《外科护理学》课程阅读资料（英文）骨折 fracture.pdf_大学文库

The new england journal o f medicine n engl j med 361;6 nejm.org august 6, 2009 569 original article A Randomized Trial of Vertebroplasty for Osteoporotic Spinal Fractures David F. Kallmes, M.D., Bryan A. Comstock, M.S., Patrick J. Heagerty, Ph.D., Judith A. Turner, Ph.D., David J. Wilson, F.R.C.R., Terry H. Diamond, F.R.A.C.P., Richard Edwards, F.R.C.R., Leigh A. Gray, M.S., Lydia Stout, B.S., Sara Owen, M.Sc., William Hollingworth, Ph.D., Basavaraj Ghdoke, M.D., Deborah J. Annesley-Williams, F.R.C.R., Stuart H. Ralston, F.R.C.P., and Jeffrey G. Jarvik, M.D., M.P.H. From the Mayo Clinic, Rochester, MN (D.F.K., L.A.G.); the University of Washington, Seattle (B.A.C., P.J.H., J.A.T., L.S., B.G., J.G.J.); Nuffield Orthopaedic Centre NHS Trust, Oxford (D.J.W., S.O.), Gartnavel General Hospital, Glasgow (R.E.), the University of Bristol, Bristol (W.H.), Nottingham University Hospital NHS Trust, Nottingham (D.J.A.-W.), and Western General Hospital, University of Edinburgh, Edinburgh (S.H.R.) — all in the United Kingdom; and St. George Hospital, University of New South Wales, Sydney (T.H.D.). Address reprint requests to Dr. Kallmes at the Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, or at kallmes.david@ mayo.edu. N Engl J Med 2009;361:569-79. Copyright © 2009 Massachusetts Medical Society. Abstract Background Vertebroplasty is commonly used to treat painful, osteoporotic vertebral compression fractures. Methods In this multicenter trial, we randomly assigned 131 patients who had one to three painful osteoporotic vertebral compression fractures to undergo either vertebroplasty or a simulated procedure without cement (control group). The primary outcomes were scores on the modified Roland–Morris Disability Questionnaire (RDQ) (on a scale of 0 to 23, with higher scores indicating greater disability) and patients’ ratings of average pain intensity during the preceding 24 hours at 1 month (on a scale of 0 to 10, with higher scores indicating more severe pain). Patients were allowed to cross over to the other study group after 1 month. Results All patients underwent the assigned intervention (68 vertebroplasties and 63 simulated procedures). The baseline characteristics were similar in the two groups. At 1 month, there was no significant difference between the vertebroplasty group and the control group in either the RDQ score (difference, 0.7; 95% confidence interval [CI], −1.3 to 2.8; P=0.49) or the pain rating (difference, 0.7; 95% CI, −0.3 to 1.7; P=0.19). Both groups had immediate improvement in disability and pain scores after the intervention. Although the two groups did not differ significantly on any secondary outcome measure at 1 month, there was a trend toward a higher rate of clinically meaningful improvement in pain (a 30% decrease from baseline) in the vertebroplasty group (64% vs. 48%, P=0.06). At 3 months, there was a higher crossover rate in the control group than in the vertebroplasty group (43% vs. 12%, P<0.001). There was one serious adverse event in each group. Conclusions Improvements in pain and pain-related disability associated with osteoporotic compression fractures in patients treated with vertebroplasty were similar to the improvements in a control group. (ClinicalTrials.gov number, NCT00068822.) The New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

Thr NEW ENGLAND JOURNAL Of MEDICINE PONTANEOUS VERTEBRAL FRACTURES ARE to be less than 1 year old,as indicated by the dura ssociated with nain disahility and death in tion sly had found that a fra patients with osteoporosis.Percutaneous ver-ture duration of up to 1 vear was associated with tebroplasty,the injection of medical cement,or a good response to vertebroplasty.For fractures polymethylmethacrylate (PMMA),into the frac- of uncertain age,an additional requirement wa ured vertebra pain wide ce marrow edem tance as an f ef ar on bor suspi es guidelin the to were evide ral for fractures that have not responded to medical tial retropulsion of bony fragments.con treatment.Typically,the duration of such fractures hip fracture,active infection,uncorrectable bleed ranges from several weeks to several months or ing diatheses,surgery within the previous 60 days longer for fractures that have not hea ed lack of access to a telephone,inability to commu umerous case mall,un nicate in English,and dem blinded, efr mized The prot relieving pain from oste porotic precise mechanism of action remains unknown However,in the absence of blinded,randomized MEASURES At baseline,patients completed the self-report fec dity index s an n th n andomized cont rolled trial,called the and Effic res were rtorme nd at Th Trial ONVESD.we evaluated the efficacy of PMMA focus of this renort is the nrima infusion in vertebroplasty for patients with pain- 1 month.We also describe outcomes at 3.14.and ful osteoporotic compression fractures,as com 90 days.The prespecified primary outcome mea ithout PMMA vere scores on the modified Roland-Morris ents wh had und Disability Que naire (RDQ and patients'ra 9 h in an ngs o e pr mary ourcomes)than those in the res indicating ain)The RDC METHODS ated with back pain and has been shown to be valid,reliable,and responsive to change in severa TIENT: dingastudy olled patients s at f s in the United The on a s nter in Australia The sites We the basis of having an established vertebrop (pos tion ofn e of 30 prop practice for osteoporotic fractures an enthusiastic on the rdo and measures of pain intensity which local principal investigator,and an available re- was the minimal change on each scale that was ds have beer considered to be clinically important.2 a previo scores on the Pa secondary outcome re 2 th an OF 50 ivities of Daily Livine (SOF-ADD three pain ful osteoporotic vertebral compr scale 27 and the furonean ouality of life-5 Di fractures between vertebral levels T4 and L5,in- mensions(EQ-5D)scale2(a generic health-status adequate pain relief with standard medical ther measure.reflecting mobility.self care.activity lim apy,and a cur Laingforpeiniaensrecfe least3on a scale from 0to 10. Fractures need or oplo cations:and 570 N ENGLI MED 361:6 NEIM.ORG AUGUST 6.2000 Downloaded from nejm

