Balloon kyphoplasty in malignant spinal fractures: a systematic review and meta-analysis.

Background

Spinal fractures are a common source of morbidity in patients with osteolytic metastasis and multiple myeloma [ 1 - 3 ]. Located principally in the thoracic and lumbar spine [ 4 , 5 ], these fractures often result in intractable back pain and impaired mobility because of vertebral height loss and spinal deformity [ 2 , 3 , 6 ]. In addition, the severe physiological and functional consequences have negative impacts on physical function, pulmonary capacity, nutritional state, psychological well-being and quality of life. Furthermore, spinal fractures increase the risk of new fractures, the number of hospitalizations and the incidence of all-cause mortality [ 1 , 3 , 6 - 8 ].

Traditional medical and surgical options often prove inadequate in spinal fracture patients. Due to the fragility and comorbidities associated with these patients, the surgical risk is high and open surgery is reserved only for cases with neurological involvement [ 1 , 5 , 6 ]. Additionally, non-surgical supportive treatments (e.g., analgesics, bed rest, use of braces or other external support systems, radiotherapy, hormone therapy, chemotherapy, radiopharmaceuticals and bisphosphonates) show variable outcomes, and single modality approaches are rarely effective [ 1 , 6 , 9 , 10 ].

In recent years, minimally invasive surgical techniques have emerged as an attractive option that reduce recovery time and surgical risks [ 1 , 5 , 11 , 12 ]. Balloon Kyphoplasty (BKP) is a percutaneous procedure used to relieve pain, restore vertebral height and reduce biomechanical alterations of the spine caused by fractures, and in turn improve physiological and functional outcomes [ 12 - 14 ]. BKP involves the introduction of a cannula into the vertebral body under image guidance, followed by the insertion of an inflatable bone tamp which is used to elevate the endplates. This reduces the deformity and creates a cavity within the vertebral body, and this cavity is subsequently filled with bone cement (polymethyl methacrylate, PMMA) in a controlled manner so as to minimize the risk of cement leakage [ 12 - 14 ].

Several reviews have recently shown that BKP is a relatively effective and safe treatment for painful osteoporotic vertebral fractures, its most common indication [ 12 , 15 , 16 ]. However, to our knowledge, BKP use in cancer patients has not been specifically analyzed.

The present study performed a meta-analysis of published reports describing the use of BKP in patients with spinal fractures of malignant origin. The study examined patient outcome data in order to determine the efficacy and safety of using BKP for spinal fractures in cancer patients.

Methods

A systematic literature search was carried out up to September 2008 using several databases (MEDLINE, EMBASE, CINAHL, ISI Proceedings, The Cochrane Library, DARE, NHS EED and the HTA Database of the CRD). The search strategy was: #1: (balloon kyphoplasty), #2: (fracture*) or (vertebra*) or (neoplasm*) or (tumor*), #3: #1 and #2. There were no language restrictions. The search was completed manually using references from identified studies and reviews [ 17 ], and contact was made with experts in the field. No contact was made with industry.

Inclusion criteria

Sackett's criteria [ 18 ], duly amended, were applied as follows: 1) population: studies conducted on more than 10 adults with spinal fractures of malignant origin; 2) intervention: BKP; 3) comparator: any medical or surgical treatment; 4) results: including a description of clinical outcomes regarding at least one of the following variables: pain, functional capacity, quality of life, vertebral height, kyphotic angle, cement leakages, clinical complications and new vertebral fractures.

No limitations were placed on study design or duration of follow-up [ 17 ].

Selection of studies

The located studies were examined by two independent reviewers, and any disagreements were settled by discussion of the respective study data. During the data screening and extraction process, reviewers were not blinded to authors, institutions, or journals.

Data extraction

Original data were extracted on a standard form that included details of the study design, information on the study population, and information on efficacy and safety outcomes.

Analysis of methodological quality and scientific evidence

This was conducted in accordance with validated recommendations [ 19 ]. The possibility of bias in the studies was evaluated using published guidelines for systematic reviews [ 20 ].

