion,¹⁰ and 91% as an extender in PLF.¹¹ However, those initially published fusion rates were based on early level III or IV evidence^10,13 and recently published reviews conclude that the live cells in CBM offer inconsequential benefit in spinal fusions.^12-13  Published data on BMPs report fusion rates of 79-88% in PLF as autograft extender,¹⁶ 94-97% with use in interbody fusion,^27-28 and 79-88% with use as autograft extender in posterolateral fusions,¹⁶ although, as yet, PLF is an off-label indication for use.

Because there is no gold standard alternative to autograft, research into second generation synthetics has flourished. One systematic review reported an overall successful fusion rate of 86.4% for all ceramic products as a bone graft extender in the lumbar spine.² Additionally, a retrospective review published in the Journal of Spine Surgery in 2020 evaluated the fusion rate of a synthetic bioglass bone graft and reported a lumbar fusion rate of 89%.²⁹ Our study reported a much higher fusion rate of 96.9% for all levels across all approaches used in the lumbar cohort.

A recent meta review of fusion rates in ACDF reported increasing pseudarthrosis rates which correlated to the number of levels fused: 0-4.3% (1-level), 24% (2-level), 42% (3 level) to 56% (4 levels).³⁰ Another meta-review by Shriver et al from 2015 reported an overall pseudarthrosis rate of 2.6%.31 Specifically looking at bone graft choice, a retrospective review from 2019 reported no difference in fusion rate in single level ACDF between an allograft group and an autograft group.³² However, there are reports of higher pseudarthrosis rates in the literature, with one study reporting a 32.6% incidence of pseudarthrosis at 1 year following single-level ACDF,³³ and another reporting a 13% pseudarthrosis rate at the 2-year follow-up.³⁴ Our study reported a fusion rate of 93.8% which is comparable to other studies using synthetic bone grafts in the cervical spine.

As surgeons continue to search for a gold standard alternative to autograft, recent research has focused on Osteoimmunology, or the study of how the immune and skeletal systems interact. Several publications reveal how immune suppressing medications like Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Disease Modifying Anti-Rheumatic Drugs (DMARDs) and steroids negatively affect bony fusions,^35-37 and recent analyses of biomaterials have uncovered that harnessing the immune system in a positive way will contribute to bony healing. One recent study concluded that surface topography and of a bone graft particle can influence macrophages to a pro-healing phenotype.³⁸  Expanding on that study, researchers in pre-clinical studies found that a Biphasic Calcium Phosphate bone graft which was submicron in and had needle-shaped surface features (BCP<µm) promoted bone formation in soft tissues without the addition of cells or growth factors.³⁹ Additionally, BCP<µm has performed equivalently to autograft in instrumented PLF in clinically relevant animal models.40 In our retrospective review of this novel BCP<µm, both the lumbar and cervical cohorts had significant fusion rates when compared to comparable studies with similar patient cohorts.

One advantage of this study is that the cohort is indicative of a general patient population undergoing spinal reconstructions with common comorbidities, seen in a real-world private practice setting.  Additionally, a contemporary technique was utilized for the lumbar spine anterior column reconstruction with titanium 3D printed cages. This is highly relevant, as it is increasingly more common for adult sagittal deformity correction. As such, anterior fusions are often solely relied upon to keep the spine stable over time, with merely a tension-band construct posteriorly placed via minimally invasive (MIS) techniques.

Limitations of this study included limited patient-reported outcomes, as well as the retrospective nature and relatively small sample .

Conclusion

Because of the limited availability of autologous bone, the search to identify the most effective, affordable, and advanced bone graft substitute with a comparable outcome continues. The data from these retrospective lumbar and cervical spine cohorts demonstrate that BCP<µm is safe to use without any identified graft-related side effects. Additionally, this study demonstrates that BCP<µm is a valid bone graft extender with encouraging radiographic fusion results and clinical outcomes. Future studies with longer-term follow-up and patient-reported outcomes are indicated. At this time, level-one prospective randomized studies are currently being conducted on BCP<µm.⁴¹

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