Summary
Vertebral augmentation procedures (vertebroplasty and kyphoplasty) provide benefit for debilitating vertebral compression fractures (VCFs) or fractures refractory to nonsurgical management (NSM). These procedures involve the image-guided reduction of the vertebral fracture and injection of cement into the vertebral body. The key goals are the relief of back pain, enhancement of functional status, and biomechanical stabilization of the vertebral body. Successful integration of vertebral augmentation into clinical practice is assisted by a good understanding of the current evidence in the medical literature. Although historically there has been occasional controversy over the efficacy of vertebroplasty for VCFs, there is now high-quality evidence from well-designed, large randomized controlled trials to support its use for acute osteoporotic VCFs with intractable pain despite medical therapy or for VCFs secondary to spinal neoplasm. Moderate-quality evidence supports vertebral augmentation to treat chronic and subacute osteoporotic VCFs. The current evidence suggests that vertebroplasty and kyphoplasty are both effective in providing pain relief although kyphoplasty has a small advantage in pain relief and is significantly better for improving patients’ quality of life. The risk of major complications associated with vertebral augmentation is low with rare reports described across large trials. The risk of morbidity and mortality of patients treated with NSM has been reported in multiple analyses to be significantly higher than those patients treated with vertebroplasty or kyphoplasty. This chapter provides an analysis of the current literature on the safety and efficacy of vertebral augmentation procedures. The design, inclusion criteria, outcomes, and limitations of major randomized controlled trials on efficacy are presented along with data on procedural safety, complication rates, cement extravasation, and secondary fracture.
Keywords: vertebral augmentation, vertebral compression, fracture, vertebroplasty, kyphoplasty, osteoporosis, metastasis
Vertebral augmentation procedures (vertebroplasty [VP] and kyphoplasty) involve the image-guided injection of polymethyl methacrylate (PMMA) cement into a fractured vertebral body. The majority of these minimally invasive procedures are performed for a subset of vertebral compression fractures (VCFs) that are refractory to nonsurgical management (NSM) or that are severely debilitating to the patient. The key goals are the relief of back pain, the enhancement of functional status, and biomechanical stabilization of the vertebral body. Vertebral augmentation was first described in 1987, and early enthusiasm was driven by positive results in observational studies. Since that time, over 3,000 articles have been published on vertebral augmentation procedures, and a number of randomized controlled trials (RCTs) have investigated the efficacy and safety of VP and kyphoplasty. The most recent literature provides high-quality evidence that vertebral augmentation procedures are safe and effective in the treatment of VCFs due to osteoporosis and malignancy.
The aim of this chapter is to analyze the current literature on vertebral augmentation procedures. A historical background is presented using early observational data. The design, key outcomes, and limitations of major RCTs are examined. High-quality data on procedural safety outcomes, including overall complication rates, cement leakage, and secondary fracture, are reviewed.
VP was first performed in 1984 but not reported in literature until 1987 by Galibert et al, for the treatment of an aggressive vertebral hemangioma at C2.1 The procedure provided complete pain relief for the patient, and was subsequently performed for six other patients. Shortly thereafter, the procedure was applied to treat the pain associated with osteoporotic and neoplastic compression fractures.2 Following further success in small European series, Jensen et al introduced VP to the United States. In 1997, they published results from 29 patients with 47 painful osteoporotic compression fractures. Almost all (90%) patients reported pain relief and improved mobility within 24 hours of the procedure. The publication of several series followed.3 In 2006, a pooled analysis of VP studies from 1989 to 2004 included 2,086 patients. In the 19 studies that reported pain outcomes from VP, there was significant postprocedure reduction of pain (mean visual analog scale [VAS] reduction of 8.1 to 2.6; p < 0.001) and serious complications occurred in less than 1%.4
Kyphoplasty was first described in 2001 by Lieberman et al as an alternative procedure with potentially lower risks of cement extravasation and a potential for greater height restoration of the vertebral body.5 A pooled analysis of 26 kyphoplasty studies that included 1,710 patients found significant postprocedure improvements in pain intensity, mobility, and functional capacity. Vertebral alignment was also improved, with increased anterior vertebral height and reduction of kyphosis.6
These promising early data led medical societies to support vertebral augmentation as an effective treatment for osteoporotic VCF refractory to medical management.7 However, there remained a lack of robust RCT data to support the efficacy of VP over NSM.