Data analysis and synthesis of results

To obtain an overall measure of the efficacy and safety of BKP, standard meta-analytical techniques were applied using the SE-STATA 9 computer software package (StataCorp LP Texas USA 1984-2007). Meta-analysis was conducted using a random-effects model [ 21 ]. Dichotomous outcomes were analyzed using rate ratios (RR) and corresponding 95% confidence interval. Continuous variables were analyzed using standardized or weighted differences in means (with 95% confidence intervals) between pre- and post- treatment values at the respective assessment dates. When an original study failed to provide a standard deviation of a continuous variable, it was estimated from the publication data (range or P-value) [ 22 ]. When the original study provided a standard error rather than a standard deviation, the latter was calculated using standard formulas. The degree of inconsistency across studies was evaluated using I 2 statistics, considering a value > 50% to be relevant [ 20 ]. We used sensitivity analysis to explore statistical heterogeneity. Results were deemed significant at a P-value < 0.05. In accordance with recent publications, funnel-plots were not used to estimate possible publication bias [ 23 ].

Results

The literature selection process is summarized in Figure 1 . After excluding references without an abstract and redundancies arising from the use of several databases, 208 potentially relevant references were identified. Eleven of these publications [ 24 - 34 ] were selected based on our inclusion criteria. Of those, 4 were excluded [ 24 , 29 , 31 , 32 ] because of data duplication in subsequent or more complete publications [ 25 , 33 , 34 ]. Hand searching of retrieved articles yielded no additional studies to be included.

The seven remaining studies were the basis of the present meta-analysis. These studies comprised three retrospective [ 26 , 28 , 30 ] and four prospective [ 25 , 27 , 33 , 34 ] single-center clinical series published from 2003 to 2008, and included data on 306 patients with 741 treated levels. The principal characteristics and quality assessment of these studies are summarized in Tables 1 and 2 . The patients had a mean age of 62 years, 51% were male and 57% had multiple myeloma. The population mostly comprised patients with persistent pain secondary to thoracic or lumbar collapses, despite painkillers and medical therapy [ 25 , 27 , 30 , 34 ]. Around 30% of patients required devices to assist with walking. In all studies, symptomatic levels were identified by correlating the clinical data with MRI findings of marrow signal changes. In all but Kose's study [ 30 ], BKP was performed under general anesthesia. The mean number of spinal levels treated varied among the studies (range:1-6). Follow-up periods varied from 3 months [ 27 ] to 2 years [ 33 , 34 ].

The studies were examined for bias in accordance with validated references [ 19 , 20 ]. We found that most studies were designed to avoid most types of bias, with some exceptions (Table 2 ). However, a number of studies did not provide information on whether the results were assessed independently (Table 2 ). No study was randomized and the level of evidence corresponded to grade III [ 19 ]. However, the samples were representative and the studies were found to provide effective information on pre- and post-intervention variables and evaluated objective outcomes, and more than half reported follow-up of over 80% of patients [ 20 ].

Efficacy outcomes

Pain Relief

The six studies that analyzed this variable before and after BKP reported reductions in pain intensity, and that the reduction was maintained during follow-up [see Additional file 1 ]. Combined analysis of studies that contributed Visual Analog Scale (VAS) data showed that BKP resulted in a reduction in mean pain score both in the postoperative period and at the end of the follow-up period (Table 3 ). A substantial level of inconsistency was found across studies, with the mean pre-procedure VAS being related to the effect size.

Fourney's study [ 26 ] showed that both BKP and vertebroplasty relieved pain to a similar degree in a high percentage of patients. Kose's study [ 30 ] indicated that although both BKP and vertebroplasty relieved pain, BKP provided greater pain relief at 6 and 12 months postoperatively [see Additional file 1 ].

Functional Capacity

Changes in functional capacity were recorded in four studies using the validated Oswestry Disability Index (ODI 0-100) [ 25 , 27 , 33 , 34 ]. In all studies, comparisons between preoperative and postoperative values showed a significant decrease in ODI scores after treatment, indicating a decrease in impairment [see Additional file 1 ]. The combined analysis indicated improved functional capacity after BKP, and that the improvement was sustained over the follow-up period (Table 3 ). Heterogeneity was found to be related to differences in the mean basal pre-procedure ODI scores.