The new england journal o f medicine 570 n engl j med 361;6 nejm.org august 6, 2009 S pontaneous vertebral fractures are associated with pain, disability, and death in patients with osteoporosis. Percutaneous vertebroplasty, the injection of medical cement, or polymethylmethacrylate (PMMA), into the fractured vertebral body has gained widespread acceptance as an effective method of pain relief and has become routine therapy for osteoporotic vertebral fractures. Guidelines recommend vertebroplasty for fractures that have not responded to medical treatment.1 Typically, the duration of such fractures ranges from several weeks to several months or longer for fractures that have not healed. Numerous case series and several small, unblinded, nonrandomized, controlled studies have suggested the effectiveness of vertebroplasty in relieving pain from osteoporotic fractures.2-12 The precise mechanism of action remains unknown. However, in the absence of blinded, randomized, controlled trials, the role of active treatment effects of PMMA versus nonspecific effects remains unknown. In this randomized, controlled trial, called the Investigational Vertebroplasty Safety and Efficacy Trial (INVEST), we evaluated the efficacy of PMMA infusion in vertebroplasty for patients with painful osteoporotic compression fractures, as compared with a simulated procedure without PMMA. We hypothesized that patients who had undergone vertebroplasty would report less pain and back pain–related disability at 1 month (the primary outcomes) than those in the control group. Methods Patients We enrolled patients at five centers in the United States, five centers in the United Kingdom, and one center in Australia. The sites were selected on the basis of having an established vertebroplasty practice for osteoporotic fractures, an enthusiastic local principal investigator, and an available research coordinator. The study methods have been described previously.13 Because initial recruitment was slow, after the first three patients were enrolled, we liberalized the inclusion criteria to an age of 50 years or older, a diagnosis of one to three painful osteoporotic vertebral compression fractures between vertebral levels T4 and L5, inadequate pain relief with standard medical therapy, and a current rating for pain intensity of at least 3 on a scale from 0 to 10. Fractures needed to be less than 1 year old, as indicated by the duration of pain. We previously had found that a fracture duration of up to 1 year was associated with a good response to vertebroplasty.14 For fractures of uncertain age, an additional requirement was marrow edema on magnetic resonance imaging or increased vertebral-body uptake on bone scanning. Exclusion criteria were evidence or suspicion of neoplasm in the target vertebral body, substantial retropulsion of bony fragments, concomitant hip fracture, active infection, uncorrectable bleeding diatheses, surgery within the previous 60 days, lack of access to a telephone, inability to communicate in English, and dementia. The protocol was approved by the institutional review board at each study center. All patients provided written informed consent. Measures At baseline, patients completed the self-report version of the Charlson comorbidity index15 and provided demographic and clinical information. Evaluation measures were performed before randomization and at various times up to 1 year. The focus of this report is the primary outcomes at 1 month. We also describe outcomes at 3, 14, and 90 days. The prespecified primary outcome measures were scores on the modified Roland–Morris Disability Questionnaire (RDQ) and patients’ ratings of average back-pain intensity during the preceding 24 hours (on a scale of 0 to 10, with higher scores indicating more severe pain). The RDQ is widely used to assess physical disability associated with back pain and has been shown to be valid, reliable, and responsive to change in several studies,16-21 including a study of vertebroplasty.22 The modified RDQ23 is scored on a scale of 0 to 23, with higher scores indicating greater physical disability. We present the (post-specified) proportion of patients who had a decrease of 30% or more on the RDQ and measures of pain intensity, which was the minimal change on each scale that was considered to be clinically important.24-26 Prespecified secondary outcomes included scores on the Pain Frequency Index and the Pain Bothersomeness Index,23 the Study of Osteoporotic Fractures–Activities of Daily Living (SOF–ADL) scale,27 and the European Quality of Life–5 Dimensions (EQ–5D) scale28 (a generic health-status measure, reflecting mobility, self-care, activity limitations, pain, and psychological distress); the use of opioid medications; and scores on the Physical The New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

