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The Effectiveness of Intraosseous Basivertebral Nerve Radiofrequency Ablation for the Treatment of Vertebrogenic Low Back Pain: An Updated Systematic Review with Single-Arm Meta-analysis

Abstract Objective To provide an estimate of the effectiveness of basivertebral nerve (BVN) radiofrequency ablation (RFA) to treat vertebrogenic low back pain (LBP). Design Systematic review with single-arm meta-analysis. Population Persons ≥18 years of age with chronic LBP associated with type 1 or 2 Modic changes. Intervention Intraosseous BVN RFA. Comparison Sham, placebo procedure, active standard care treatment, or none. Outcomes The proportion of patients treated with BVN RFA who reported ≥50% pain score improvement on a visual analog scale or numeric rating scale. The main secondary outcome was ≥15-point improvement in Oswestry Disability Index score. Methods Three reviewers independently assessed articles published before December 6, 2021, in MEDLINE and Embase. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework was used to evaluate the overall quality of evidence. Results Of the 856 unique records screened, 12 publications met the inclusion criteria, representing six unique study populations, with 414 participants allocated to receive BVN RFA. Single-arm meta-analysis showed a success rate of 65% (95% confidence interval [CI] 51–78%) and 64% (95% CI 43–82%) for ≥50% pain relief at 6 and 12 months, respectively. Rates of ≥15-point Oswestry Disability Index score improvement were 75% (95% CI 63–86%) and 75% (95% CI 63–85%) at 6 and 12 months, respectively. Conclusion According to GRADE, there is moderate-quality evidence that BVN RFA effectively reduces pain and disability in most patients with vertebrogenic LBP. Further high-quality studies will likely improve our understanding of the effectiveness of this procedure.


Introduction
Intraosseous basivertebral nerve (BVN) radiofrequency ablation (RFA) has gained attention as a target-specific treatment for pain arising from pathological degeneration of the vertebral endplates (VEPs) of the lumbosacral spine. At lumbar levels, the BVN is a paired branch of the bilateral sinuvertebral nerves that passes through the basivertebral foramen at the posterior aspect of the vertebral body to provide sensory innervation to the vertebral body and VEPs. Effective neurotomy of the BVN can be accomplished through careful transpedicular access under either fluoroscopy or computed tomography (CT) guidance, followed by ablation at a location 30-50% of the sagittal plane distance from the posterior cortex of the vertebral body [1,2]. Since 2017, this treatment has been studied exclusively in populations believed to have pain arising from pathologically degenerated VEPs as evidenced by Modic 1 (MC1) and 2 changes (MC2) on magnetic resonance imaging (MRI) [1,[3][4][5][6][7][8][9][10][11][12].
Although BVN RFA is a relatively new treatment, studies investigating the pathological degeneration of the discovertebral complex began in the early 1990s. Initially, scientists postulated that the BVN might be implicated in nociception in some cases of chronic low back pain (LBP) after histological studies demonstrated that the BVN contained numerous neuropeptide Y-and PGP 9.5-positive nerve fibers [13,14]. The case for VEPdriven pain was further strengthened when immunohistochemical analysis of the BVN demonstrated an abundance of nerve fibers in the BVN that stained positive for substance P, CGRP, and PGP 9.5 [15,16]. Compared with controls, surgical specimens from patients with a history of chronic LBP and advanced disc degeneration were noted to have increased nociceptor density in the endplate region and adjacent vertebral body. This same pattern was observed in surgical specimens taken from patients with a history of "discogenic" LBP, where greater concentrations of PGP 9.5-and tumor necrosis factor (TNF)-immunoreactive cells near the VEPs were found compared with controls [17]. These histological findings were strongly associated with MC1 and MC2 findings on MRI.
Modic type 1 and 2 marrow changes are a radiographic manifestation of the underlying inflammatory response and fatty infiltration, respectively. These occur in the presence of prolonged mechanical stress and endplate failure, coupled with the ensuing chemical sensitization from leakage of proinflammatory cytokines from the intervertebral disc [25]. The epidemiology and clinical significance of MC1 and MC2 lesions have been discussed and debated ad nauseum [2,[18][19][20][21][22][23][24]. Modic changes are observed in the context of advanced disc degeneration or disc herniation [18,19], but even stronger associations exist with endplate defects in large population-based cohort studies [20,21]. Endplate injuries can be classified according to their pathoanatomic features: 1) avulsion of annulus fibrosus ("annulus") fibers from their insertion at the cartilage endplate (tidemark avulsion), 2) separation of endplate from the bone (cartilage endplate avulsion), 3) degeneration of the bone-annulus interface (rim degeneration), and 4) traumatic or erosive ingrowth of nucleus pulposis material through the endplate (nodal) [22]. Although of unclear clinical significance, these descriptors help paint a more detailed picture of the discendplate relationship. Endplate injuries are likely the predisposing event that, in a subset of individuals, results in chronic inflammation, high bone turnover, and fatty infiltrative changes that can be observed with conventional T1-and T2-weighted MRI sequences [23]. This cascade of events can culminate in what is often referred to as "vertebrogenic" LBP, with nociception transmitted predominantly via the BVN.