Individual studies [ 26 , 28 , 30 ] reported that most patients were mobilized on the same day following the procedure and regained activity, social functions and physical capacity.

Quality of Life

All studies reported obvious improvement in patient quality of life after the procedure. However, only one study [ 25 ] evaluated the effect on quality of life using the SF-36 questionnaire. That study found significant improvements in physical function, physical role, bodily pain, vitality, social functioning, and mental health, but no improvements in general health perception or emotional role [see Additional file 1 ].

Kyphotic Deformity

Three studies analyzed this variable using the absolute Cobb angle value [ 26 , 32 , 33 ]. Joint analysis in these studies found that BKP resulted in a decrease in the angle's absolute value (Table 3 ), although with a high degree of heterogeneity and a wide variation among studies in both baseline and post-treatment values of deformity [see Additional file 1 ]. Follow-up analysis showed partial loss of the initial effect, with the absolute value of the angle ultimately decreasing to preoperative levels (Table 2 ) and the pooled differences being not significant (Table 3 ).

Vertebral Height

Although the number of levels varied among studies, each study in which this variable was recorded [ 25 - 27 , 30 , 33 , 34 ] reported a post-BKP increase in vertebral height. However, the increase was expressed differently in each study [see Additional file 1 ]. Several authors [ 25 - 27 ] recorded the percentage of vertebral height restoration after BKP, and the mean restoration across these studies was 47% (Table 3 ). In contrast, Pflugmacher [ 33 , 34 ] measured vertebral height gained in millimeters. Pooled analysis of his data showed increases in both anterior and midline vertebral body after BKP. However, neither of these increases was statistically maintained at the end of the follow-up period.

Safety

Cement Leaks

All studies provided safety information. Overall, there were 41 cement leakages associated with BKP, none of which was symptomatic. BKP cement leakages occurred at a mean of approximately 6% across all levels (Figure 2 ). Sensitivity analysis showed that inconsistency across studies (I 2 : 84%) was related to design, with prospective studies yielding a higher rate of leakage (11.2%) than retrospective studies (0.51%, I 2 : 0%). No relationship was found with other factors such as specific etiology (multiple myeloma vs. metastasis) or estimated age of the fracture.

In Fourney's study [ 26 ], 6 asymptomatic leakages were observed in the 65 levels treated with vertebroplasty, representing 9%, while no leakages were observed in patients treated with BKP. Kose's comparative study [ 30 ] recorded no cement leaks in patients treated with either BKP or vertebroplasty.

New Vertebral Fractures

After pre-planned radiographic evaluation during follow-up, four studies reported the development of 21 new vertebral fractures in 172 patients [see Additional file 1 ]. Although fracture rates varied widely among studies, pooled analysis showed an overall rate close to 10% (Figure 3 ). Sensitivity analysis showed that inconsistency across studies (I 2 : 54%) was related to fracture etiology. The rate of new fractures was higher in patients with myeloma (12.4%) than in those with metastasis (7.9%, I 2 :0%).

Clinical Complications

Although poorly reported across the studies, a small number of patients treated with BKP experienced clinical complications, but no deaths were reported within 30 days of BKP [see Additional file 1 ]. Two studies reported complications unrelated to the procedure. In Fourney's study [ 26 ], one patient was readmitted to hospital 15 days after BKP due to an exacerbation of pre-existing congestive heart failure, while Vrionis et al. [ 28 ] recorded a case of asystole in a patient with a history of lung cancer with multiple brain metastases. No evidence of pulmonary embolism due to cement leakage was seen postoperatively and the exact cause of asystole was undetermined. That patient recovered to her preoperative level, but died 1 month after surgery from unrelated causes.

In a comparative study, Kose [ 30 ] recorded no post-surgical neurological or pulmonary complications after any intervention. Although that article stated that two patients suffered minor clinical complications (wound infection and temporary respiratory difficulties while being placed in position for surgery), the authors did not indicate which intervention had been performed (i.e., BKP or vertebroplasty).

