Regional Bone Mineral Density Differences measured by Quantitative Computed Tomography in Patients undergoing Anterior Cervical Spine Surgery

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Regional Bone Mineral Density Differences measured by Quantitative Computed Tomography in Patients undergoing Anterior Cervical Spine Surgery Stephan N. Salzmann MD , Ichiro Okano MD , Courtney Ortiz Miller BS , Erika Chiapparelli MD , Marie-Jacqueline Reisener MD , Fabian Winter MD , Jennifer Shue MS , John A. Carrino MD, MPH , Andrew A. Sama MD , Frank P. Cammisa MD , Federico P. Girardi MD , Alexander P. Hughes MD PII: DOI: Reference:

S1529-9430(20)30055-3 https://doi.org/10.1016/j.spinee.2020.02.011 SPINEE 58116

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The Spine Journal

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22 October 2019 12 February 2020 12 February 2020

Please cite this article as: Stephan N. Salzmann MD , Ichiro Okano MD , Courtney Ortiz Miller BS , Erika Chiapparelli MD , Marie-Jacqueline Reisener MD , Fabian Winter MD , Jennifer Shue MS , John A. Carrino MD, MPH , Andrew A. Sama MD , Frank P. Cammisa MD , Federico P. Girardi MD , Alexander P. Hughes MD , Regional Bone Mineral Density Differences measured by Quantitative Computed Tomography in Patients undergoing Anterior Cervical Spine Surgery, The Spine Journal (2020), doi: https://doi.org/10.1016/j.spinee.2020.02.011

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Regional Bone Mineral Density Differences measured by Quantitative Computed Tomography in Patients undergoing Anterior Cervical Spine Surgery Stephan N. Salzmann, MD1; Ichiro Okano, MD1; Courtney Ortiz Miller, BS1; Erika Chiapparelli, MD1; Marie-Jacqueline Reisener, MD1; Fabian Winter, MD1; Jennifer Shue, MS1; John A. Carrino, MD, MPH1; Andrew A. Sama, MD1; Frank P. Cammisa, MD1; Federico P. Girardi, MD1; Alexander P. Hughes, MD1 1

Spine Care Institute, Hospital for Special Surgery, Weill Cornell Medicine, 535 East 70th St,

New York, NY 10021, USA Corresponding Author: Alexander P. Hughes Spine Care Institute Hospital for Special Surgery 535 East 70th St. New York, NY 10021, USA Phone: 212.774.2992 Fax: 212.774.7062 [email protected]

This study was approved by the Institutional Review Board (IRB#2016-0751) at the Hospital for Special Surgery.

This manuscript does not discuss any drugs or devices requiring FDA approval. No funds were received in support of this work.

Acknowledgment: The authors would like to thank J. Waldman, Hospital for Special Surgery, J. K. Brown and A. Chason, Mindways Software, for their technical support.

ABSTRACT

Title: Cervical Bone Mineral Density Measured by QCT in Patients undergoing Anterior Cervical Spine Surgery

Background context: Clinically, the association between bone mineral density (BMD) and surgical instrumentation efficacy is well recognized. Although several studies have quantified the BMD of the human lumbar spine, comprehensive BMD data for the cervical spine is limited. The few available studies included young and healthy patient samples, which may not represent the typical cervical fusion patient. Currently no large scale study provides detailed BMD information of the cervical and first thoracic vertebrae in patients undergoing anterior cervical spine surgery.

Purpose: The objective of this study was to determine possible trabecular BMD variations throughout the cervical spine and first thoracic vertebra in patients undergoing anterior cervical discectomy and fusion (ACDF) and to assess the correlation between BMDs of the spinal levels C1-T1.

Study Design/Setting: This is a retrospective case series.

Patient Sample: Patients undergoing ACDF from 2015 to 2018 at a single, academic institution with available preoperative CT imaging were included in this study.

Outcome Measures: The outcome measure was bone mineral density measured by QCT.

Methods: Patients that underwent ACDF from 2015 to 2018 at a single, academic institution were included in this study. Subjects with previous cervical instrumentation or missing/incomplete preoperative cervical spine CT imaging were excluded. Asynchronous quantitative computed tomography (QCT) measurements of the lateral masses of C1 and the C2T1 vertebral bodies were performed. For this purpose, an elliptical region of interest (ROI) that consisted exclusively of trabecular bone was selected. Any apparent sclerotic levels that might affect trabecular QCT measurements were excluded from the final analysis. Interobserver reliability of measurements was assessed by calculating the interclass correlation coefficients (ICC). Pairwise comparison of BMD was performed and correlations between the various cervical levels were evaluated. The statistical significance level was set at p<0.05.