Early uptake of VP was rapid and driven by positive early data from observational studies and meta-analyses. However, two RCTs having a total of approximately 200 patients across both studies published in the New England Journal of Medicine (NEJM) found that VP offered no significant benefit over NSM. Since that time, these articles have been widely discredited and downgraded in their level of evidence category, but they have provided incentive for additional investigation of the efficacy of VP. Several large randomized trials have been released in recent years, focusing on rigorous inclusion criteria and minimizing methodological limitations. The key findings of the main prospective VP trials are summarized in ▶Table 15.1.
The 2007 VERTOS trial was the first multicenter prospective RCT to compare VP to medical management for pain relief in osteoporotic VCFs.8 Inclusion criteria included severe back pain persisting despite medical therapy for at least 6 weeks, fracture aged less than 6 months, focal tenderness on physical examination, and bone marrow edema on MRI. In total, 34 patients were randomized to receive VP (n = 18) or conservative management (n = 16). The primary outcome measures were back pain intensity (as measured by the VAS) and analgesic use at 1 day and 2 weeks. Analgesic requirement was quantified by assigning ordinal variables to different analgesic types: 0 (no analgesia required), 1 (paracetamol/acetaminophen), 2 (nonsteroidal anti-inflammatory medications) or 3 (opioids).
VP resulted in significant pain relief at 1 day postprocedure, with reduction in the baseline mean VAS from 7.1 to 4.7 (difference between groups −2.4 in favor of VP). While this effect was not maintained at the 2-week endpoint, 88% of patients from the conservative group had crossed over to the VP group. Analgesic use was reduced in the VP group (–1.4; 95% confidence interval [CI] −2.1 to −0.8). Secondary outcomes of disability—defined by Roland–Morris Disability Questionnaire (RMDQ)—and quality of life (QOL; Quality of Life Questionnaire of the European Foundation for Osteoporosis [QUALEFFO]) were also significantly improved in the VP group.
The main limitations of the VERTOS trial were its small size and lack of blinding. No long-term follow-up was possible, as crossover was permitted after 2 weeks and 14 out of 16 patients in the conservative group requested crossover to VP.
In 2009, two RCTs comparing VP to a sham procedure for osteoporotic VCFs were published in the NEJM.9,10 The results of both trials contrasted with earlier observational and meta-analysis data, and called into question the efficacy of VP. The Investigational Vertebroplasty Safety and Efficacy Trial (INVEST) screened 1,812 patients to randomize 131 to receive either VP (n = 68) or a sham procedure (n = 63).9 Due to low initial recruitment, the proposed sample size was reduced from 250 to 130 patients, and the inclusion criteria were broadened. Inclusion criteria were as follows: age older than 50 years, pain intensity of ≥3/10 on numerical rating scale (NRS), and fracture age less than 1 year. Undetermined fracture ages were confirmed using MRI or radionuclide bone scan. The sham procedure involved the injection of local anesthetic onto the periosteum of the pedicle, combined with placing pressure on the patient’s back and opening a container of methacrylate monomer to replicate PMMA odor. At 1-month follow-up, there was no difference between groups in back pain NRS (p = 0.19) or disability (measured by RMDQ score; p = 0.06). No long-term follow-up was feasible due to crossover; by 3 months, 27 patients (43%) in the control group had crossed to the VP arm.
Key limitations of the INVEST were that the trial was under-powered and suffered from prominent selection bias (screened 1,812 patients to enroll 131), the crossover of patients in the INVEST trial was far greater for those patients crossing over from sham to VP (51%) as compared to the VP patients crossing over to sham (13%), the inclusion of fractures up to 12 months old, and the lack of inclusion requirements for physical examination or advanced imaging with MRI or radionuclide bone scan. The clinical and imaging diagnostic criteria for inclusion were very different from those of most RCTs, with patients having a pain score of 3 or more on the VAS being eligible for inclusion. There was no description of a clinical examination used to determine if the pain came from the VCF itself or from another issue. There was also criticism that the INVEST trial was not a true sham, with 63% of the sham patients correctly guessing their treatment, and with the injection performed using a paraspinal injection of local anesthetic that has been used to successfully palliate patients’ pain from VCFs for up to 8 weeks.11 Despite all of these limiting factors, if the same response rate for the 131 patients had been carried out to the originally intended 250 patients, VP would have been found to be significantly better than sham treatment at a p-value of less than 0.01. Additionally, if only one patient had reported a different response (i.e., a favorable response in the VP group or an unfavorable response in the sham group), VP would have been found to be significantly better than sham with a p-value of less than 0.04.