Discussion

The present study found that there are very few reports on the efficacy and safety of BKP for treating tumor-associated spinal fractures. Furthermore, all such reports have a non-randomized design, and are limited in terms of number of patients, procedures and reported outcomes. Nonetheless, a combined analysis of these reports provided results in broad agreement with earlier reports examining osteoporotic fractures [ 15 , 16 , 34 - 37 ].

The present meta-analysis found that BKP provided immediate pain relief, and that the relief can continue for up to 2 years. This pain relief is not only clinically significant (i.e., a change of 2.0 - 2.7 points on the VAS, which is equivalent to a reduction of 30 - 41%) [ 38 ], but of great benefit because most patients have intense and refractory pain resistant to painkillers and conventional medical therapy. The mechanism underlying this pain relief remains to be identified [ 11 ].

The current study also found that BKP resulted in improved functional outcomes. BKP improved functional capacity as assessed by the Oswestry Disability Index. In addition, the study that assessed quality of life using the standard SF-36 questionnaire found improvement in nearly every domain, including vitality, social function and mental health. Interestingly, that study found no significant improvement in general health perception, which was not clearly explained but may reflect progression of the primary malignant disease.

The third major finding of this study was that BKP appeared to reduce the kyphotic angle and, at least partially, restored the height of the collapsed vertebral body. However, this evidence was limited due to the diverse methods used for these assessments. In addition, there was a progressive postoperative decrease in the amount of improvement, and the morphologic benefits were not maintained over the entire follow-up period. Hence, these findings do not suggest that the technique prevents the severe physiological and systemic effects of spinal fractures, which is one of its main objectives [ 13 , 14 ].

Regarding safety, it appears that BKP is a safe procedure. Though BKP was usually performed under general anesthesia, very few clinical complications were reported, of which none was serious. No study recorded neurological or pulmonary complications. Most studies found that any clinical complications were not directly related to the technique but to comorbidities or the progression of the initial disease. However, given the typical frailty of BKP patients, the procedure should be carried out in centers equipped to treat possible neurological or cardiopulmonary complications.

Cement leakages occurred in approximately 6% of all treated levels. While study design influenced that analysis, leakages were asymptomatic in all cases. Our results indicate that approximately 10% of patients will develop a new vertebral collapse within two years after treatment. The development of new vertebral fractures seems to be more frequent (nearly double) in patients with multiple myeloma than in metastatic cases. This is not surprising given several studies have found myeloma patients are more vulnerable to fractures [ 2 ]. The present figures compare favorably with other published data [ 15 , 16 , 35 ]. Overall, the data suggest that the incidence of new fractures after a BKP-based intervention is not higher than the spontaneous incidence of new vertebral fractures (19-24%) described for untreated patients [ 8 ].

Finally, mention should be made to the fact that, at this time, there is an evident lack of studies comparing BKP with other interventions, both invasive and non-invasive. The present findings indicate that BKP and vertebroplasty provide similar pain relief, but that BKP is associated with a lower cement leakage rate, as has been observed elsewhere [ 35 - 37 ].

The current study has several potential limitations. Publication bias may exist by limiting our search to peer-reviewed literature. Nevertheless, we feel that any such bias would have been minimized by the scope of and systematic strategy used in the search of the literature, and we are confident that most research conducted in this field was identified [ 17 , 39 ]. We did not include unpublished data from industry given both the difficulties encountered in obtaining such information and the recognition that the use of such data may not necessarily reduce the bias in a meta-analysis [ 39 , 40 ].

The methodological quality of the studies, particularly their non-randomized design, may constitute another limitation of this work [ 20 ]. To our knowledge, there are no published reports of randomized clinical trials examining the use of BKP for malignant spinal fractures. However, such an absence should not prevent analysis of its efficacy and safety, and evaluation of new technologies and procedures, as this would deprive patients, professionals and health authorities of essential information for decision-making [ 41 - 44 ]. The present study followed the guidelines outlined by the Meta-analysis of Observational Studies in Epidemiology Group [ 43 ] in order to identify and collate relevant data from available studies.

Lastly, we should recognize that the present findings were based on original studies involving relatively small sample sizes, making them susceptible to the inherent problems associated with such a study design [ 45 ].

