Percutaneous Vertebroplasty or Kyphoplasty for Vertebral Fractures Caused by Osteoporosis
Executive Summary
Background
Percutaneous vertebroplasty and kyphoplasty are procedures for alleviating the pain of vertebral fractures due to osteoporosis. Both involve the injection of bone cement into the body of the fractured vertebra. Kyphoplasty uses a specialized bone tamp with an inflatable balloon to expand a collapsed vertebral body as close as possible to its natural height before introducing mechanical fixation by injecting bone cement into the expanded cavity. However, because they are distinct procedures, the evidence examining each procedure will be evaluated independently.
Objective
This Assessment evaluates the available evidence to determine whether either percutaneous vertebroplasty or kyphoplasty improves the net health outcome for individuals with painful vertebral fractures caused by osteoporosis. This Assessment updates the 2009 Assessment (Vol. 24, No. 7), incorporating two open-label vertebroplasty studies published in 2010. There were no new relevant studies published for kyphoplasty; therefore, that section of the document is essentially unchanged.
Beneficial effects of interest include relief of associated symptoms (e.g., pain), as well as improvement in ability to function (e.g., activities of daily living). Adverse effects include complications associated with either procedure.
Search Strategy
Studies of vertebroplasty were identified through a computerized online search of the MEDLINE® (via PubMed) database through April 2011, using various textwords including: “vertebroplast*”; “cementoplast*”; and “methylmethacrylate” combined with (“vertebral” OR “spinal”). To identify more recent studies, the MEDLINE® search was supplemented by manual searches of the most recent issues of the pertinent journals and by reading the reference lists in the most recently published papers.
Studies of kyphoplasty were identified through a MEDLINE® (via PubMed) search through April 2011, using various textwords, including: “kyphoplast*”; “cementoplast*”; and “methylmethacrylate” combined with (“vertebral” OR “spinal”). To identify more recent studies, the MEDLINE® search was supplemented by manual searches of the most recent issues of the pertinent journals and by reading the reference lists in the most recently published papers.
Selection Criteria
Studies were included in the Assessment “Review of Evidence” if the study characteristics met the following criteria:
* Full-length article published in the English language
*Population consisted of patients with vertebral fractures due to osteoporosis only
*Patient population was a consecutive series of patients, or near-consecutive series (≥90%)
*Treatment used vertebroplasty or kyphoplasty
*Reported on relevant clinical outcomes of pain, functional status, or quality of life
*Pre- and post-procedure values for outcomes were reported, as quantitative measures
*Sample size was ≥100 patients for single-arm studies on vertebroplasty or kyphoplasty; for comparative studies, no minimum sample size was required
Main Results
Vertebroplasty. Two placebo-controlled, randomized trials, 3 open-label, randomized trials, 1 comparative study, and 6 case series studies met selection criteria. Results of the 2 placebocontrolled randomized trials were similar, with both concluding that vertebroplasty conferred no additional benefit over a sham procedure (injection of local anesthetic into the facet capsule and/or periosteum). These studies were designed to determine short-term efficacy and safety of vertebroplasty for alleviating pain and improving physical functioning in persons with painful osteoporotic vertebral fractures. Results of the 3 open-label randomized trials showed significant differences in immediate pain relief among those receiving vertebroplasty versus those undergoing medical management; one concluding that among patients with acute fractures vertebroplasty conferred a benefit over conservative management through 12 months, the other 2 reported immediate drops in pain 1 day after the procedure; however, significant between-group differences in pain were not observed at later time points.
The first placebo-controlled randomized trial recruited 38 participants into the treatment group and 40 into the control arm; 91% completed the 6 months of follow-up. Participants had back pain of less than 12 months’ duration and at least 1, but no more than 2 vertebral fractures. For the primary outcome of overall pain, the authors reported no significant difference in VAS pain score at 3 months, 2.6 versus 1.9, respectively, mean difference 0.6 (95% CI: -0.7, 1.8).
The second placebo-controlled trial was also a multicenter, randomized, double-blind, sham- controlled trial in which participants with 1 to 3 painful osteoporotic vertebral fractures of duration less than 1 year were assigned to undergo vertebroplasty or sham procedure (i.e., injection of local anesthetic into the facet capsule and/or periosteum). Sixty-eight participants had vertebroplasty while 63 received sham; 97% completed 1 month of follow-up and 95% completed 3 months. For the primary endpoints at 1 month, there were no significant between-group differences. Both randomized, controlled trials showed a greater frequency of clinically meaningful improvements in pain.