A second multicenter sham-controlled RCT on VP for osteoporotic VCFs was published in the NEJM in 2009, by Buchbinder et al.10 This trial included patients with back pain of less than 12 months’ duration and fracture confirmed on MRI with bone marrow edema or fracture line. A total of 78 patients were enrolled from four recruiting centers, and randomized to VP (n = 38) or sham procedure (n = 40) groups. The sham procedure did not involve the injection of anesthetic; a needle was inserted onto the lamina, with the sharp stylet replaced by a blunt stylet. To further simulate VP, the vertebral body was lightly tapped, and PMMA was mixed in the room but not injected. No significant difference between groups in pain scores was observed at 1 week, 3 months, or 6 months. There was also no difference in disability and quality-of-life (QOL) scores.
As with INVEST, Buchbinder and colleagues did not require a physical examination component and there was no description of a clinical examination used to ascertain VCF-related pain. The Buchbinder trial assessed “overall pain” rather than spine-related pain, undermining the validity of the measurement in this population replete with potentially comorbid painful conditions. Both subacute and chronic fractures (up to 12 months old) were included, with only 32% of patients having fractures less than 6 weeks old. Similar to the INVEST, the Buchbinder trial experienced difficulties with enrolment, taking 4.5 years to enroll only 78 patients, and making this trial subject to selection bias. Additionally, 68% of patients in the study were recruited at one of the four centers, with two of the remaining centers recruiting only five patients. This may have caused outcomes to be weighted to the treatment effect at a single center. This single center tended to inject only small amounts of PMMA with the mean volume of cement being 2.8 mL. A later review by Boszczyk et al concluded that the data strongly indicate that the treatment arm included patients who were not treated in a reasonably effective manner.12
In 2012, a meta-analysis was published that included prospective randomized and nonrandomized trials comparing VP to NSM or sham therapy for osteoporotic VCFs.13 Nine trials were analyzed, including INVEST, Buchbinder et al, and VERTOS II, with a total of 886 patients. No difference in pain relief was found between VP and sham procedure groups due to the reliance on the previously discussed VP versus sham trials as the only two trials of this type. When compared to the NSM used to treat patients with painful VCFs, however, VP was found to be superior to NSM at all time points studied, in both pain relief and QOL measures.
Several authors expressed dissatisfaction with the findings of the 2009 trials, raising concerns about the inclusion and exclusion criteria, the use of small volumes of PMMA cement, the selection bias, the precarious statistical calculations, the high rate of crossover, the low initial pain scores, the inclusion of worker compensation patients, the use of a sham that is a known active treatment, the absence of an appropriate physical examination component, and the lack of long-term follow-up.14–16 In response, in 2013 Comstock et al published a study that followed up the INVEST cohort over 12 months to determine long-term outcomes.17 At 1 year, there was a modest pain reduction in the VP arm, although no differences in disability measures were found. The potential for the INVEST sham group to have acted as an “active control,” thus confounding results, was also raised.18,19 The same year, a meta-analysis by Anderson et al was published that analyzed both NEJM sham studies and downgraded them to level II data based on flawed inclusion criteria (in both studies) and a subsequent high crossover rate (in the Comstock et al study). This downgrade was based on the Cochrane Risk of Bias table and Levels of Evidence for Primary Research as adopted by the North America Spine Society.20
There remained no large multicenter RCT comparing VP with medical management, until the 2010 publication of VERTOS II by Klazen and colleagues.21 Addressing some previous concerns from the 2009 trials, it included fractures of less than 6 weeks’ duration, with pain severity of ≥5/10, focal tenderness on examination, and bone marrow edema on MRI. The 202 enrolled patients were randomized equally into VP and conservative management groups. At 1 month, VP resulted in significantly reduced back pain. The mean reduction in VAS score was 2.6 greater (95% CI: 1.74–3.37; p < 0.0001) in the VP arm than in the conservative arm, and this effect was durable at 1 year. VP also resulted in improved QOL (as measured by several standardized questionnaires) and significant (VAS reduction >3 points) pain relief was achieved earlier in VP (30 vs. 116 days; p < 0.0001).
Farrokhi et al followed with a trial comparing VP and medical management for osteoporotic VCFs in 2011.22 Inclusion criteria included severe pain despite NSM for 4 weeks, fractures aged 4 weeks to 1 year, focal tenderness on examination, and bone marrow edema or fracture cleft on MRI. Eighty-two patients were randomized to receive VP (n = 40) or NSM. At 1 week, there was reduction in VAS (difference of −3.1; p < 0.001) and improvement in the QOL measures in the VP arm. Pain relief was durable to 6 months, while QOL outcomes sustained to 36 months. All VP patients were able to ambulate at 24 hours postprocedure, compared with 2% in the conservative group. VP also resulted in increased vertebral body height (mean 8 mm) and reduction in kyphosis (mean 8 degrees).