Objectives and Rationale
Given the recent increase in studies investigating the treatment of vertebrogenic LBP, the present systematic review was performed to provide an updated estimate of the effectiveness of BVN RFA for the treatment of this condition. We also calculate the aggregate rates of treatment success defined by clinically important pain and functional improvement observed thus far in published clinical trials and cohort studies.

Protocol and Registration
This systematic review is an update of a prior systematic review for which the protocol was registered with PROSPERO (ID:CRD42020192001) on July 14, 2020. No changes were made to the review methodology, but to avoid redundancy, a 15-point Oswestry Disability Index (ODI) threshold was chosen to measure functional improvement [24]. A 15-point ODI improvement is a robust threshold that exceeds the known minimum clinically important difference for chronic LBP [25,26]. The methods and results are reported in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [27].

Population
The population of interest was adults 18 years of age or older with chronic LBP associated with MC1 and MC2 changes on MRI.

Intervention
The intervention considered was intraosseous BVN RFA.

Comparison
Sham, placebo procedure, active standard care treatment, or none.

Outcome
The primary outcome considered for this review was the proportion of individuals with 50% pain improvement on the visual analog scale (VAS) or numeric rating scale (NRS). Secondary outcomes included 15-point improvement in ODI score and 2-point improvement in NRS score. Outcomes reported at any time point were included.

Studies
Both randomized controlled trials (RCTs) and observational study designs (nonrandomized comparative studies and single-group observational studies) were included. Non-English language articles and case reports were excluded. No restrictions were placed on the publication date.
An experienced librarian developed the search strategy. One author (AC) performed the search, and the search was confirmed for accuracy and reproducibility by a second author (TC). Additional eligible records were sought from the cited references of retrieved publications.

Study Selection
Two authors (AC and TC) independently assessed each abstract for eligibility. Any disagreements about inclusion were resolved by a third reviewer (ZM). Publications selected for full-text review were further assessed for inclusion by two authors (AC and TC), with disagreements resolved by a third reviewer (ZM).

Data Items and Collection
The following information was extracted from each study: 1) outcome measures for VAS/NRS and ODI, as well as any information related to pain medication usage or healthcare utilization; 2) bibliographic details; 3) study design; 4) selection criteria; 5) technical details of the procedure; and 6) funding and author disclosures. If data considered critical to the research questions were missing from included studies, attempts were made to contact author groups to obtain this information.

Risk of Bias and Methodological Assessment
The quality of evidence across outcomes was evaluated with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system [32]. Accordingly, risk of bias, imprecision, inconsistency, indirectness, and publication bias were all assessed. Disagreements about determinations of evidence quality according to GRADE were resolved by consensus decision. Our previous systematic review included a GRADE evidence profile based on calculations of between-group success measurements for the included RCTs, and this was again planned for the present review.