Vertebroplasty for Osteoporotic Spinal Fractures n engl j med 361;6 nejm.org august 6, 2009 571 Component Summary (PCS) and Mental Component Summary (MCS) subscales of the self-administered Medical Outcomes Study 36-Item ShortForm General Health Survey (SF-36), version 2.29 The PCS assesses limitations in self-care and physical, social, and role activities; bodily pain; and perceived health. The MCS provides an indication of psychological distress and social and role disability because of emotional problems. Patients were asked before discharge on the day of the procedure and at each follow-up assessment to guess which procedure they had undergone and to rate their confidence in their guess on a scale from 0 (no confidence) to 10 (complete confidence). Study Treatment All vertebroplasty practitioners in the trial were highly experienced, having performed a mean of approximately 250 procedures (range, 50 to 800). Patients were brought to the fluoroscopy suite, where conscious sedation was induced and sterile preparation for surgery was performed. Using fluoroscopic guidance, the practitioner infiltrated the skin and subcutaneous tissues overlying the pedicle of the target vertebra or vertebrae with 1% lidocaine and infiltrated the periosteum of the pedicles with 0.25% bupivacaine. Patients were then randomly assigned to undergo either the full vertebroplasty procedure or the control intervention. 33p9 131 Underwent randomization 1813 Patients were assessed for eligibility 1682 Were excluded 368 Had a tumor 201 Had no compression fracture 111 Had pain level <3/10 104 Had no osteoporosis 102 Had coagulopathy 92 Had dementia 404 Had other exclusion criteria 300 Declined to participate 68 Were assigned to undergo vertebroplasty 68 Underwent vertebroplasty 63 Were assigned to undergo control intervention 63 Underwent control intervention 1 Missed an interview 1 Missed an interview 1 Withdrew 67 Completed 1-mo assessment 1 Underwent crossover intervention at <1 mo 61 Completed 1-mo assessment 2 Underwent crossover intervention at <1 mo 4 Missed an interview 2 Missed an interview 64 Completed 3-mo assessment 8 Underwent crossover intervention at <3 mo 61 Completed 3-mo assessment 27 Underwent crossover intervention at <3 mo AUTHOR: FIGURE: JOB: ISSUE: 4-C H/T RETAKE SIZE ICM CASE EMail Line H/T Combo Revised AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. REG F Enon 1st 2nd 3rd Kallmes 1 of 3 08-06-09 ARTIST: ts 36106 Figure 1. Enrollment and Outcomes. The single patient in the vertebroplasty group who missed the 1-month assessment completed the 3-month assessment. The two patients in the control group who missed the 1-month assessment also missed the 3-month assessment. The New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

VERTEBROPLASTY FOR OSTEOPOROTIC SPINAL FRACTURES Table1.(Continued.) characteristic Vertetr roup Cor SF-36 scorel 25.3+7.8 25373 44.8+118 415+141 3.040.3 3.140.8 erso meness Index sc 3.10 -5D scorefi 0.54±0.23 SOF-ADL score 10.0±3.6 103±2.8 y15 Scores vities of Daily Living (SOF-ADL)scale range with PMMA reached to the posterior aspect of the ver- groups.The block sizes ranged from 4 to 12 pa- tebral body or ente extraosse s space,such tients and ass e concealed from the as th bralwertet or an e ural or para rc tants mv signments we by h th patient's back were given.and the methacrylate and were then t placed in number d monomer was opened to simulate the odor asso opaque sealed envelopes with a series ofervelope ciated with mixing of PMMA,but the needle was for each study center.The protocol specified that not placed and MMA was not infused.After the study-group assignments should b conceale om all tients and study personn o pe supine pos or th ere told at the time ofc onsent that ny contact with the they would be allowed to cross over to the other blinded data. procedure 1 month or later after the intervention if adequate pain relief was not achieved.Specific STATISTICAL ANALYSIS numerical th sholds of outcome measures were The study initially had a power of more than80 not us ents we to d s in ry and c for the month of0.05. es over to pmeieiernaietherpts on the rdoand a 10- ce an the nain No commercial entity paid for any mate rating after early difficulty in recruitment and a used in the study.Research funds paid for all costs planned interim analysis of the first 90 patients, related to the contro w e reduced the target sample size to 130 pa ent vertebroplasty proced re were Dll with approval nt data ng bo ify t RANDOMIZAT We used stratified blocked randomizatio ord. ing to study center to achieve roughly balanced reduced sample size,the study had a power of more N ENGLJ MED 361:6 NEJM.ORG AUGUST 6,2009 53 The New Engl d Journal of Medicin other us thout permission

Vertebroplasty for Osteoporotic Spinal Fractures n engl j med 361;6 nejm.org august 6, 2009 573 PMMA reached to the posterior aspect of the vertebral body or entered an extraosseous space, such as the intervertebral disk or an epidural or paravertebral vein.30 During the control intervention, verbal and physical cues, such as pressure on the patient’s back, were given, and the methacrylate monomer was opened to simulate the odor associated with mixing of PMMA, but the needle was not placed and PMMA was not infused. After the procedure, both groups of patients were monitored in the supine position for 1 to 2 hours before discharge. Patients were told at the time of consent that they would be allowed to cross over to the other procedure 1 month or later after the intervention if adequate pain relief was not achieved. Specific numerical thresholds of outcome measures were not used for allowance of crossover. Patients were seen in the clinic for the 1-month follow-up visit by a vertebroplasty practitioner to discuss whether to cross over to receive the alternative therapy. No commercial entity paid for any materials used in the study. Research funds paid for all costs related to the control interventions. Costs of the vertebroplasty procedure were billed to insurance. Randomization and Blinding We used stratified, blocked randomization according to study center to achieve roughly balanced groups. The block sizes ranged from 4 to 12 patients, and assignments were concealed from the research assistants involved in recruitment. These assignments were generated by the data coordinating center with the use of a random-number generator and were then