Results: In all, 194 patients (men, 62.9%) met inclusion criteria. The patient population was 91.2% Caucasian with a mean age of 55.9 years and mean BMI of 28.2 kg/m2. The ICC of cervical QCT measurements was excellent (ICC 0.92). The trabecular BMD was highest in the mid-cervical spine (C4) and decreased in the caudal direction (C1 average = 253.3 mg/cm3, C2 = 276.6 mg/cm3, C3 = 272.2 mg/cm3, C4 = 283.5 mg/cm3, C5 = 265.1 mg/cm3, C6 = 235.3 mg/cm3, C7 = 216.8 mg/cm3, T1 = 184.4 mg/cm3). The BMD of C7 and T1 was significantly lower than those of all other levels. Nonetheless, significant correlations in BMD among all measured levels were observed, with a Pearson’s correlation coefficient ranging from 0.507 to 0.885. Conclusions: To the authors’ knowledge this is the largest study assessing trabecular BMD of the entire cervical spine and first thoracic vertebra by QCT. The patient sample consisted of

patients undergoing ACDF, which adds to the clinical relevance of the findings. Knowledge of BMD variation in the cervical spine might be useful to surgeons utilizing anterior cervical spine plate and screw systems. Due to the significant variation in cervical BMD, procedures involving instrumentation at lower density caudal levels might potentially benefit from a modification in instrumentation or surgical technique to achieve results similar to more cephalad levels.

Keywords: regional BMD differences; bone mineral density; computed tomography; osteoporosis; quantitative computed tomography; QCT; dual-energy X-ray absorptiometry; DXA; cervical spine; spinal fusion

INTRODUCTION

Surgery to the anterior column of the cervical spine is commonly performed for a variety of spinal pathologies. The rate of anterior cervical discectomy and fusion (ACDF) in the United States has increased significantly over the past two decades [1–3]. The highest increase in utilization of ACDF was found in the elderly population including patients with several comorbidities [3].

Clinically, the association between bone mineral density (BMD) and surgical instrumentation efficacy is well recognized. Prior studies have shown an association between cervical bone mineral density and pullout strength of anterior cervical screws [4], as well as cervical endplate failure stress [5,6]. In addition, caudal cervical levels have been found to be more prone to failure compared to the rostral ends of cervical fusion constructs suggesting possible level dependent regional differences in cervical BMD [6–9].

Although several studies quantified the BMD of the human lumbar and thoracic spine [10–13], comprehensive BMD data for the cervical spine is limited. The few available spine BMD studies mainly included young and healthy patient samples, which may not represent the typical cervical fusion patient [14–17]. Currently no large scale study provides detailed BMD information of the cervical and first thoracic vertebrae in patients undergoing anterior cervical spine surgery.

The objective of this study was to determine possible trabecular BMD variations throughout the cervical spine and first thoracic vertebra in patients undergoing ACDF and to assess the correlation between BMDs of the spinal levels C1-T1.

MATERIALS AND METHODS

Patient population The hospital institutional review board approved this study. Patients that underwent ACDF from 2015 to 2018 at a single, academic institution with available pre-operative cervical CT imaging were included in this study. Subjects with previous cervical instrumentation or missing/incomplete preoperative cervical spine CT imaging were excluded. Electronic medical records were reviewed. Collected demographic information included age, gender, body mass index (BMI), and race.

QCT measurements Asynchronous quantitative computed tomography (QCT) measurements of the lateral masses of C1 (Figure 1) and the C2-T1 vertebral bodies (Figure 2 and Figure 3) were performed using Mindways QCT Pro software (Mindways Software, Inc., Austin, TX, USA) [18–20]. For this purpose, an elliptical region of interest (ROI) that consisted exclusively of trabecular bone was measured. Any apparent sclerotic bone regions that might affect trabecular QCT measurements were excluded. If the sclerotic region was too large to set an adequate ROI in the vertebral body, the vertebra was excluded from further analyses. Since QCT measurements of the cervical spine are a novel measurement, a validation study was conducted. Two independent raters performed QCT measurements on 144 randomly selected cervical levels. The measurements were conducted in completely blinded manner.