Summary Measures and Synthesis of Results
The primary outcome of interest was the percentage of participants reporting 50% pain improvement, and the main secondary outcome of interest was 15-point ODI improvement after BVN RFA. A between-group comparison of categorical success rates with calculated relative risk and risk difference was planned. Conventional pairwise and single-arm meta-analysis was also planned for this review if the collected data were found to be sufficient for such analysis.
Meta-analyses were planned to examine the following binary outcome variables (yes/no) over time points of 6 months, 12 months, 24 months, and 60 months: 1) proportions of patients reporting 15-point ODI improvement and 2) proportions of patients reporting 50% NRS/VAS improvement. Proportions and their standard errors of the included studies were used to calculate a pooled effect size (ES) and its 95% confidence interval (CI) in each meta-analysis. A random-effects model was used for all meta-analyses, as heterogeneity was expected in observational studies [28], which was also verified by heterogeneity and I 2 statistics [29]. Specifically, the calculations were performed with (inverse-variance) Freeman-Tukey double arcsine transformation [30,31] and the exact CIs for the ESs of individual studies [32]. Forest plots were produced for the data at 6 months and 12 months to illustrate the ESs of individual studies, as well as the pooled ES from those studies [28]. Furthermore, line graphs were constructed to visualize ESs over the time points. Publication bias was assessed with Egger's test [33,34]. Funnel plots were not used, as the number of included studies for each meta-analysis was fewer than 10, which is the recommended minimum number of studies for the assessment of publication bias with a funnel plot [35]. Lastly, sensitivity analysis was conducted to assess the between-study heterogeneity and impact of an individual study on the pooled ES; this was done through the leave-one-out approach, which recalculated the pooled ES after a study was omitted, one by one [28,29]. All of the analyses were performed in Stata 17.0 (StataCorp LLC, College Station, TX, USA).

Results
A total of 856 unique records were identified from the search ( Figure 1). After abstract screening for relevant publications, 12 full-text articles were assessed and deemed eligible for inclusion. There were no disagreements among reviewers about study inclusion. These included one RCT comparing BVN RFA with sham, with outcomes reported at up to 1, 2, and 5 years [4,7,9,10]; one RCT comparing BVN RFA with standard care treatment, with outcomes reported at up to 3, 6, 12, and 24 months [8,11,36]; and four single-group cohort studies, with outcomes reported between 3 and 12 months [1, 3, 5, 6, 12].

GRADE Quality Assessment
As no new RCTs are included in this updated systematic review, an updated GRADE evidence profile is not presented, but GRADE judgments are described narratively. The evidence from these two RCTs was downgraded from "high quality" because of the risk of bias in the form of selective outcome reporting and the inability to blind participants effectively. The possibility of publication bias was also considered, given that the majority of studies have been industry funded [3,7,11,12]; however, two recently performed independent studies have shown similar results [1,5]. According to GRADE, there is moderate-quality evidence that intraosseous BVN RFA effectively reduces LBP and related disability in those with vertebrogenic LBP, compared with sham RFA [7] and continued standard care treatment [11].

Publication Bias and Sensitivity Analysis
According to Egger's tests, there was no evidence of serious publication bias in the meta-analysis on the proportions of patients reporting 15-point ODI improvement at 6 months or 12 months (P ¼ 0.802 and 0.756, respectively) or on the proportions of patients reporting 50% NRS/VAS improvement at 6 months or 12 months (P ¼ 0.409 and 0.369, respectively). The sensitivity analysis showed that the point estimate and CI of the pooled ES from all meta-analyses did not change substantially after exclusion of any individual study. Omitting the study by Fischgrund (2018)