placed in numbered, opaque, sealed envelopes, with a series of envelopes for each study center. The protocol specified that study-group assignments should be concealed from all patients and study personnel who performed follow-up assessments for the duration of the study. Only the study statisticians, who did not have any contact with the patients, saw unblinded data. Statistical Analysis The study initially had a power of more than 80% to detect differences in both primary and secondary outcomes in 250 patients, with a two-sided alpha of 0.05, on the basis of a 2.5-point difference on the RDQ and a 1.0-point difference on the pain rating. After early difficulty in recruitment and a planned interim analysis of the first 90 patients, we reduced the target sample size to 130 patients, with approval from the independent data and safety monitoring board. The decision to modify the target enrollment was driven primarily by accrual rates and revised power calculations. With the reduced sample size, the study had a power of more Table 1. (Continued.) Characteristic Vertebroplasty Group (N=68) Control Group (N=63) SF-36 score‖ Physical component 25.3±7.8 25.3±7.3 Mental component 44.8±11.8 41.5±14.1 Pain Frequency Index score** 3.0±0.8 3.1±0.8 Pain Bothersomeness Index score** 2.9±0.7 3.1±0.8 EQ–5D score†† 0.57±0.18 0.54±0.23 SOF–ADL score‡‡ 10.0±3.6 10.3±2.8 * Plus–minus values are means ±SD. † Race was self-reported. ‡ Scores on the comorbidity index range from 0 to 28, with higher scores indicating greater severity.15 § Scores on the Roland–Morris Disability Questionnaire (RDQ) range from 0 to 23, with higher scores indicating more severe disability. ¶ The pain-intensity rating ranges from 0 (no pain) to 10 (worst pain). ‖ Scores on the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), version 2, range from 0 to 100, with lower scores indicating a worse outcome. ** Scores on the Pain Frequency Index and Pain Bothersomeness Index range from 0 to 4, with higher scores indicating more severe pain. †† Scores on the European Quality of Life–5 Dimensions (EQ–5D) scale range from −0.1 to 1.0, with higher scores indicating a better quality of life. ‡‡ Scores on the Study of Osteoporotic Fractures–Activities of Daily Living (SOF–ADL) scale range from 0 to 18, with higher scores indicating more back-related disability. The New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

Thr NEW ENGLAND JOURNAL Of MEDICINE than8%to detect important differ nces in the RESULts 30. oint diffor PATIENTS sumed SD of 6.7)and a 1.5-point difference on From June 2004 through August 2008,a total of ) at 131 patients were enrolled and underwent random For our primary analys ,we e used to un ty a n-to-tica ith pati ol in ad ots and fidence intervals were calculated from analysis of ups were similar (Table 1).One patient (1%) covariance (ANCOVA)models with adjustment for in the vertebroplasty group and two patients (3% baseline values of the outcome measure,recruit. in the control group were lost to follow-up before ment site,and an indicator of study group as the 1 month.One patient (1%)in the vertebroplasty predictor of interest.In a post h group and two patier s(3%)in the control grou nd b ustmen proportion of patients in ntly with respe to either of the twe each group who had at least a 30%improvement fied primary outcomes at 1 month.The mean in the RDQ score and pain rating,as recommend- (SD)RDQ score in the vertebroplasty group was 12.0t6.3,as compared with 13.0t6.4 in the con the clin reatment, men Fu .3t pos in the ve d46+30in the (adiusted tre nt effect.0.7:95%CL.-0.3 to 1.7 intensity pain (as an index of fracture age)inter- P=0.19)(Table 2).The two study groups had sub pain in- stantial improve ement in back-related disability and pain immediately (3days)after the procedure,wit from I to I similar improv two groups The study ps did not differ significantly o interaction terms equaled zero.the results wer any of the secondary outcomes.including mea similar for the two analyses,and we report the sures of pain and quality of life,at 1 month (Fig results for the categorical measures the p ne pos -specified resul ally m nd effc d ni mont atien s in the and 41%of patients in the control g p=099).There wa and infection.The board used O'Brien-Fleming? trend toward a higher rate of clinically mean stopping rules of P<0.001 and P<0.019 for two ingful improvement in pain in the vertebroplasty prespecified interim analyses in order to eval group than in the control group (64%vs.48% ate th lating eviden atment eft 065 rest t reach e rmed with the of R statistical soft to the p and hac rersion 2733 A p value of less than 0043 for be tween-group differences in the primary outcomes patients in the vertebroplasty group who crossed was considered to indicate statistical significance over reported higher levels of disability and pain All reported values two-sided and have not not cross over (Fig.3).Patients in th 574 N ENGLJ MED 361:6 NEJM.ORG AUGUST 6,2006 ciety