Conclusion

The present study found that there is level III evidence showing that BKP is a well-tolerated, relatively safe and effective method for reducing pain and improving functional outcomes in patients with painful neoplastic spinal fractures. While BKP also provided immediate improvement in vertebral height loss and spinal deformity, these morphologic changes were not long-term. The limited data available in this area indicate the need for long-term high-quality controlled studies to ascertain the clinical role of BKP for patients with painful neoplastic spinal fractures. Future studies should also have consistent reporting of clinically useful outcomes.

Competing interests

CB and JMA have received prior grant support from Kyphon Iberica SL (to Instituto de Salud Carlos III). No other potential competing interests relevant to this article exist. No corporate/industry funds were received in support of this work. None of the authors has a financial interest in any of the devices discussed in this report.

Authors' contributions

CB conceived the study, participated in its design, performed statistical analysis and drafted the manuscript. TL participated in the design of the study and performed statistical analysis. PC participated in acquisition, analysis and interpretation of data and helped draft the manuscript. ZS participated in acquisition, analysis and interpretation of data, and drafted the manuscript. JMA conceived the study and participated in design and coordination. All authors read and approved the final manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here:

Supplementary Material

Additional file 1

Efficacy of BKP for malignant spinal fractures: Individual description of outcomes . The data provided represent the individual studies description of outcomes.

Click here for file

Acknowledgements

This study was supported by the Spanish I+D Program (grant PI060816). We also thank Raimundo Alcázar for assistance with literature searches.

Coleman RE Management of bone metastases Oncologist 2000 5 463 470 11110597 10.1634/theoncologist.5-6-463

Melton LJ Kyle RA Achenbach SJ Oberg Al Rajkumar SV Fracture risk with multiple myeloma: a population-based study J Bone Miner Res 2005 20 487 493 15746994 10.1359/JBMR.041131

Coleman RE Clinical features of metastatic bone disease and risk of skeletal morbidity Clin Cancer Res 2006 12 6243 6249 10.1158/1078-0432.CCR-06-0931 17062708

Lecouvet FE Berg BC Vande Maldague BE Michaux L Laterre E Michaux JL Ferrant A Malghem J Vertebral compression fractures in multiple myeloma. Part I. Distribution and appearance at MR imaging Radiology 1997 204 195 199 9205246 10.1148/radiology.204.1.9205246

Klimo P Schmidt MH Surgical management of spinal metastases Oncologist 2004 9 188 196 15047923 10.1634/theoncologist.9-2-188

Costa L Badia X Chow E Lipton A Wardley A Impact of skeletal complications on patients' quality of life, mobility, and functional independence Support Care Cancer 2008 16 879 889 18392862 10.1007/s00520-008-0418-0

Silverman SL The clinical consequences of vertebral compression fracture Bone 1992 13 S27 S31 1627411 10.1016/8756-3282(92)90193-Z

Lindsay R Silverman SL Cooper C Risk of new vertebral fracture in the year following a fracture JAMA 2001 285 320 323 11176842 10.1001/jama.285.3.320

Francis RM Baillie SP Chuck AJ Crook PR Dunn N Fordham JN Kelly C Rodgers A Acute and long-term management of patients with vertebral fractures Q J Med 2004 97 63 74 10.1093/qjmed/hch012 14747620

von Moos R Strasser F Gillessen S Zaugg K Metastatic bone pain. treatment options with an emphasis on bisphosphonates Support Care Cancer 2008 16 1105 1115 18682990 10.1007/s00520-008-0487-0

Masala S Fiori R Massari F Simonetti G Vertebroplasty and Kyphoplasty: New equipment for malignant Vertebral fractures treatment J Exp Clin Cancer Res 2003 22 75 79 16767911

Halpin RJ Bendok BR Liu JC Minimally invasive treatments for spinal metastases: vertebroplasty, kyphoplasty, and radiofrequency ablation J Support Oncol 2004 2 339 351 15357518

Garfin SR Yuan HA Reiley MA New technologies in spine: kyphoplasty and vertebroplasty for the treatment of painful osteoporotic compression fractures Spine 2001 26 1511 1515 11462078 10.1097/00007632-200107150-00002