Discussion
This updated systematic review identified several new publications that reported on the long-term effectiveness of BVN RFA. No new randomized trials were identified; however, substantially more data are now available to describe the short-, medium-, and long-term success rates    of treatment with BVN RFA. Single-arm meta-analysis of these studies demonstrated that approximately 65% and 75% of patients report clinically significant pain and functional improvement at 6 and 12 months after BVN RFA (Figures 2 and 3). The calculated proportions of responders remained remarkably stable at 24 and 60 months, with less than 5% variance in the estimated VAS/ODI responder proportions (see Figures 4 and 5). According to GRADE, the evidence quality was determined to be "moderate." The designation of "moderate quality" suggests that future research will likely improve our understanding of the effectiveness of BVN RFA for vertebrogenic pain [37]. In addition to safety, careful transpedicular access is required to achieve targeting success with BVN RFA. In studies that analyzed post-ablation lesion geometry on MRI, targeting success appeared slightly higher when the BVN was targeted at a point 30-50% from the posterior wall [3,8,11] compared with earlier targeting in SMART (40-60% from the posterior wall) [7], though the targeting success rate remained above 90% in all studies (Table 1). DeVivo et al. reported 100% targeting success with the use of CT guidance and an alternative device to that used in other studies [1]. Given that studies after SMART have reported targeting success rates greater than 95%, it appears that successful neurotomy of the BVN is achieved frequently with established techniques.
Because the BVN contains many unmyelinated fibers [14,15,38,39], appropriately targeted thermal ablation can produce a long-lasting neurotomy and durable symptom improvement in those with significant pain and disability due to vertebrogenic LBP. This appears to be supported by the existing literature, in which the vast majority of study participants observed to initially benefit from BVN RFA continued to report significant pain and functional improvement at 1, 2, and 5 years (Figures 2-5). This pattern appears to be the same in industry-funded [3,[7][8][9][10]36] and independently performed studies [1,5]. Along with robust improvements in pain and function, healthcare utilization appears to decrease substantially after BVN RFA. In published studies, individuals treated with BVN RFA have seldom required further interventional or surgical treatment. Of the participants who were followed in the SMART trial, only 3% had received a lumbosacral facet joint RFA treatment or spinal injection in the year preceding the 5-year data collection time point [9]. Similarly, 5% of participants from INTRACEPT received an epidural steroid injection at a treated level by the 2-year data collection time point [36]. In both of these studies, a minority of participants progressed to a fusion surgery (8% and 4.5%, respectively). Opioid utilization decreased in participants over time after BVN RFA in most studies but did not differ significantly from the sham or standard-of-care groups at 3-12 months [4,8,10]. Despite the lack of significant difference between control arms in the RCTs at 3 months, the 5-year observational data from SMART (which included crossover of sham patients to active treatment) suggested that only 8% of participants were taking opioids at long-term follow-up (compared with 30% at baseline) [9].
No delayed complications were noted in any study report. The most common reported adverse event remains transient leg pain, which is thought to be secondary to pedicle breach (see Table 1). Investigators reported an 11% rate (n ¼ 14) of pedicle breach resulting in "nonserious" leg pain in the 127 participants treated with  BVN RFA from the INTRACEPT study [36]. The median time to resolution for these symptoms was 48.5 days, and most were successfully treated with a single course of oral steroids. Similar transient leg symptoms were observed in the SMART population [7]. Two cases of retroperitoneal hemorrhage have been reported, which may be due to excessive lateral positioning resulting in violation of the lumbar segmental artery [5,7]. Over the years, many interventional treatments have been used for those with chronic "discogenic" LBP, with varying success. Notable examples have included biaculoplasty, intradiscal RFA, methylene blue, and intradiscal steroid injection [40][41][42][43][44][45]. More recently, case series of patients treated with extraosseous, epiduroscopic BVN/ sinuvertebral nerve (SVN) laser ablation and bipolar RFA have reported positive results [46][47][48]. Orthobiological treatments are also being adapted to treat vertebrogenic LBP; a technique for intraosseous delivery of plasma-rich growth factor (PRGF-Endoret) has been proposed [49]. Additionally, two recent RCTs investigating the effectiveness of intradiscal steroid in patients with MC1 have been published, but they found only short-term benefit at 1 month compared with intradiscal saline or anesthetic [41,42]. Although there are no head-to-head trials comparing BVN RFA with any of these interventions in an appropriate population, there are now multiple studies and 5-year outcomes to support the use of BVN RFA for the treatment of vertebrogenic pain. This is not the case for any of these other treatments.