The largest of the open-label randomized trials was a multicenter, prospective, nonblinded trial where participants with at least 1 painful osteoporotic vertebral fracture of duration of 6 weeks or less were assigned to undergo vertebroplasty or conservative management (i.e., bed rest, analgesia, and cast and physical support). One-hundred and one participants were randomized to each group. Ninety-three participants received vertebroplasty while 95 received conservative management; 81% of participants completed 1-year follow-up. For the primary endpoints of pain relief at 1 month and 1 year, there were significant between-group differences in mean visual analog scale (VAS) scores 2.6 (95% CI: 1.74 to 3.37, p<0.0001) at 1 month and 2.0 (95% CI: 1.13 to 2.80, p<0.0001) at 1 year. Significant pain relief (i.e., 30% change) was quicker (29.7 vs. 115.6 days) and was achieved in more patients after vertebroplasty than after conservative management.
Results of the 2 other randomized trials and one comparative study come from trials of less rigor than the previously mentioned randomized trials. These appeared to show an effect favorable to vertebroplasty immediately following the procedure. However, differences between groups quickly diminished. One trial reported no difference at 2 weeks’ follow-up; another showed diminished differences at 6 weeks post-procedure, with the third study reporting no differences at 3 and 12 months’ follow-up.
Based on the study quality ratings, based on the USPSTF criteria, 3 randomized trials were determined to be of good quality, one was fair, and one was deemed poor.
Kyphoplasty. One randomized trial, 2 nonrandomized studies comparing kyphoplasty to medical management, one study comparing kyphoplasty to vertebroplasty, and 4 case series studies met selection criteria. The randomized trial showed a greater improvement in mean SF-36 physical component score for the kyphoplasty group over medical management. The comparative studies showed greater improvement in pain scores and other outcomes compared to medical management. In the study that compared kyphoplasty to vertebroplasty, improvements in pain were reported in both study groups, and there were no differences between the 2 procedures. The case series studies showed a consistent 4- to 5-point improvement in VAS pain ratings (0–10 scale) after kyphoplasty. The improvement appeared to be durable out past 1 year, but all studies suffered from losses to follow-up.
Analysis and interpretation are difficult in a nonrandomized setting, as it is difficult to separate out effects of the intervention from differences between the treatment and control groups. These studies enrolled different patients with respect to age of fracture; one study enrolled patients with fractures older than 1 year, while another enrolled patients with acute fractures meeting specific radiologic criteria for instability. The brief format of the acute fracture study does not allow an assessment of the similarity of the kyphoplasty and control groups. Contrary to a nonrandomized 2003 study of vertebroplasty, the control groups in this study did not improve appreciably over a period of weeks to months.
Author’s Comments and Conclusions
Vertebroplasty. The key limitation to both placebo controlled randomized trials is that they were underpowered. While neither used as a primary outcome the most robust measure of clinical significance, both provided calculations of the proportion of patients who had a clinically meaningful change. One randomized trial reported that response or meaningful improvement (i.e., a 2.5-point change on the VAS) in overall pain at 1, 3, and 6 months was more frequent with vertebroplasty— respective relative risks of 1.2 (95% CI: 0.7–2.0), 1.5 (95% CI: 0.9 –2.6), and 1.3 (95% CI: 0.8–2.1) and the other reported 64% vs. 48% (p=0.06) of participants with a clinically meaningful improvement in pain at 1 month.
Without adequate power, it is not possible to determine if vertebroplasty was effective or not. Thus, the results should be interpreted as uncertain, rather than as a lack of effect.
The sham procedure use raises interesting questions as to the mechanisms of action of vertebroplasty. The frequency of response to the sham procedure, which included injection of local anesthetic into the facet capsule and/or periosteum, raises the question of whether the anesthesia itself might interrupt the pain cycle for these patients. With uncertainty regarding the effect of the local anesthetic on alleviation of pain, it may be reasonable to investigate this hypothesis.
The 3 open-label randomized studies are limited by the inability to blind participants, investigators, or assessors to treatment assignment due to the lack of inclusion of a sham procedure. The trial by Klazen and colleagues was performed among participants with acute fracture, a population different those enrolled in the two placebo-controlled trials. The analysis included as a primary outcome a responder analysis, the authors defined a priori a clinically significant change in pain as a 3-point difference on the VAS scale and used survival analysis to plot the results.
Kyphoplasty. Historically, there has been a lack of rigorous comparative trials of kyphoplasty. A 2009 randomized, controlled trial of kyphoplasty versus medical management was both unblinded and lacked a sham control. The authors concluded that kyphoplasty was superior to medical management at reducing pain from vertebral compression fractures from osteoporosis. Case series studies described 4- to 5-point improvements in VAS pain ratings after kyphoplasty. In light of the well-known, strong placebo effect for invasive procedures, which was highlighted in the 2 recent randomized trials of vertebroplasty, the results of nonrandomized studies and case series should be interpreted with caution. The principal adverse effect of kyphoplasty is leakage of cement out of the vertebral body; however, complications due to this leakage are infrequent. Fractures in vertebrae adjacent to the treated vertebrae do occur; however, it has not been demonstrated whether this is more common after such treatment.