The new england journal o f medicine 574 n engl j med 361;6 nejm.org august 6, 2009 than 80% to detect important differences in the primary outcome measures — a 3.0-point difference between groups on the RDQ (with an assumed SD of 6.7) and a 1.5-point difference on the pain rating (with an assumed SD of 2.7) — at 1 month.26 For our primary analyses, we used an intention-to-treat strategy, with patients analyzed in their assigned group. Treatment effects and confidence intervals were calculated from analysis of covariance (ANCOVA) models with adjustment for baseline values of the outcome measure, recruitment site, and an indicator of study group as the predictor of interest. In a post hoc analysis, we used logistic-regression models with adjustment for site and baseline values of the outcome measures to compare the proportion of patients in each group who had at least a 30% improvement in the RDQ score and pain rating, as recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials II to assess the clinical importance of improvement.31 Furthermore, we performed two post hoc subgroup analyses to determine whether continuous and categorical measures of the duration of baselineintensity pain (as an index of fracture age) interacted with treatment in predicting the pain intensity at 1 month in the ANCOVA models; these measures compared the periods from 1 to 13 weeks, from 14 to 26 weeks, and from 27 to 52 weeks. Formal evaluation of effect modification was based on a partial F-test of whether the two interaction terms equaled zero. The results were similar for the two analyses, and we report the results for the categorical measures. The data and safety monitoring board reviewed the blinded study results every 6 months to evaluate safety and efficacy and monitored any deaths, events involving paralysis, hospitalizations, newonset fractures, new radiculopathy or myelopathy, and infection. The board used O’Brien–Fleming32 stopping rules of P<0.001 and P<0.019 for two prespecified interim analyses in order to evaluate the accumulating evidence of treatment efficacy; the interim study results did not reach either threshold. All statistical analyses were performed with the use of R statistical software, version 2.7.33 A P value of less than 0.043 for between-group differences in the primary outcomes was considered to indicate statistical significance. All reported P values are two-sided and have not been adjusted for multiple testing. Results Patients From June 2004 through August 2008, a total of 131 patients were enrolled and underwent randomization (Fig. 1). Of these patients, 68 were assigned to undergo vertebroplasty and 63 to undergo the control intervention; all underwent the assigned intervention. The baseline characteristics of the groups were similar (Table 1). One patient (1%) in the vertebroplasty group and two patients (3%) in the control group were lost to follow-up before 1 month. One patient (1%) in the vertebroplasty group and two patients (3%) in the control group crossed over to the other group before 1 month. The two study groups did not differ significantly with respect to either of the two prespecified primary outcomes at 1 month. The mean (±SD) RDQ score in the vertebroplasty group was 12.0±6.3, as compared with 13.0±6.4 in the control group (adjusted treatment effect, 0.7; 95% confidence interval [CI], −1.3 to 2.8; P=0.49). The mean pain-intensity rating was 3.9±2.9 in the vertebroplasty group and 4.6±3.0 in the control group (adjusted treatment effect, 0.7; 95% CI, −0.3 to 1.7; P=0.19) (Table 2). The two study groups had substantial improvement in back-related disability and pain immediately (3 days) after the procedure, with similar improvement in the two groups. The improvement in each group at 3 days was maintained at 1 month. The study groups did not differ significantly on any of the secondary outcomes, including measures of pain and quality of life, at 1 month (Fig. 2). Furthermore, the two groups did not differ in the post-specified proportion of patients who had clinically meaningful improvement in physical disability related to back pain at 1 month (40% of patients in the vertebroplasty group and 41% of patients in the control group, P=0.99). There was a trend toward a higher rate of clinically meaningful improvement in pain in the vertebroplasty group than in the control group (64% vs. 48%, P=0.06). At 3 months, 8 patients (12%) in the vertebroplasty group and 27 patients (43%) in the control group had crossed over to the other group and had undergone the alternative procedure (P<0.001). The patients in the vertebroplasty group who crossed over reported higher levels of disability and pain at 3 days and 14 days, as compared with patients who did not cross over (Fig. 3). Patients in the The New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

VERTEBROPLASTY FOR OSTEOPOROTIC SPINAL FRACTURES control group who crossed over had some early Table 2.Primary Outcomes (Intention-to-Treat Analyses).* improvement after the control procedure,but this improvement had disappeared by the 1-month as owever,even an ati they underwent ents wh were orig PVa RDQ or the control group did not have the same leve At baseline 16.6±3.8 17.5+4. of improvement at 3 months as did patients who At 3 days 13.0±5.2 12.5±5.5 -0.9-2.7t00.810.30 did not cross over At 14 davs 124+58 123459 -0.6-2.4to1.20.35 At 14 days,63%of patients in the control grou At 1 me 12046.3 13.046.4 0.7-1.3to2.80.49 and sy had that undergone th Pain int group corre ed tha the At ba 6920 7241. At 3 days 4.2±2.4 3.9±2.9 -04-1.5to0.5) the vertehronlasty groun and the con rol e At 14 days 4.3±2.9 4.5±2.8 0.1-0.8to1.1)0.77 expressed a moderate degree of confidence,ona At 1 mo 3.9+29 4.6+3.0 0.7-0.3to1.刀0.19 scale of 0(not certain)to 10(extremely certain) in their treatment gues (mean scores, 4.0an In the control group,1 u5tmentfortucr n02t14 ove ve treatmen ts favor the procedure,and positive treatmen they had unde one the pared with 20 of 27 patients (74%)who ever is D re(RDQ)range from to tually crossed over (P=0.12).Notably,among the eight patients in the vertebroplasty group who crosse over to the contro six vertebroplasty or a control interv ention consisting w the did sis the effect of cedure functional disability.and quality of life.In this on pain at 1 month did not differ significantly study,the confidence interval for the comparison across the three baseline pain-duration categorie of the RDQ score (-1.3 to 2.8)excluded a treat- (P=0.58).The treatment effect for patients with ment benefit of 3 points or more and therefore less thar 13 weeks of pain (difference n score provided ev 804 sim me the respect to f ffect for patients with 14 to 26 weeks of nair 13(95%cI-08 to 34:P=023)and the effect a benefit of 2 noints or more Patients in the two for patients with 27 to 52 weeks of pain was 0.0 study groups showed immediate improvement in 95%C1.