A further RCT comparing VP with medical management for osteoporotic VCFs followed in 2012, by Blasco and colleagues.23 Inclusion criteria were moderate pain (VAS ≥ 4/10), fractures aged ≤12 months, and edema on MRI or increased uptake on radionuclide bone scan. A total of 125 patients were enrolled and randomized to VP (n = 64) or NSM (n = 61) arms. VP resulted in greater VAS and lower requirement for rescue analgesia (5% of patients requiring rescue analgesia compared with 25% of the medical arm).
In 2016, the VAPOUR (Vertebroplasty for Acute Painful Osteoporotic Fractures) trial aimed to compare VP with a sham procedure while addressing some of the limitations of earlier trials.24,25 An appropriately higher pain threshold was utilized (>7/10 compared with >3 in INVEST and no pain threshold in Buchbinder et al), all fractures were less than 6 weeks old, and all fractures were imaged with MRI or single photon emission computed tomography (SPECT). In total, 120 patients were randomized to receive VP (n = 61) or a sham procedure involving subcutaneous injection of local anesthetic (n = 59). At 2 weeks, VP resulted in significant pain reduction, with NRS scores decreasing to less than 4/10 in 44% of VP patients. This effect was sustained at 1 and 6 months. VP also led to improved QOL questionnaire scores, reduced functional disability, reduced analgesic requirements, and increased height of the vertebral body.
In a 2016 prospective trial, Yang et al randomized 135 patients aged ≥70 years to receive VP or conservative therapy.26 Early VP resulted in faster and greater pain relief and improved QOL, at 1 week, 1, 3, and 6 months, and 1 year (p < 0.0001). Surveys conducted at follow-up revealed that patients in the VP arm had greater overall satisfaction with their given treatment.
There are fewer high-quality studies available for VP in the treatment of neoplasm-related VCFs. A 2011 systematic review of 30 studies, with a total of 987 patients, found reductions in back pain ranging from 20.3 to 78.9% at 1 month following VP. At 6 months, pain reduction ranged between 47 and 87%.27 A 2016 systematic review performed by Health Quality Ontario included 78 studies, with a total of 2,545 VP patients with fractures due to spinal metastases, multiple myeloma, or hemangioma.28 They reported an overall rapid (within 48 hours) reduction in mean pain intensity scores following VP, along with parallel reduction in disability measures and opioid use.
The Fracture Reduction Evaluation (FREE) trial, published in 2009, was a multicenter prospective randomized trial comparing kyphoplasty to NSM for VCFs.29 Inclusion criteria were severe back pain (≥4/10) for ≤3 months, focal tenderness on examination, and MRI findings of bone marrow edema, vertebral body height loss, or pseudoarthrosis. A total of 300 patients were randomized to receive kyphoplasty (n = 149) or conservative management (n = 151). The primary outcome was QOL at 1 month, as measured by change in short-form 36 questionnaire (SF-36) physical component summary (PCS) scale. These measures, along with back pain intensity scores and disability (RMDQ), were also evaluated at 1, 3, 6, and 12 months.
Kyphoplasty resulted in significant improvement in QOL when compared to NSM, with mean SF-36 scores improving 5.2 points more in the kyphoplasty group than the NSM arm (95% CI: 2.9–7.4; p < 0.0001). This outcome was durable at 3 and 6 months (p < 0.0008; p < 0.0064), but not at 12 months (p = 0.208). Kyphoplasty also led to significantly reduced back pain scores at 1 week (p < 0.0001) and 12 months (p = 0.0034). Analgesic use was reduced in the kyphoplasty group at 1 and 6 months. Two-year outcome data released by the FREE authors revealed that there remained a significant reduction in back pain scores for patients undergoing kyphoplasty (p = 0.009). However, there were no significant differences in SF-36 or RMDQ scores. The FREE trial also included both osteoporotic and neoplastic fractures, but only 4 of 300 patients had pathologic fractures.
The Cancer Patient Fracture Evaluation (CAFE) RCT compared kyphoplasty with NSM for malignant VCFs.30 Inclusion criteria included pain intensity of ≥4/10, RMDQ disability score of ≤10, and vertebral fracture demonstrated on plain radiographs or MRI. Patients with index fractures due to primary or osteoblastic bone tumors were excluded. A total of 134 patients were enrolled and received either kyphoplasty (n = 70) or NSM (n = 64). At 1 month, there was a significant reduction in RMDQ scores in the kyphoplasty arm (difference between groups of 8.4 in favor of kyphoplasty), meeting the primary outcome. Kyphoplasty also resulted in greater pain relief, reduced analgesic use, and improved QOL (measured by SF-36), at all time points throughout the 12-month follow-up period.