Although the outcomes of BVN RFA reported in the published literature are robust, there could be opportunities to further refine patient selection. Until recently, the characteristic pain patterns for those with vertebrogenic LBP were not directly described; however, analysis of responder characteristics from a large population of patients treated with BVN RFA has been reported [50]. Those with vertebrogenic pain experience predominantly midline LBP without lower leg symptoms, but they also indicated pain in the paramidline and buttock region. Notably, these descriptions are based on a case definition of significant pain relief or functional improvement after BVN RFA (for lack of a superior gold standard of "true" vertebrogenic pain). This is perhaps not surprising given the substantial overlap in the known pain referral patterns from other spinal structures, including the disc, sacroiliac joint, and zygapophyseal facet joint [51][52][53].
Given the widespread use of diagnostic/prognostic blocks in interventional pain medicine, clinicians might hope for a similar tool to help select patients for BVN RFA. However, although directly anesthetizing the intraosseous BVN seems attractive as a diagnostic test at face value, there are several major issues with this approach. Anesthetic placed at the periosteum of the pedicle before access would almost certainly anesthetize the lumbar medial branch, potentially introducing confounding from relief of lumbar zygapophyseal joint pain. Because of the vascular nature of trabecular bone, local anesthetic injection within the vertebral body might not produce a consistent blockade of the BVN, leading to false-negative tests. Significant procedural pain after transpedicular access might also be a source of false-negative results. Given these challenges, clinicians are encouraged to carefully select patients for BVN RFA on the basis of the clinical and imaging paradigm described in studies published to date.
There are important limitations to this review and for the existing literature related to BVN RFA. RCTs, although not without their own limitations [54,55], continue to represent the gold-standard study design in medical research [56]. Despite the growing interest in the treatment of vertebrogenic LBP, the present updated review found no new RCTs examining BVN RFA compared with sham or any other treatment. The majority of studies that met the inclusion criteria were supported by industry funding. When the evidence for treatment comes entirely from industry-funded studies, there is an increased risk for bias given the inherent conflict of interest, limiting the publication of negative results [57,58]. However, it is notable that results from two independently performed studies show similarly high proportions of patients reporting clinically significant pain relief and functional improvement up to 12 months after BVN RFA [1,5]. The present review was supported by an investigator-initiated research grant from Relievant Medsystems, which produces a device frequently used for BVN RFA. However, the sponsor had no role in the design or conduct of the review or approval of the final manuscript. The protocol, search, data extraction, and statistical analysis were all developed and performed independently without input or oversight from the sponsor. This review has several strengths. The review was designed, executed, and reported in accordance with quality guidelines for systematic reviews [27,59]. Although already performed in our prior work, abstract review, fulltext review, and data extraction were again performed in duplicate to ensure accuracy. When data considered critical to the review's research question were missing, the authors of included studies were contacted to obtain this information. The single-arm meta-analysis presented provides clinicians with a useful estimate of the effectiveness of BVN RFA when patients are selected on the basis of the published inclusion and exclusion criteria used to date.

Conclusion
According to GRADE, there continues to be "moderate"-quality evidence that BVN RFA effectively reduces chronic LBP and associated disability in individuals with chronic vertebrogenic LBP associated with MC1 and MC2 in the L3 to S1 vertebral bodies. Between 65% and 75% of such patients report clinically significant pain and functional improvement at 6 and 12 months after BVN RFA, with similar success rates up to 5 years.