Statistical analysis For the validation study of cervical BMD measurements, the interclass correlation coefficient (ICC) was calculated. An ICC > 0.90 was considered excellent, 0.80-0.90 good, 0.70-0.80 acceptable, and ≤0.70 poor. Pairwise comparisons of BMD were performed utilizing the paired ttest and correlations between the various cervical levels were evaluated using the Pearson’s

correlation coefficient. Subgroup analyses were performed by gender, age and BMI. We categorized BMI values into 3 groups (normal (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2) and obese (≧30.0 kg/m2)). The Student t test or one-way analysis of variance with the Bonferroni adjustment for multiple comparisons was utilized for the sub-group analyses. The significance level was set at p<0.05. All analyses were conducted in R software (R for 3.1.0 GUI 1.64).

RESULTS

194 consecutive patients (men, 62.9%) undergoing primary anterior cervical discectomy and fusion (ACDF) from 2015 to 2018 with available preoperative CT imaging met the study inclusion criteria. The patient population was 91.2% Caucasian with a mean age (± SD) of 55.9 (± 12.1) years and a mean BMI of 28.2 kg/m2. Patient demographics are displayed in Table 1.

Several levels included sclerotic regions within the vertebral body that were too large to set an adequate ROI resulting in exclusion of these levels from further analyses (Table 2). For the validation study, the ICC of cervical QCT measurements was excellent (ICC 0.92, 95% confidential interval (CI) 0.81-0.96).

The trabecular BMD was highest in the mid-cervical spine (C4) and decreased in the caudal direction (C1 average = 253.3 mg/cm3, C2 = 276.6 mg/cm3, C3 = 272.2 mg/cm3, C4 = 283.5 mg/cm3, C5 = 265.1 mg/cm3, C6 = 235.3 mg/cm3, C7 = 216.8 mg/cm3, T1 = 184.4 mg/cm3). The BMDs of C7 and T1 were significantly less than those of all other levels (p=0.001-0.016) (Table 2 and Figure 4).

Although significant variation in densities was observed throughout the cervical spine, there were significant correlations in BMDs among all measured levels, with a Pearson’s correlation coefficient ranging from 0.507 to 0.885 (Figure 5).

In the sub-group analyses, there was a trend that female patients showed lower trabecular BMD than male patients in all cervical levels, and the differences were statistically significant in C2

and C5 (p=0.011 and p=0.043, respectively) (Figure 4). Patients over 60 years of age had significantly lower trabecular BMD at all measured levels (Supplemental File 1). Patients with higher BMI tended to have higher trabecular BMD (Supplemental File 2).

DISCUSSION To the authors’ knowledge this is currently the largest study assessing trabecular bone mineral density (BMD) of the entire cervical spine and first thoracic vertebra by quantitative computed tomography (QCT) in patients undergoing anterior cervical discectomy and fusion (ACDF). Our results indicate significant regional BMD differences in the cervical spine depending on cervical level. While the BMD was highest in the mid-cervical spine, it gradually decreased in the caudal direction. Nonetheless, significant correlations in BMD among all measured levels were observed. Osteoporosis is a major public health concern [21,22]. Accurate assessment of an individual’s bone strength is critical for clinical decision making [23]. Although bone strength is known to depend on both bone quality and bone quantity, only the latter is routinely measured in the clinical setting through bone mineral density (BMD) measurements [24]. Thus, BMD acts as the most commonly used surrogate measure for bone strength [25].

The current gold standard to measure spinal BMD in vivo is dual energy x-ray absorptiometry (DXA) of the lumbar spine. The major advantages of DXA include that it is a well-standardized and easy to use technique with high precision and low radiation dose [26]. However, DXA has some inherent limitations. Its results may be affected by bone size [27], BMI [28], vascular calcification [29], degenerative changes and previous spinal surgery[26]. Furthermore, DXA is not a routine evaluation tool in the cervical spine [15]. Due to the anatomy of the lower cervical spine, measurements of the entire cervical spine including the first thoracic vertebra are technically challenging with DXA due to projection artifacts [5,30]. In addition, compared to the lumbar spine, no accepted BMD thresholds exist for the cervical spine [5].

Given these shortcomings of cervical DXA, BMD measurements were performed using QCT for this study. This technique has several advantages, including measurements of volumetric BMD (compared to the areal BMD of DXA), less susceptibility to degenerative changes and greater sensitivity to changes in BMD [31].

A main concern for the novel QCT measurements of the cervical spine was the reproducibility of our BMD measurements. Since commercially available QCT analysis software is designed to assess lumbar vertebra, measurements of the cervical spine necessitates the operator to manually adjust the region of interest (ROI). Due to possible different sizing and positioning of the ROI, a measurement bias could be introduced and therefore reliability testing was performed. Our results demonstrated that cervical BMD measurement reliability was excellent with an ICC of 0.92. This is as high as in a previously published study by Pompe et al. that determined the interobserver reliability of manual attenuation measurements in the lumbar spine (ICC 0.70-0.91) [32]. Therefore we suggest that cervical BMD measurements can be reliably utilized for future studies.

In terms of regional BMD variation, there are several prior reports which attempted to quantify level-specific BMD in different spinal regions (cervical, thoracic, lumbosacral). We compared the results of the previous studies with the findings of this study. Our results are largely in agreement with the QCT study by Yoganandan et al. [15] that assessed the trabecular BMD of the cervical spine and compared it to other regions. In their study including 57 young adult healthy male volunteers, a decrease in trabecular BMD from rostral to caudal along the entire spine was observed with a mean BMD of the cervical, thoracic and lumbar spine of 256 mg/cm3, 194.3 mg/cm3 and 172.2 mg/cm3, respectively. Similarly, in a QCT study of 50 healthy volunteers, Weishaupt et al. found the trabecular BMD of the cervical spine to be significantly higher compared to the thoracic and lumbar spine [14]. The higher BMD of the cervical spine may contribute to the fact that osteoporotic fractures primarily occur in the thoracic and lumbar spine and less commonly involve the cervical vertebrae [14,15]. The higher BMD in the cervical spine compared to other spinal regions might be due to several factors including differences in bone size, in-vivo forces and range of movement [10,14,33,34].

In addition to the overall high BMD values of the cervical spine, this study reveals another important finding. Bone density within the cervical region is not uniform, but shows considerable variability. While the BMD was highest in the mid-cervical spine (C4), it gradually decreased in caudal direction with C7 and T1 being significantly lower than those of all other levels. The mean BMD of C4 (283.5 mg/cm3) was approximately 1.5 times the mean BMD of T1 (184.4 mg/cm3). The observed trend of a gradual BMD decrease from mid-cervical levels to T1 is in general agreement with several previous smaller studies of non-surgical subjects [5,15– 17,33,35,36].

The wide BMD variation over the cervical spine with significantly lower BMD in the caudal part might partially contribute to several clinically relevant phenomena. In a recent study on the incidence of cervical spine fractures, Khanpara et al. [37] reported the highest number of vertebral body fractures in the subaxial spine occurring at C7 followed by C6 and C5. The lowest number of vertebral body fractures occurred at C4, which could be attributed to the high BMD at this level. In another study by Truumees et al., it was shown that cervical endplates below C5 fail at significantly lower compressive loads compared to more cranial levels [6]. A correlation between endplate failure stress and cervical trabecular BMD measured by QCT has been described by Zhang et al. [38]. Furthermore, several studies of multilevel anterior cervical fusion procedures have shown that construct failure most commonly occurs at the caudal ends of the cervical construct [7–9].

Preoperative assessment of cervical spinal fusion patients often includes CT scans of the cervical spine. Most of these scans carry unutilized information about cervical BMD. The ability to retrospectively analyze these scans with asynchronous QCT allows surgeons to assess the BMD of each individual cervical vertebra prior to instrumentation [18]. Hitchon et al. have shown an association between cervical bone mineral density measured by lateral DXA and pullout strength of anterior cervical screws [4]. The potential benefits of preoperative cervical BMD assessment of individual vertebra on level-specific instrumentation and device performance after anterior surgery should be investigated in future prospective studies.

It is important to highlight that the measurements for this study were performed on the central vertebral body (C2-T1) and the lateral masses (C1) providing exclusively trabecular BMD information. Trabecular BMD measurements are used in other spinal regions and are easy to evaluate clinically [5,15,16]. Trabecular bone is more metabolically active than cortical bone and therefore age- and treatment-related changes are more apparent than in cortical bone [39]. Nonetheless, cortical bone and endplate quality play important roles in cervical fusion procedures with cervical instrumentation including uni- or bicortical screws [40,41]. The purely trabecular ROIs used in this study may not fully capture the screw insertion trajectories in their entirety and do not include the cortical compartment. It is, however, technically challenging to accurately assess BMD of the cortex and endplates with the traditional clinically available QCT technique using elliptical ROIs due to the contour and angle of the endplate as well as the limited spatial resolution of clinical CT scanners [5,39]. Previous cervical QCT studies using advanced custom software found high correlation between the central vertebral body trabecular BMD and other cervical regions including cortical bone. Therefore, the trabecular BMD of the central vertebral body was found to adequately reflect BMD of anatomical locations where instrumentation is commonly attached [17,33]. However, future longitudinal studies using advanced software should evaluate whether site specific cervical measurements including the cortical compartment may allow for better prediction of hardware failure than the traditional trabecular QCT measurements used in this study.

The present study has several unique strengths. First, it provides level-specific BMD in a large sample of both men and women undergoing ACDF, which clearly adds to the clinical relevance of the findings. Previous studies were mainly limited to young and healthy patients, which is not representative of the typical cervical fusion patient. Furthermore, in contrast to previous studies that only included a limited number of levels, we assessed the entire cervical spine including the first thoracic vertebra as anterior surgical procedures often extend to this level. Most importantly, by analyzing readily available saved CT images with the asynchronous QCT technique retrospectively, additional radiation exposure for the subjects of this study was avoided.

This study has a number of limitations. First, our study population consisted of patients from a tertiary-care orthopedic referral hospital with a limited sub-group of non-Caucasian patients

possibly limiting the generalizability of the results to other patient populations. Furthermore, this cross-sectional study focused on regional BMD differences and did not include clinical outcomes. Future longitudinal studies are needed to quantify the influence of the observed regional BMD differences on hardware failure, interbody subsidence, pseudoarthrosis, or adjacent segment compression fractures and to elucidate the clinical importance of this finding. Lastly, since experimental cervical DXA measurements were not available a direct comparison between the two modalities was not possible.

In conclusion, there is significant variation in trabecular BMD among cervical vertebrae. Knowledge of intersegmental BMD variation in the cervical spine might be useful to surgeons utilizing anterior cervical spine plate and screw systems or other anterior cervical devices including cervical total disc arthroplasty. Due to the significant variation in cervical BMD, procedures involving instrumentation at lower density caudal levels might potentially benefit from a modification in instrumentation or surgical technique to achieve results similar to more cephalad levels.

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FIGURE LEGENDS

Figure 1: Axial and coronal view of the right and left lateral mass region of interest (ROI)

Figure 2: Axial and coronal view of the C2 region of interest (ROI)

Figure 3: Axial and coronal view of the C3 region of interest (ROI)

Figure 4: Mean quantitative computed tomography (QCT) bone mineral density (BMD) (in mg/cm3) with standard deviation (SD) bar of the C1 lateral masses and C2-T1 vertebral bodies by gender. *Significant difference with p<0.05

Figure 5: BMD correlation matrix showing p-values and correlation coefficients for the cervical and first thoracic spinal levels

Table 1: Patient demographics Factors Age Gender (%)

N Mean (SD) Female Male 2 BMI (kg/m ) Mean (SD) (%) 18.5 - 24.9 25 - 29.9 30 - 34.9 35 ≤ Race (%) White Black or African American Asian Other (Abbreviations: SD, standard deviation; BMI, body mass index)

194 55.9 (12.1) 72 (37.1) 122 (62.9) 28.3 (5.3) 57 (29.4) 76(39.2) 36(18.6) 25(12.9) 177 (91.2) 4 (2.1) 7 (3.6) 6 (3.1)

Table 2: Mean bone mineral density (BMD) in each level Pairwise comparison p-value BMD, mg/cm3

C1 left

C1 right

C2

C3

C4

Level

N

(mean ± SD)

C1 left

16 0

255.97 ± 46.47

-

C1 right

15 6

250.64 ± 48.19

0.982

-

C2

14 4

276.41 ± 46.84

0.003

<0.00 1

-

C3

13 0

272.19 ± 46.66

0.064

0.002

0.998

-

C4

11 2

283.51 ± 47.27

<0.00 1

<0.00 1

0.948

0.593

-

C5

11 1

265.06 ± 44.42

0.796

0.209

0.512

0.954

0.063

C5

-

C6

C7

T 1

C6

C7

T1

13 0

235.26 ± 45.70

0.103

<0.00 1

<0.00 1

<0.00 1

<0.00 1

0.004

-

16 8

216.80 ± 41.64

<0.00 1

<0.00 1

<0.00 1

<0.00 1

<0.00 1

<0.00 1

0.016

-

19 1

184.37 ± 43.31

<0.00 1

<0.00 1

<0.00 1

<0.00 1

<0.00 1

<0.00 1

<0.00 1

<0.00 1

(Abbreviations: SD, standard deviation; BMD, bone mineral density)

-