A limitation of the CAFE trial was the lack of histological confirmation of fracture etiology. Although all participants were cancer patients, it was not known whether the fracture was caused by metastasis, osteoporosis, radionecrosis, or a combination thereof. The trial featured an opportunity for patients to crossover at 1 month with 38 of the 52 (73%) patients in the conservative group that completed the 1-month evaluation crossing over to kyphoplasty and 55% of these patients crossed over within 1 week after their 1-month visit.
The 2019 EVOLVE study, the largest trial of kyphoplasty efficacy conducted to date, compared 12-month disability and safety outcomes in a Medicare-eligible population.31 A total of 350 patients enrolled at 24 U.S. sites received kyphoplasty for painful VCFs. Four primary endpoints were evaluated: NRS back pain scores, disability (represented by Owestry Disability Index [ODI] score), and QOL (EQ-5D and SF-36 scores). At 3 months, there were significant improvements in all primary outcomes. Mean NRS improved from 8.7 to 2.7, while ODI improved from 63.4 to 27.1. These effects were significant at all other time points measured (7 days and 1, 3, 6, and 12 months). Of all treated patients, only 5 procedure-related complications were reported; each event resolved with treatment.
Kyphoplasty may involve the adjunct use of a curet before or after inflation of the balloon tamp in an attempt to scrape away sclerotic bone that may impede the restoration of vertebral body height. The 2013 randomized trial comparing 2 techniques of balloon kyphoplasty and curette use for obtaining vertebral body height restoration and angular-deformity correction in vertebral compression fractures due to osteoporosis (SCORE) trial randomized patients with osteoporotic VCFs to receive kyphoplasty procedures in which the curet was used prior to balloon inflation (n = 57), or following inflation, followed by a second balloon tamp (n = 55).32 Vertebral body height restoration and pain relief were significantly improved in both treatment approaches, with no significant difference between groups.
The randomized trial comparing balloon kyphoplasty and vertebroplasty for vertebral compression fractures due to osteoporosis (KAVIAR) trial, published in 2014, directly compared VP and kyphoplasty in the treatment of osteoporotic VCFs.33 A total of 381 patients with acute painful VCFs due to osteoporosis were randomly assigned to receive VP (n = 190) or kyphoplasty (n = 191), and were not blinded to the treatment received. All fractures were confirmed by imaging with MRI, radioisotope bone scan, or CT. The trial was terminated early, significantly short of the enrolment target of 1,234 with only 404 patients. Despite the lack of statistical power needed to demonstrate the difference between VP and kyphoplasty, both techniques resulted in statistically significant and sustained clinical improvement from baseline for pain, function, and QOL measurements.
Liu et al also compared VP and kyphoplasty for the treatment of painful VCFs in their 2010 prospective RCT.34 One-hundred patients with osteoporotic VCFs were randomized to receive VP or kyphoplasty (comprising 50 in each group). Both procedures resulted in significantly reduced VAS pain scores, as well as improvements in vertebral height and kyphotic wedge angle. While there was no significant difference between groups in clinical outcomes, kyphoplasty resulted in higher periprocedural costs.
Röllinghoff et al found comparable results in their prospective study of 90 patients with VCFs treated with VP or kyphoplasty.35 Both procedures provided significant benefits in QOL and pain relief (p < 0.001), with no statistically significant difference between the two in these clinical outcomes. However, kyphoplasty resulted in greater restoration of vertebral body height than VP, while the rate of cement leakage was lower in the VP group.
A 2015 meta-analysis (including eight studies with 845 total patients) found that VP and kyphoplasty were similar with regard to long-term pain relief, short- and long-term functional improvement, and risk of new adjacent VCF.36 Kyphoplasty was superior to VP in short-term pain reduction, improvement of the kyphotic angle, and also resulted in lower rates of cement leakage.
The most complete meta-analysis published in 2012 examined the English-language articles and found that out of 1,587 vertebral augmentation manuscripts there were 27 level I and II articles including 8 randomized studies.37 There were nine articles that compared VP to kyphoplasty. Pooled patient data were combined into one analyzable study group. Following this analysis of the highest quality data available, the authors concluded that kyphoplasty decreased pain to a greater degree than VP (5.07 vs. 4.55 points on the VAS) and resulted in significantly better improvement in QOL than both VP and NSM.