Belkoff SM Mathis JM Fenton DC Fenton DC Scribner RM Reiley ME Talmadge K An ex vivo biomechanical evaluation of an inflatable bone tamp used in the treatment of compression fracture Spine 2001 26 151 156 11154534 10.1097/00007632-200101150-00008

Bouza C López T Magro A Navalpotro L Amate JM Efficacy and safety of balloon kyphoplasty in the treatment of vertebral compression fractures: a systematic review Eur Spine J 2006 15 1050 1067 16429288 10.1007/s00586-005-0048-x PMC3233932

Taylor RS Fritzell P Taylor RJ Balloon kyphoplasty in the management of vertebral compression fractures: an updated systematic review and meta-analysis Eur Spine J 2007 16 1085 1100 17277923 10.1007/s00586-007-0308-z PMC2200787

Royle P Waugh N Literature searching for clinical and cost-effectiveness studies used in health technology assessments reports carried out for the National Institute for Clinical Excellence appraisal system Health Technol Assess 2003 7 1 51 10.3310/hta7340 14609481

Sackett DL Richardson WS Rosenberg W Evidence-Based Medicine How to Practice and Teach EBM 1997 New York: Churchill Livingstone

National Institute for Clinical Excelence Guide to the Methods of Technology Appraisal London 2004 10.1016/S0895-4356(99)00204-8

Cochrane Handbook for Systematic Reviews of Interventions Version 500 [updated February 2008) The Cochrane Collaboration 10.1200/JCO.2002.09.097

Sterne JA Meta-analysis in STATA™ Systematic Reviews in Health Care: Meta-Analysis in Context 2001 London: BMJ books 347 369 10.1136/bmj.323.7304.101 PMC1120714 11451790

Schwartz D Méthodes statistiques à l'usage des médecins et des biologistes 1981 Paris: Flammarion Médecine-Science

Tang J Liu JL Misleading funnel plot for detection of bias in meta-analysis J Clin Epidemiol 2000 53 477 484 10812319 10.1097/01.blo.0000093841.72468.a8

Dudeney S Lieberman IH Reinhardt MK Hussein M Kyphoplasty in the treatment of osteolytic vertebral compression fractures as a result of multiple myeloma J Clin Oncol 2002 20 2382 2387 11981012 10.3171/jns.2003.98.1.0021

Lieberman I Reinhardt MK Vertebroplasty and kyphoplasty for osteolytic vertebral collapse Clin Orthop Relat Res 2003 415S S176 S186 14600608 10.1097/01.blo.0000131642.96984.74

Fourney DR Schomer DF Nader R Nader R Chlan-Fourney J Suki D Ahrar K Rhines LD Gokaslan ZL Percutaneous vertebroplasty and kyphoplasty for painful vertebral body fractures in cancer patients J Neurosurg 2003 98 21 30 12546384 10.1053/j.trap.2005.01.003

Lane JM Hong R Koob J Kiechle T Niesvizky R Pearse R Siegel D Poynton AR Kyphoplasty enhances function and structural alignment in multiple myeloma Clin Orthop Relat Res 2004 426 49 53 15346051 10.1007/s00198-006-0068-3

Vrionis FD Hamm A Stanton N Sullivan M Obadia M Miguel RVl Kyphoplasty for tumor-associated spinal fractures Techniques in Regional Anesthesia and Pain Management 2005 9 35 39

Khanna AJ Reinhardt MK Togawa D Lieberman IH Functional outcomes of kyphoplasty for the treatment of osteoporotic and osteolytic vertebral compression fractures Osteoporos Int 2006 17 817 826 16518574 10.1080/02841850600570425

Kose KC Cebesoy O Akan B Altinel l Dincer D Yazar T Functional results of vertebral augmentation techniques in pathological vertebral fractures of myelomatous patients J Natl Med Assoc 2006 98 1654 1658 17052058 10.1080/02841850601026427 PMC2569744

Pflugmacher R Kandziora F Schroeder RJ Melcher I Haas NP Klostermann CK Percutaneous balloon kyphoplasty in the treatment of pathological vertebral body fracture and deformity in multiple myeloma: a one-year follow-up Acta Radiol 2006 47 369 376 16739696 10.1055/s-2007-960502

Pflugmacher R Beth P Schroeder RJ Schaser KD Melcher I Balloon kyphoplasty for the treatment of pathological fractures in the thoracic and lumbar spine caused by metastasis: one-year follow-up Acta Radiol 2007 48 89 95 17325932 10.1007/s00586-008-0701-2

Pflugmacher R Schulz A Schroeder RJ Schaser KD Klostermann CK Melcher I[A prospective two-year follow-up of thoracic and lumbar osteolytic vertebral fractures caused by multiple myeloma treated with balloon kyphoplasty] Z Orthop Ihre Grenzgeb 2007 145 39 47 17345542 10.1016/j.spinee.2007.04.004

Pflugmacher R Taylor R Agarwal A Melcher I Dish A Haas NP Klostermann C Balloon kyphoplasty in the treatment of metastatic disease of the spine: a 2-year prospective evaluation Eur Spine J 2008 17 1042 1048 18560905 10.1097/01.brs.0000229254.89952.6b PMC2518756

Eck JC Nachtigall D Humphreys SC Hodges SD Comparison of vertebroplasty and balloon kyphoplasty for treatment of vertebral compression fractures: a meta-analysis of the literature Spine J 2008 8 488 497 17588820 10.1097/01.brs.0000244639.71656.7d

Hulme PA Krebs J Ferguson SJ Berlemann U Vertebroplasty and kyphoplasty: a systematic review of 69 clinical studies Spine 2006 31 1983 2001 16924218 10.1016/j.jpain.2007.09.005

Taylor RS Taylor RJ Fritzell P Balloon kyphoplasty and vertebroplasty for vertebral compression fractures: a comparative systematic review of efficacy and safety Spine 2006 31 2747 2755 17077747 10.1097/01.brs.0000244639.71656.7d

Dworkin RH Turk DC Wyrwich KW Beaton D Cleeland CS Farrar JT Haythornthwaite JA Jensen MP Kerns RD Ader DN Brandenburg N Burke LB Cella D Chandler J Cowan P Dimitrova R Dionne R Hertz S Jadad AR Katz NP Kehlet H Kramer LD Manning DC McCormick C McDermott MP McQuay HJ Patel S Porter L Quessy S Rappaport BA Rauschkolb C Revicki DA Rothman M Schmader KE Stacey BR Stauffer JW von Stein T White RE Witter J Zavisic S Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations J Pain 2008 9 105 121 18055266 10.1017/S0266462300103150

Song F Eastwood AJ Gilbody S Duley L Sutton AJ Publication and related biases Health Technol Assess 2000 4 1 105 10932019

Ferguson D Laupacis A Salmi LR McAlister FA Huet C What should be included in meta-analysis? An exploration of methodological issues Int J Technol Assess Health Care 2000 16 1109 1119 11155831 10.1017/s0266462300103150

Atkins D Fink K Slutsky J Better Information for Better Health Care: The Evidence-based Practice Center Program and the Agency for Healthcare Research and Quality Ann Intern Med 2005 142 1035 1041 15968027 10.1001/jama.283.15.2008

Hartling L Mcalister FA Rowe BH Ezekowitz J Friesen C Klassen TP Challenges in Systematic Reviews of Therapeutic Devices and Procedures Ann Intern Med 2005 142 1100 1111 15968035 10.1016/S1072-7515(03)00112-1

Stroup DF Berlin JA Morton SC Olkin I Williamson GD Rennie D Moher D Becker BJ Sipe TA Thacker SB for the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group Meta-analysis of observational studies in epidemiology a proposal for reporting JAMA 2000 283 2008 2012 10789670 10.1016/S0304-3959(98)00140-7

Strasberg SM Ludbrook PA Who oversees innovative practice? Is there a structure that meets the monitoring need of new techniques? J Am Coll Surg 2003 196 938 948 12788432 10.1016/S1072-7515(03)00112-1

Moore RA Gavaghan D Tremer MR Collins Sl McQuay HJ Size is everything-large amounts of information are needed to overcome random effects in estimating direction and magnitude of treatment effects Pain 1998 78 209 216 9870574 10.1016/S0304-3959(98)00140-7