-1.7to1.6:p=0.96 pain and disability after the procedure,and this Improvement was sustain at 1 month. hese re the vertebroplas ty group had that factors as atio r th resultant hospitalization ant in the facto include the e effect of local anesthesia trol group was hospitalized overnight after the as well as nonspecific effects,such as expectations procedure with tachycardiaand rigors ofunknown of pain relief(the so-called placebo effect),the cause. natural history of the fracture,and regression to- a the m DISCUSSION The pohi ole of the placebo effect on ou Patients with osteoporotic vertebral fractures who ies have doc edpain reduction in were randomly as signed to undergo either a full groups,on the order of 6 to7mm on a 100-mm N ENGLJ MED 361:6 NEJM.ORG AUGUST 6,2009 575 The New Engla d Journal of Medicin ther us thout permission d

Vertebroplasty for Osteoporotic Spinal Fractures n engl j med 361;6 nejm.org august 6, 2009 575 control group who crossed over had some early improvement after the control procedure, but this improvement had disappeared by the 1-month assessment. However, even after they underwent the alternative intervention, patients who were originally assigned to either the vertebroplasty group or the control group did not have the same level of improvement at 3 months as did patients who did not cross over. At 14 days, 63% of patients in the control group correctly guessed that they had undergone the control intervention, and 51% of patients in the vertebroplasty group correctly guessed that they had undergone vertebroplasty. Patients in both the vertebroplasty group and the control group expressed a moderate degree of confidence, on a scale of 0 (not certain) to 10 (extremely certain), in their treatment guess (mean scores, 4.0 and 4.1, respectively; P=0.78). In the control group, 18 of 33 patients (55%) who did not cross over to vertebroplasty correctly guessed at 14 days that they had undergone the control intervention, as compared with 20 of 27 patients (74%) who eventually crossed over (P=0.12). Notably, among the eight patients in the vertebroplasty group who crossed over to the control group, six (75%) guessed incorrectly at 1 month that they had received the control intervention. In a post hoc subgroup analysis, the effect of treatment (vertebroplasty vs. control procedure) on pain at 1 month did not differ significantly across the three baseline pain-duration categories (P=0.58). The treatment effect for patients with less than 13 weeks of pain (difference in score, 0.8; 95% CI, −0.8 to 2.4; P=0.31) was similar to the results for the overall analysis. The treatment effect for patients with 14 to 26 weeks of pain was 1.3 (95% CI, −0.8 to 3.4; P=0.23), and the effect for patients with 27 to 52 weeks of pain was 0.0 (95% CI, −1.7 to 1.6; P=0.96). Adverse Events One patient in the vertebroplasty group had an injury to the thecal sac during the procedure, with resultant hospitalization. One patient in the control group was hospitalized overnight after the procedure with tachycardia and rigors of unknown cause. Discussion Patients with osteoporotic vertebral fractures who were randomly assigned to undergo either a full vertebroplasty or a control intervention consisting of a simulated vertebroplasty without infusion of PMMA did not differ significantly at 1 month after the procedure on measures of back-pain intensity, functional disability, and quality of life. In this study, the confidence interval for the comparison of the RDQ score (−1.3 to 2.8) excluded a treatment benefit of 3 points or more and therefore provided evidence against clinically meaningful treatment effects with respect to functional disability. Similarly, the confidence interval for the comparison of pain ratings (−0.3 to 1.7) excluded a benefit of 2 points or more. Patients in the two study groups showed immediate improvement in pain and disability after the procedure, and this improvement was sustained at 1 month. These results suggest that factors aside from the instillation of PMMA may have accounted for the observed clinical improvement after vertebroplasty. Such factors may include the effect of local anesthesia, as well as nonspecific effects, such as expectations of pain relief (the so-called placebo effect), the natural history of the fracture, and regression toward the mean. The possible role of the placebo effect on outcomes in this trial remains unclear. Previous studies have documented pain reduction in placebo groups, on the order of 6 to 7 mm on a 100-mm Table 2. Primary Outcomes (Intention-to-Treat Analyses).* Measure Vertebroplasty Group Control Group Treatment Effect (95% CI)† P Value† RDQ‡ At baseline 16.6±3.8 17.5±4.1 At 3 days 13.0±5.2 12.5±5.5 −0.9 (−2.7 to 0.8) 0.30 At 14 days 12.4±5.8 12.3±5.9 −0.6 (−2.4 to 1.2) 0.35 At 1 mo 12.0±6.3 13.0±6.4 0.7 (−1.3 to 2.8) 0.49 Pain intensity§ At baseline 6.9±2.0 7.2±1.8 At 3 days 4.2±2.8 3.9±2.9 −0.4 (−1.5 to 0.5) 0.37 At 14 days 4.3±2.9 4.5±2.8 0.1 (−0.8 to 1.1) 0.77 At 1 mo 3.9±2.9 4.6±3.0 0.7 (−0.3 to 1.7) 0.19 * Plus–minus values are means ±SD. † Between-group comparisons, confidence intervals, and P values were calculated with the use of analysis-of-covariance models with adjustment for studygroup assignment, baseline value of the outcome measure, and study center. Negative treatment effects favor the control procedure, and positive treatment effects favor vertebroplasty. ‡ Scores on the Roland–Morris Disability Questionnaire (RDQ) range from 0 to 23, with higher scores indicating more severe disability. § Scores on the pain-intensity scale range from 0 (no pain) to 10 (worst pain). The New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