The 2015 KAST study evaluated the Kiva system, a novel vertebral augmentation implantation device used to treat painful VCFs with minimal cement leakage.38 A total of 300 patients with painful osteoporotic VCFs were randomized to receive Kiva (n = 153) or kyphoplasty (n = 147). At 12-month follow-up, Kiva was shown to be noninferior to kyphoplasty with regard to the primary outcomes of back pain (VAS) and disability (ODI) reduction. Secondary outcomes included cement volume usage, cement leakage, and adjacent vertebral fracture; analysis of these endpoints revealed superiority of the Kiva system over kyphoplasty.
The overall risk of serious complications from vertebral augmentation is very low.39–42 Although uncommon, potential major complications that have been reported in the literature include neurologic damage from nerve or spinal cord injury, pulmonary embolism from cement or fat emboli, infection, hematoma, allergic or idiosyncratic reactions, hemothorax, pneumothorax, and fracture to vertebrae, ribs, or sternum.43–47 Mortality from vertebral augmentation is exceedingly rare, with no procedural mortalities across all RCTs reviewed. Rare cases of death from cement anaphylaxis or cardiovascular collapse have been reported.48
Across major RCTs of vertebral augmentation for osteoporotic fractures, the rate of major complications was approximately 1%.40–42 In the VERTOS II trial, the only complications occurring in the 101 patients referable to VP were 1 urinary tract infection (UTI) and 1 case of asymptomatic cement leakage into a segmental pulmonary artery. Buchbinder et al reported one thecal sac injury that did not require any specific treatment, while INVEST reported one case of osteomyelitis in a patient who did not receive prophylactic antibiotics. In the VAPOUR trial, there was one case of respiratory arrest following sedation prior to the procedure. This patient was treated with vertebral augmentation uneventfully 48 hours later. One patient in the VP group sustained a humeral fracture during transfer onto the procedure table. Conversely, two patients in the conservative arm had interval vertebral collapse with spinal cord compression. In the FREE trial, the only complications referable to kyphoplasty from the 149 patients were 1 soft-tissue hematoma and 1 UTI.
In the 2013 meta-analysis by Anderson et al, which examined prospective RCTs (including VERTOS, VERTOS II, INVEST, Buchbinder et al, and FREE) comparing VP or kyphoplasty to sham or conservative treatment for osteoporotic fractures,20 there were no statistically significant differences in adverse events between vertebral augmentation and conservative arms. Minor adverse events reported from augmentation included asymptomatic cement leaks, soft-tissue hematoma, and vasovagal events.
Extraosseous leakage of PMMA cement is the major source of complications from vertebral augmentation. Asymptomatic leakage is common on postprocedural CT imaging; cement embolization may occur frequently, while symptomatic leakage is rare.43–49 In VERTOS II, 72% of treated vertebral bodies had cement leakage on CT, with all patients remaining asymptomatic. Most leaks were diskal or into segmental veins, while none occurred in the spinal canal.21 Reported rates of cement extravasation were lower in other RCTs, occurring in 36% of patients in the trial by Buchbinder et al and 34% in VAPOUR, likely related to the assessments with conventional radiography.10,24
While embolization to the pulmonary arteries has previously been characterized as an adverse event, it in fact can occur quite commonly, with reported rates of 5 to 23% of all patients.50–52 It is important to note, however, that the vast majority of embolisms and extravasation are neither symptomatic nor produce adverse outcomes.53
Kyphoplasty has been shown to result in lower rates of cement extravasation, as inflation of the balloon tamp creates a path of least resistance into which cement is subsequently injected. In the FREE study, cement leakage occurred in 27% of treated vertebrae on imaging with intraoperative fluoroscopy and postoperative radiographs. All patients remained asymptomatic.29 Cement extravasation occurred in only 2 of 70 patients in the CAFE trial; 1 case was asymptomatic, while the other, a diskal leakage, was associated with adjacent-level fracture on day 1 postprocedure.30
Malignant tumors frequently lead to regions of destroyed bone at the vertebral cortex, which may increase the risk of cement leakage into the surrounding tissues.4 In a retrospective study of CT-guided VP for malignant vertebral fractures, local cement leak was evident in 59% of vertebrae (194 of 331).54 Six percent of leaks occurred into the spinal canal through the posterior cortex, despite osteolysis of the posterior wall being apparent in 49%. Pulmonary cement emboli were demonstrated in 2% (1 of 53) of chest radiographs and 11% (10 of 88) of chest CT scans.47 In a prospective study of 106 patients with multiple myeloma treated with VP, cement leakage was detected on CT in 23% of vertebrae.55 Most leaks occurred into perivertebral veins (85%), and all events of leakage were asymptomatic. Pulmonary cement emboli were detected in 5% of patients.48