Summary According to the Technology Evaluation Criteria—Vertebroplasty
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether vertebroplasty for vertebral fractures caused by osteoporosis meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
Vertebroplasty is a surgical procedure and, as such, is not subject to U.S. Food and Drug Administration (FDA) approval. Polymethyl methacrylate (PMMA) bone cement was available as a drug product prior to enactment of the FDA’s device regulation and was at first considered what the FDA terms a “transitional device.” It was transitioned to a class III device requiring premarketing applications. Several orthopedic companies have received approval of their bone cement products for purposes other than vertebroplasty or kyphoplasty since 1976. In October 1999, PMMA was reclassified from class III to class II, which requires future 510(k) submissions to meet “special controls” instead of “general controls” to assure safety and effectiveness. FDA issued a guidance document on July 17, 2002 (accessed May 2011 at http://www.fda.gov/downloads/ MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm072837.pdf) that outlines the types of special controls required and describes the following recommended labeling information:
*Intended Use. PMMA bone cement is intended for use in arthroplastic procedures of the hip, knee, and other joints for the fixation of polymer or metallic prosthetic implants to living bone.
*Contraindications. PMMA bone cement is contraindicated in the presence of active or incompletely treated infection, at the site where the bone cement is to be applied.
*Warnings. Monitor patients carefully for any change in blood pressure during and immediately following the application of bone cement. Adverse patient reactions affecting the cardiovascular system have been associated with the use of bone cements. Hypotensive reactions have occurred between 10 and 165 seconds following application of bone cement; they have lasted from 30 seconds to 5 or more minutes. Some have progressed to cardiac arrest. Patients should be monitored carefully for any change in blood pressure during and immediately following the application of bone cement.
There have been several bone cement products cleared for marketing via 510(k) by the FDA for use in vertebroplasty or kyphoplasty (e.g., Vertaplex or Spineplex™ Radiopaque Bone Cement [Stryker], KyphX® HV-R™ Bone Cement [Kyphon, Inc.], Vertebroplastic™ Radiopaque Bone Cement [DePuy Spine, Inc.]). Continuing concern about other cement and bone-void-filling products led to an FDA Public Health Web Notification that notes the types of complications that can occur with these products and offers advice to physicians regarding use of such products. FDA requires hospitals and facilities to report deaths and serious injuries associated with the use of such medical devices. Use of cement products not receiving FDA clearance specifically for vertebroplasty or kyphoplasty represents an off-label use.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
The 2 published randomized, double blind, sham-controlled trials provide evidence that vertebroplasty may not improve health outcomes when compared to a sham procedure. An open-label randomized trial showed a significant and sustained improvement in pain following vertebroplasty compared to conservative management for patients with acute fractures. However, due to the methodologic issues highlighted earlier, the interpretation of these data is unclear. Two additional published randomized trials of vertebroplasty showed short-term efficacy of the procedure, but in one follow-up was only 2 weeks and the other showed no sustained benefit at 3- and 12-month follow-up. Further, case series studies are subject to many sources of bias and are generally not reliable evidence of efficacy.
3. The technology must improve the net health outcome; and 4. The technology must be as beneficial as any established alternatives.
The evidence is insufficient to determine whether vertebroplasty improves the net health outcome or is as beneficial as any established alternatives.
5. The improvement must be attainable outside the investigational settings.
Whether vertebroplasty for vertebral fractures from osteoporosis improves health outcomes has not yet been established in the investigational setting. For the above reasons, percutaneous vertebroplasty for vertebral fractures from osteoporosis does not meet the TEC criteria.
Summary According to the Technology Evaluation Criteria––Kyphoplasty
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether kyphoplasty for vertebral fractures from osteoporosis meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
Kyphoplasty is a surgical procedure and, as such, is not subject to U.S. Food and Drug Administration (FDA) approval. Both the PMMA bone cement (see Criterion one discussion, preceding) and the balloon tamp used in kyphoplasty are cleared for marketing by the FDA. One such tamp, the KyphX® inflatable bone tamp, received 510(k) marketing clearance from the FDA in July 1998.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
There are relatively few comparative trials of kyphoplasty, but many case series have been published. While there is one randomized trial of kyphoplasty, without the inclusion of a sham procedure, it is not possible to quantify the real benefit of the procedure over a nonspecific effect to determine the effect of kyphoplasty on the net health outcome.
3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.
The evidence is insufficient to determine whether kyphoplasty improves the net health outcome or is as beneficial as any established alternatives.
5. The improvement must be attainable outside the investigational settings.
Whether kyphoplasty for vertebral fractures from osteoporosis improves health outcomes has not yet been established in the investigational setting.
For the above reasons, percutaneous kyphoplasty for vertebral fractures from osteoporosis does not meet the TEC criteria.
Full Study
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