The new england journal o f medicine 576 n engl j med 361;6 nejm.org august 6, 2009 33p9 100 Score 80 60 40 20 0 Vertebroplasty Control Baseline 1 Month A SF-36 Physical Component Summary Treatment effect: 1.0 (95% CI, −1.7 to 3.7) P=0.45 AUTHOR: FIGURE: JOB: 4-C H/T RETAKE SIZE ICM CASE EMail Line H/T Combo Revised AUTHOR; PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. REG F Enon 1st 2nd 3rd Kallmes 2 of 3 08-06-09 ARTIST: ts 36106 ISSUE: Vertebroplasty: 29.7±9.6 Control: 28.7±8.0 100 Score 80 60 40 20 0 Baseline 1 Month B SF-36 Mental Component Summary Treatment effect: 1.0 (95% CI, −3.7 to 4.6) P=0.83 Vertebroplasty: 46.9±12.0 Control: 45.6±14.8 4 Score 3 2 1 0 Baseline 1 Month C Pain Frequency Index Treatment effect: 0.2 (95% CI, −0.2 to 0.6) P=0.33 Vertebroplasty: 2.1±1.2 Control: 2.3±1.1 4 Score 3 2 1 0 Baseline 1 Month D Pain Bothersomeness Index Treatment effect: 0.2 (95% CI, −0.2 to 0.6) P=0.33 Vertebroplasty: 1.9±1.1 Control: 2.1±1.1 1.0 Score 0.8 0.6 0.4 0.2 0.0 Baseline 1 Month E EQ–5D Index Treatment effect: 0.05 (95% CI, −0.01 to 0.11) P=0.13 Vertebroplasty: 0.70±0.18 Control: 0.64±0.20 18 Score 15 12 9 6 3 0 Baseline 1 Month F SOF–ADL Treatment effect: 0.4 (95% CI, −0.8 to 1.6) P=0.51 Vertebroplasty: 7.7±3.7 Control: 8.2±3.6 G Opioid Use 100 Patients (%) 80 60 40 20 0 Baseline 1 Month Treatment effect: 1.15 (95% CI, 0.98 to 1.35) P=0.08 Vertebroplasty: 54% Control: 43% Figure 2. Secondary Outcome Measures at 1 Month (Intention-to-Treat Analyses). Prespecified secondary outcomes included mean (±SD) scores on the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), version 2, including both the Physical Component Summary (Panel A) and the Mental Component Summary (Panel B), the Pain Frequency Index (Panel C), the Pain Bothersomeness Index (Panel D), the European Quality of Life–5 Dimensions (EQ–5D) scale (Panel E), and the Study of Osteoporotic Fractures–Activities of Daily Living (SOF–ADL) scale (Panel F), as well as the proportion of patients who were taking any opioid analgesics (Panel G). Scores on the SF-36 range from 0 to 100, with lower scores indicating a worse outcome. Scores on the Pain Frequency Index and the Pain Bothersomeness Index range from 0 to 4, with higher scores indicating more severe pain. Scores on the EQ-5D scale range from −0.1 to 1.0, with higher scores indicating a better quality of life. Scores on the SOF–ADL scale range from 0 to 18, with higher scores indicating more back-related disability. For continuous outcome measures, treatments were compared with the use of analysis-of-covariance models with adjustment for study-group assignment, baseline value of the outcome measure, and study center, with all positive numbers favoring vertebroplasty. The treatment effect for opioid use is reported as an odds ratio from a logistic-regression model with adjustment for baseline opioid use and study center. The I bars denote 95% confidence intervals. The New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

Vertebroplasty for Osteoporotic Spinal Fractures n engl j med 361;6 nejm.org august 6, 2009 577 scale.34-36 The treatment effect in our trial was substantially larger than those in previous studies, even though the previous studies included both pharmacologic and psychological interventions in addition to physical interventions.34 There was a trend toward a higher proportion of patients in the vertebroplasty group with clinically meaningful improvement in pain at 1 month. Furthermore, there was a higher crossover rate in the control group than in the vertebroplasty group after 1 month. The reasons for the higher crossover rate are unknown. It is possible that more 33p9 A RDQ AUTHOR: FIGURE: JOB: 4-C H/T RETAKE SIZE ICM CASE EMail Line H/T Combo Revised AUTHOR; PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. REG F Enon 1st 2nd 3rd Kallmes 3 of 3 08-06-09 ARTIST: ts 36106 ISSUE: B Pain Intensity 20 Score 15 10 5 0 3 Days 3 Months 3 Months 1 Month 1 Month 10 Score 8 6 4 2 0 3 Days 14 Days 14 Days Follow-up Follow-up No. of Patients Control, adhered Vertebroplasty, adhered Control, crossover Vertebroplasty, crossover 36 60 27 8 36 59 27 7 35 59 27 7 35 59 26 8 34 56 27 8 Control, adhered Control, crossover Vertebroplasty, adhered Vertebroplasty, crossover Figure 3. Scores on Measures of Disability and Pain over a 3-Month Period. Scores on the Roland–Morris Disability Questionnaire (RDQ) range from 0 to 23, with higher scores indicating more severe disability (Panel A). Scores on the pain-intensity rating range from 0 (no pain) to 10 (worst pain) (Panel B). Patients were classified as having adhered to their random study-group assignment if they did not subsequently undergo the alternative procedure before the 3-month follow-up. Patients who underwent the alternative procedure during this period were said to have crossed over to the other study group. At 3 months, 8 patients (12%) in the vertebroplasty group and 27 patients (43%) in the control group had crossed over to the other group and had undergone the alternative procedure (P<0.001). The black vertical lines indicate the time when baseline measures were taken, and the colored vertical lines represent 95% confidence intervals. The New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved

The new england journal o f medicine 578 n engl j med 361;6 nejm.org august 6, 2009 patients in the control group than in the vertebroplasty group had unsatisfactory pain outcomes but that we were unable to detect this difference with our measure of pain intensity. However, we used a common, validated measure that has been shown to indicate responsiveness to clinical improvement. It is possible that vertebroplasty was more effective than the control intervention for a subgroup of patients; further research is needed to explore this possibility. Finally, it is possible that despite efforts to conceal study-group assignments, some patients became aware of their assigned intervention, and those who still had pain and learned that they were in the control group may have elected to cross over to the vertebroplasty group. Our study had several limitations. First, we allowed crossover at 1 month because both physicians and patients were reluctant to accept a longer period. This factor complicated the interpretation of between-group differences in outcomes after 1 month. However, there is evidence that nearly all the benefits of vertebral augmentation occur within the first month.37 In addition, since the half-life of bupivacaine is only 3 hours, any benefit from this drug would have disappeared at 1 month. Second, we did not compare the study groups with respect to other medical treatments that they received that might have affected their outcomes. Third, the persistence of pain after vertebroplasty or fracture healing may indicate causes of the pain other than fracture, a possibility that our baseline imaging excluded to a certain extent but not entirely. Fourth, even though there was no differential treatment effect according to the baseline duration of pain, a result that is consistent with our previous finding that the fracture age is not associated with the response to vertebroplasty,14 it remains possible that vertebroplasty is effective only for fractures of a certain age or healing stage. Finally, we limited our study to vertebroplasty and did not evaluate the efficacy of kyphoplasty, which is similar to vertebroplasty except that intraosseous balloons are inflated before cement infusion.38 In conclusion, at 1 month, clinical improvement in patients with painful osteoporotic vertebral fractures was similar among those treated with vertebroplasty and those treated with a simulated procedure. These data suggest that further studies should be undertaken to determine whether the long-term outcome is similar in the two groups, especially because our crossover study design limited our ability to shed light on the long-term efficacy of vertebroplasty. Supported by a grant (R01-AR49373) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Kallmes reports receiving consulting fees from Zelos Therapeutics and grant support from ArthroCare, Stryker, Cardinal, and Cook and serving as an unpaid consultant to Bone Support; Dr. Heagerty, receiving grant support from GlaxoSmithKline; Dr. Annesley-Williams, receiving lecture fees from Stryker; Dr. Ralston, receiving consulting fees from Procter & Gamble, Novartis, and Merck, lecture fees from Novartis and Procter & Gamble, and grant support from Novartis and Wyeth; and Dr. Jarvik, receiving consulting fees from HealthHelp and having an equity interest in PhysioSonics and Nevro. No other potential conflict of interest relevant to this article was reported. We thank Arash Ehteshami Rad at the Mayo Clinic; Tom Marshall and Clare Darrah at the Norfolk and Norwich University Hospital, Norwich, United Kingdom; Avery Evans and Selene Boutin at the University of Virginia; Juan Tejada and Vijay Bharati at Indiana University; Andy DeNardo and Judy Jackson at Indianapolis Methodist Hospital; Jonas Goldstein at Asheville Radiology Associates, Asheville, NC; and Sophie Clare at the University of Washington. References 1. McGraw JK, Cardella J, Barr JD, et al. Society of Interventional Radiology quality improvement guidelines for percutaneous vertebroplasty. J Vasc Interv Radiol 2003;14:827-31. 2. Alvarez L, Alcaraz M, Perez-Higueras A, et al. Percutaneous vertebroplasty: functional improvement in patients with osteoporotic compression fractures. Spine 2006;31:1113-8. 3. Diamond TH, Bryant C, Browne L, Clark WA. Clinical outcomes after acute osteoporotic vertebral fractures: a 2-year non-randomised trial comparing percutaneous vertebroplasty with conservative therapy. Med J Aust 2006;184:113-7. 4. Diamond TH, Champion B, Clark WA. Management of acute osteoporotic vertebral fractures: a nonrandomized trial comparing percutaneous vertebroplasty with conservative therapy. Am J Med 2003; 114:257-65. 5. Do HM, Kim BS, Marcellus ML, Curtis L, Marks MP. Prospective analysis of clinical outcomes after percutaneous vertebroplasty for painful osteoporotic vertebral body fractures. AJNR Am J Neuroradiol 2005;26:1623-8. 6. Kobayashi K, Shimoyama K, Nakamura K, Murata K. Percutaneous vertebroplasty immediately relieves pain of osteoporotic vertebral compression fractures and prevents prolonged immobilization of patients. Eur Radiol 2005;15:360-7. 7. Layton KF, Thielen KR, Koch CA, et al. Vertebroplasty, first 1000 levels of a single center: evaluation of the outcomes and complications. AJNR Am J Neuroradiol 2007;28:683-9. 8. McGraw JK, Lippert JA, Minkus KD, Rami PM, Davis TM, Budzik RF. Prospective evaluation of pain relief in 100 patients undergoing percutaneous vertebroplasty: results and follow-up. J Vasc Interv Radiol 2002;13:Suppl 1:883-6. 9. Peh WC, Gilula LA, Peck DD. Percutaneous vertebroplasty for severe osteoporotic vertebral body compression fractures. Radiology 2002;223:121-6. 10. Voormolen MH, Lohle PN, Lampmann LE, et al. Prospective clinical follow-up after percutaneous vertebroplasty in patients with painful osteoporotic vertebral compression fractures. J Vasc Interv Radiol 2006;17:1313-20. 11. Voormolen MH, Mali WP, Lohle PN, et al. Percutaneous vertebroplasty compared with optimal pain medication treatment: short-term clinical outcome of patients with subacute or chronic painful osteoThe New England Journal of Medicine Downloaded from nejm.org on October 19, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved