[18F]-Sodium Fluoride PET MR–Based Localization and Quantification of Bone Turnover as a Biomarker for Facet Joint–Induced Disability

SUMMARY: Our aim was to prospectively evaluate the relationship between low back pain–related disability and quantitative measures from [18F]-sodium fluoride ([18F]-NaF) MR imaging. Six patients with facetogenic low back pain underwent dynamic [18F]-NaF PET/MR imaging. PET metrics were correlated with clinical measures and MR imaging grading of lumbar facet arthropathy. A significant positive correlation was observed between maximum facet joint uptake rate and clinical disability (P < .05). These data suggest that dynamic [18F]-NaF PET may serve as a useful biomarker for facetogenic disability.

C linical assessment for facetogenic low back pain is often hampered by overlapping and nonspecific symptoms and physical examination findings. 1 Conventional imaging techniques limited to evaluation of structural changes in the spine may identify morphologic abnormalities in asymptomatic spinal structures that are indistinguishable from degenerative structural alterations that produce severe pain and disability. 2 Objective and quantitative biomarkers that are more specific for active generators of low back pain would greatly aid in the effective, targeted treatment of patients with low back pain.
[18F]-sodium fluoride ([ 18 F]-NaF) is a positron-emission tomography radiotracer, which is chemically absorbed into hydroxyapatite in the bone matrix by osteoblasts and can noninvasively detect osteoblastic activity. [ 18 F]-NaF has been increasingly used for evaluating bone diseases, particularly for identification of bone metastases and primary tumors. [3][4][5] The utility of [ 18 F]-NaF PET for evaluating degenerative disease of the lumbar spine remains largely unexplored. 6 The goal of this prospective pilot study was to examine the potential correlation between facetogenic low back pain measures of disability with quantitative and semiquantitative [ 18 F]-NaF PET/MR imaging measures of bone turnover and structural MR imaging changes in lumbar facet joints.

Patient Population
This prospective feasibility study recruited patients after obtaining human study institutional review board approval and complying with Health Insurance Portability and Accountability Act regulations. Patients served as internal controls with diseased and healthy subregions. Patients with a history of suspected lower lumbar facetogenic syndrome were recruited from UCSF Radiology Spine Clinic. Written informed consent was acquired before entry into the study. The study began in November 2014 and concluded in August 2015.

Inclusion and Exclusion Criteria
Inclusion criteria were as follows: 1) at least 18 years of age with the capacity for informed consent, 2) a reported history of axial nonradicular low back pain, and 3) recommended by the spine interventional radiologists. Exclusion criteria were as follows: 1) a history of fracture or tumor of the spine, including osteoblastic metastases, 2) women who were pregnant or breastfeeding, 3) contraindications to MR imaging or administration of tracer or contrast, and 4) prior lumbar surgery or instrumentation.
Immediately before PET/MR imaging, subjects completed questionnaires measuring pain (numeric rating scale, from 0 to 10 with 0 equal to no pain and 10, the most severe intensity of pain), quality of life (Oswestry Disability Index Low Back Pain Disability Questionnaire [ODI]), and activity (International Physical Activity Questionnaire [IPAQ]). 7,8

PET/MR Protocol and Image Review
A 3T Signa PET/MR imaging scanner (GE Healthcare, Milwaukee, Wisconsin) was used for a simultaneous PET and MR image acquisition. Dynamic PET was initiated as 0.08 mCi/Kg of [ 18 F]-NaF (mean dose, 4.6 Ϯ 0.8 mCi) injected intravenously.

MR Imaging Facet Joint Grading
Two board-certified neuroradiologists with 3 (J.F.T.) and Ͼ30 (W.P.D.) years' postfellowship experience were blinded to the clinical data and interpreted clinical MR imaging sequences on a reprocessing workstation. Facet synovitis was graded as previously described by Czervionke and Fenton (On-line Fig 1). 10

Data Analysis
Quantitative and semiquantitative PET analysis included all facet joints from the L1-L2 to L5-S1 levels. Volumes of interest were selected using anatomic T2 MR images. A spheric VOI (7.5-mm diameter) was constructed around the center of each facet joint. A 5-mm-diameter VOI was placed in the right iliac crest in the central marrow cavity as a reference region. All PET analysis was performed with PMOD licensed software (PMOD Technologies, Zurich, Switzerland). This software facilitates model-based analysis of dynamic PET data. PMOD allows only validated kinetic models that have been extensively studied, and the output of the results is highly reproducible.

Standard Uptake Value Calculations and Kinetic Data
Placement of facet joint (FJ) VOIs is shown in On-line Fig 2A. A cylindric VOI covering 2 axial sections was placed on the abdominal aorta, and the partial volume correction coefficient was calculated. Maximum standard uptake value (SUV max ) and SUV mean values (Equation 1) for each subsite were calculated using the 60-minute time point.
The 3-compartment model used for kinetic modeling is shown in On-line Fig 2B. In Equation 2, C i represents the bone tissue activity concentration and is the sum of C e (extravascular compartment) and C t (target tissue bound compartment); C p is the concentration of tracer in the blood; V is the effective distribution volume of the tracer. 11 A 3-compartment irreversible linear model was used for the Patlak linear model. 11 The 2-tissue irreversible compartment model was used to calculate the regionspecific influx rate constants (in minute Ϫ1 ) for [ 18 F]-NaF. 12 Uptake was normalized by using the iliac crest as the reference region. The tracer influx rate from the blood pool to the bone matrix was calculated with Equation 2 for K i_Patlak . K i_Patlak represents the rate at which [ 18 F]-NaF leaves the arterial blood pool and irreversibly binds to a subsite bone matrix. The kinetic analysis was performed by using PMOD. For each subject, FJs with maximum uptake were identified, henceforth referred to as FJ max .

Statistical Analyses
The statistical significance of the correlations between PET/MR imaging and clinical disability metrics was tested with the Pearson correlation. A 2-samples t test was used (P Ͻ .05) to assess the significance of differences in the K i_Patlak influx rate between the mean FJ max and mean FJ minimum (min) K i_Patlak and among FJ MR imaging grades.

Patient Profile
Patient demographic and clinical disability scores are summarized in the Table. [

F]-NaF Uptake Measurements and MR Imaging Grading
Uptake values were measured in bilateral facet joints across 5 levels in all subjects for a total of 60 measurements. For all 60 sampled regions, the relationship between semiquantitative SUV max and K i_Patlak produced a linear correlation (r ϭ 0.58, P Ͻ .001; On-line Fig 3A). A similar statistically significant linear correlation was observed between K i_Patlak and SUV mean (r ϭ 0.7, P Ͻ .001; On-line Fig 3B). For each patient, the single facet joint with the highest K i_Patlak (FJ max K i_Patlak ) was identified. When FJ max K i_Patlak was plotted against the ODI score, a strong, statistically significant positive correlation was observed (r ϭ 0.96, P ϭ .0013; Fig 1). The FJ SUV max and SUV mean for each subject (n ϭ 6) were plotted against the ODI score, and no significant correlations were observed (r ϭ Ϫ0.55, P ϭ .35, and r ϭ Ϫ0.47, P ϭ .35). The correlation between the maximum MR imaging grade and ODI (n ϭ 6) was not significant (r ϭ 0.38, P ϭ .44). FJ max K i_Patlak plotted against corresponding patient maximum pain scores showed no correlation (r ϭ 0.06, P ϭ .91). FJ max K i_Patlak plotted against corresponding patient IPAQ categoric scores showed no correlation (r ϭ 0.15, P ϭ .77).
A weak-to-moderate, but statistically significant, correlation was observed between the MR imaging grade of facet arthropathy and K i_Patlak (r ϭ 0.37, P ϭ .03; Fig 2A). The average uptake rate as measured by K i_Patlak for FJ min (0.019 milliliter/cubic centimeter/ min [mL/ccm/min]) and FJ max (0.032 mL/ccm/min) showed that FJ max was significantly higher with close to twice the uptake rate (P Ͻ .001).

DISCUSSION
In this prospective pilot study of patients with suspected facetogenic low back pain, we show a strong positive linear correlation between a kinetic measure of dynamic NaF uptake by the FJ with maximum uptake (FJ max K i_Patlak ) and disability as measured with ODI. These data suggest that FJ max K i_Patlak may be a useful metric for quantifying and localizing lumbar facetogenic-related disability. Thus, [ 18 F]-NaF PET may aid in treatment planning and longitudinal monitoring of degenerative lumbar facet disease. With our small sample size of 6 subjects with relatively mild disability and the lack of a healthy control cohort, these data are preliminary. However, our observed strong correlation between [ 18 F]-NaF uptake as measured with FJ max K i_Patlak and clinical disability, even in this small cohort of patients with facet syndrome, is reassuring that FJ max K i_Patlak may serve as a useful biomarker for facet joint-related disability. Further larger scale studies are warranted to validate these preliminary data, and a costbenefit analysis will need to be performed. Most important, our average measurement for FJ max K i_Patlak across all subjects (0.32 Ϯ 0.003, n ϭ 6) is like that of Brenner et al 13 in areas of high bone turnover, including bone grafts, supporting the validity of our quantitative PET measurements.
Neither SUV max nor SUV mean showed a statistically significant correlation with the ODI score or any other clinical measure of low back pain and disability. While larger studies are needed to confirm this result, the primary finding of this study is that the kinetic variable K i_Patlak may be useful for evaluating facetogenic pathology by providing a quantitative value that more accurately reflects the dynamic process of bone turnover and osteoblastic activity. SUV values assume that radiotracer is evenly distributed throughout the entire body and base the measurement off a lean body mass coefficient. K i_Patlak measures specific concentrations of radiotracer reaching the target via the arterial system during the scan. This added information may reveal subtle changes in the flow of the tracer to ROIs that would otherwise be missed.
It is also of interest that a weak, but statistically significant, correlation was observed between the MR imaging morphologic grade of facet arthropathy and quantitative PET measures or ODI. This finding is consistent with a previous study in which a similarly weak correlation was found between NaF-PET uptake and CT measures of facet arthropathy, further supporting the hypothesis that physiologic information afforded by NaF uptake may supplement conventional structural imaging for identifying symptomatic facet joints. 6 As a pilot study, the small number of patients and relatively  mild disability represent a primary limitation of this study. Despite this limitation, the observed strong and statistically significant correlation between FJ max K i_Patlak and ODI in this small, inclusive cohort suggests that [ 18 F]-NaF may serve as a robust biomarker for facet syndrome, and future larger studies are warranted to confirm these data. Also, we provide only correlative evidence that FJ max K i_Patlak and clinical disability are related. Future studies involving targeted facet joint injections based on dynamic PET/MR imaging data are planned and will be needed to validate the present results.

CONCLUSIONS
In the lumbar spine, [ 18 F]-NaF uptake rates in facet joints as measured with K i_Patlak strongly correlate with patient-reported ODI scores. These pilot data suggest that kinetic measurements of [ 18 F]-NaF facet joint uptake may serve as sensitive, quantitative, and noninvasive biomarkers of facetogenic low back pain.