It is very unlikely that vertebral augmentation increases the risk of new or adjacent-level VCF compared to NSM.49,56 An initial single-arm prospective study by Tanigawa et al followed up 194 patients with 500 osteoporotic VCFs treated by VP over the long term.57 New VCFs were detected in 33.5% of patients using conventional radiographs. Of the new fractures, 63.1% were in adjacent vertebrae, and 36.9% in nonadjacent vertebrae. Of note, 12 patients with new VCFs diagnosed remained asymptomatic. No significant link was noted between the volume of cement injected and the rates of adjacent VCF. In a retrospective study of 88 postmenopausal women treated with VP, 14 patients suffered collapse of an adjacent vertebra within 1 month. Risk of collapse was significantly associated with advanced age and decreased lumbar and hip bone mineral density (BMD).58
However, in a 2017 meta-analysis of 12 comparative studies encompassing 1,328 patients, Zhang et al compared the incidence of new VCFs following vertebral augmentation and conservative management. No significant difference was seen between the two cohorts in either total new vertebral fractures or adjacent fractures.59 Comparable results were displayed in the meta-analysis by Anderson et al, which found no significant differences between vertebral augmentation and conservative arms with regard to rates of subsequent fracture.20 Shi et al, who performed a meta-analysis of prospective trials comparing VP with sham or conservative management for osteoporotic VCFs, also found no difference between arms in the risk of new VCF (p = 0.82).13 In a larger meta-analysis, Papanastassiou et al analyzed all of the level I and II data on vertebral augmentation and determined that the additional fracture rate for those patients treated with vertebral augmentation was 12% compared with 23% for those patients treated with NSM.37 A 2014 prospective study of 290 patients receiving vertebral augmentation or NSM found no significant difference between groups in additional VCFs.60 However, additional VCFs occurred sooner in the vertebral augmentation group. This temporal difference in fracture appearance after vertebral augmentation could explain the perception that vertebral augmentation can predispose the patient to more subsequent fractures because the subsequent fractures after vertebral augmentation happen sooner than in patients treated with NSM. In a meta-analysis of 19 studies, Xiao et al compared postprocedure complication rates between VP and kyphoplasty. The authors of this study found no significant difference between procedures in subsequent adjacent-level fractures.61
A 2017 biomechanical study on cadaveric spines aimed to assess how fractures and VP affect vertebral deformation and loading.62 Fracture of the vertebrae caused deformations to both the fractured and adjacent levels, and transferred compressive load onto the neural arch. These effects were significantly reduced by VP, which reduced anterior vertebral body deformation by 62% at fractured levels and 52% at adjacent levels.
The potential benefits of prophylactic VP to reduce postaugmentation adjacent-level fracture was investigated by Eichler et al in a retrospective study.63 Thirty-seven patients treated with kyphoplasty for osteoporotic VCFs were included; 19 patients received kyphoplasty alone and 18 were treated with additional VP at the adjacent level. Prophylactic VP at adjacent levels did not reduce the rate of subsequent fractures after kyphoplasty. The authors concluded that adjacent-level fractures following vertebral augmentation are most likely related to underlying osteoporosis rather than the procedure itself.
The excess mortality risk from osteoporotic VCF is considerable, ranging from 2 to 42% in the first year following fracture.64 An analysis of the U.S. Medicare population (97,142 patients with VCF and 428,956 controls) revealed 3- and 5-year mortality rates of 46 and 69%, respectively, in VCF patients, compared with 22 and 36% in the control group.65
While none of the currently published large RCTs were powered to evaluate mortality reduction, there is some evidence that vertebral augmentation may confer a mortality benefit. A 2017 review of U.S. Medicare data, encompassing 261,756 kyphoplasty patients and 117,232 VP patients, evaluated vertebral augmentation utilization and VCF mortality risk.6 In the years following the 2009 sham-controlled RCTs, there was a sharp decline in vertebral augmentation procedures. This time period was associated with elevated mortality risk in VCF patients when compared with the years preceding 2009, which saw higher uptake of vertebral augmentation procedures.
The first longitudinal, population-based comparison of mortality risk between interventional and NSM groups was performed in 2011 and included 858,978 patients treated with kyphoplasty, VP, or NSM.67 Patients who received augmentation had a significantly higher survival rate than the NSM group (60.8% compared with 50%; p < 0.001). At 4-year follow-up, median life expectancy was 2.2 to 7.3 years greater across the vertebral augmentation groups than for NSM. However, due to its retrospective, observational design, this study was limited by the inability to evaluate causal relationships between surgical management, NSM, and patient survival.
In 2015, the same authors published a similar retrospective study of the U.S. Medicare population that identified 1,038,956 VCF patients, of which 141,343 underwent kyphoplasty and 75,365 underwent VP.68 The nonoperated cohort had a 55% higher mortality risk than those treated with kyphoplasty, and a 25% higher risk than those treated with VP (p < 0.001). Of note, the nonoperated cohort had higher rates of pneumonia, UTI, deep vein thrombosis, and cardiac complications than the kyphoplasty cohort. In an analysis of Taiwanese health insurance data, 10,785 patients with painful VCF were identified. The mortality risk was 39% higher in those receiving medical management than in those treated with VP.69 In a similar analysis of German claims data (including 3,607 VCF patients), those who received vertebral augmentation had a 43% lower mortality risk over the 5-year period.70
A comparative study of 5,766 VCF patients, of which 17% underwent kyphoplasty, revealed that kyphoplasty was associated with greater likelihood of discharge home (38.4 vs. 21% for NSM) and lower in-hospital mortality rate (26.1 vs. 34.8%).71 In 2011, a retrospective study of a large hospital patient database compared mortality rates after vertebral augmentation with inpatient pain management and bracing.72 Augmentation significantly improved survival for up to 2 years compared with NSM, regardless of patient age or gender, the number of VCFs, or comorbidity profile.
Contrasting results were found by McCullough et al, who selected 9,017 pairs from Medicare claims data treated with vertebral augmentation or NSM, matched by patient demographics and comorbidities.73 While initial mortality and rates of medical complications were lower in the vertebral augmentation group, there were no significant differences between groups in mortality at 1 year, and the vertebral augmentation group had higher rates of health care utilization. However, this study is potentially subject to methodological limitations. The authors hypothesized that vertebral augmentation patients are healthier than patients given NSM, and hence attempted to control for selection bias by matching comorbidities between groups. Yet patient selection only considered a limited set of baseline comorbidities, and did not account for other conditions that may have led to VCFs. Furthermore, data showed that the control group, theorized to have poorer health compared with augmentation patients, had significantly lower Quan comorbidity scores and lower rates of prior inpatient admissions; this is suggestive of improved health in the control group. To investigate preprocedure health status, the authors selected a subgroup of 3,023 patients who had not yet undergone augmentation by 30 days post-VCF. This excluded patients who may have needed emergent care, and thus may have led to a misleading estimation of preprocedure health status. Finally, the authors concluded that there was no mortality improvement for patients after vertebral augmentation despite three of their four analysis points showing statistically significant mortality improvement and the fourth point was close to statistical significance at p = 0.18. Their conclusion of no mortality benefit was at odds with their own data that suggest otherwise.
There is robust evidence to support vertebral augmentation as a safe and effective option to improve patients’ pain, function, and QOL on those individuals presenting with moderate to severe pain and functional debilitation due to a VCF. Evidence for the efficacy of VP in osteoporotic VCFs has evolved over time. Early sham-controlled RCTs were designed to mitigate the possible placebo effects, but they had very problematic methodological limitations. More recent studies, including a large sham-controlled RCT that utilized rigorous inclusion criteria, have shown treatment benefits. Two large RCTs comparing kyphoplasty with conservative therapy have demonstrated benefits in both osteoporotic and neoplastic fractures, although a trial comparing kyphoplasty to a sham procedure has not yet been performed and may never be performed given the ethical concerns over the higher rates of morbidity and mortality in patients treated with NSM rather than vertebral augmentation. The risks of serious complications from vertebral augmentation are very low, and mortality directly related to the procedure is exceedingly rare. There is recent evidence to suggest that the complication rate, rate of morbidity, and rate of mortality are significantly less for patients undergoing vertebral augmentation than those patients undergoing NSM.
• Vertebral augmentation procedures provide pain relief, functional improvement, and improved QOL in patients with painful VCFs refractory to medical management.
• There is high-quality evidence to support the use of VP for pain relief in acute osteoporotic VCFs. While two large sham-controlled randomized trials found no benefit from VP, these were flawed by serious methodological limitations, and more recent RCTs have demonstrated significant improvements in pain, disability, and QOL.
• There are data from large RCTs to support the use of kyphoplasty for VCFs.
• The risk of complications is exceedingly low. Complications generally result from unrecognized extravasation of bone cement and may include nerve or spinal cord injury, pulmonary embolism, or infection. However, the vast majority of cement extravasations are asymptomatic. Mortality from vertebral augmentation is exceptionally rare.
• VCFs cause considerable excess mortality in patients with osteoporosis and vertebral neoplasm. There is recent evidence showing that vertebral augmentation confers a significant morbidity and mortality benefit in those patients treated with augmentation as opposed to those patients treated. with NSM.
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