Kallmes 2009

Methods	Design: multicentre, two‐arm, randomised placebo‐controlled cross‐over trial; cross‐over to the other treatment group was allowed at 1 month or later if adequate pain relief was not achieved Setting: USA (5 centres), UK (5 centres) and Australia (1 centre) Timing: not reported Interventions: percutaneous vertebroplasty versus sham vertebroplasty (placebo) Sample size: initial sample size calculation of 250 participants was based upon an ability to detect a 2.5‐point difference on the Roland‐Morris Disability Questionnaire (RMDQ) and a 1‐point difference on the 0‐ to 10‐point pain intensity scale, with at least 80% power and a two‐sided type 1 error of 0.05. After early difficulty in recruitment and a planned interim analysis of the first 90 participants, target enrolment was reduced to 130 participants based upon accrual rates and revised power calculations. With 130 participants, there was more than 80% power to detect a 3‐point difference between groups on the RMDQ (assumed SD 6.7), and a 1.5‐point difference on the pain rating (assumed SD 2.7) at 1 month. Analysis: intention‐to‐treat analysis
Participants	Number of participants 1813 participants were screened for eligibility 1682 excluded (1382 did not meet inclusion criteria; 300 declined to participate) 131 randomised (68 to vertebroplasty and 63 to placebo) Data for 128 (67 (99%) for vertebroplasty with 1 crossing over before 1 month, and 61 (97%) for placebo with 2 crossing over before 1 month) available at 1‐month follow‐up Data for (64 (94%) for vertebroplasty with 8 (8/68, 12%) crossing over before 3 months, and 61 (97%) for placebo with 27 (27/63, 36%) crossing over before 3 months) available at the 3‐month follow‐up. Inclusion criteria Age 50 years or older One to three painful osteoporotic vertebral compression fractures between vertebral levels T4 and L5 Inadequate pain relief with standard medical therapy A current rating for pain intensity of at least 3 on a scale from 0 to 10 Duration of pain less than one year For fractures of uncertain age, bone oedema on MRI or increased vertebral‐body uptake on bone scan was required Exclusion criteria 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 Dementia Baseline characteristics Vertebroplasty group: Mean (SD) age: 73.4 (9.4) years; 53 female:15 male Mean (interquartile range; IQR) duration of back pain: 16 (10 to 36 weeks) Duration of back pain <14 weeks: 30 (44%) Mean (SD) baseline pain score: 6.9 (2.0) points Mean (SD) baseline RMDQ score: 16.6 (3.8) points Number with 1; 2; or 3 spinal levels treated: 48 (71%); 13 (19%); 7 (10%) Opioid use: 38 (56%) Placebo group: Mean (SD) age: 74.3 (9.6) years; 46 female:17 male Mean (interquartile range; IQR) duration of back pain: 20 (8 to 38 weeks) Duration of back pain <14 weeks: 24 (38%) Mean (SD) baseline pain score: 7.2 (1.8) points Mean (SD) baseline RMDQ score: 17.5 (4.1) points Number with 1; 2; or 3 spinal levels treated: 41 (65%); 14 (22%); 8 (13%) Opioid use: 40 (63%)
Interventions	Percutaneous vertebroplasty or the sham procedure was performed by highly experienced interventional radiologists having performed a mean of 250 procedures (range: 50 to 800). Procedures were performed in a fluoroscopy suite, under conscious sedation using sterile technique. 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. Vertebroplasty 11‐gauge or 13‐gauge needles were passed into the central aspect of the target vertebra or vertebrae. Barium opacified PMMA was prepared on the bench and infused under constant lateral fluoroscopy into the vertebral body. Infusion was stopped when the PMMA reached the posterior aspect of the vertebral body or entered an extraosseous space. Sham procedure Verbal and physical cues, such as pressure on the patient’s back, were given, and the methacrylate monomer was opened to simulate the odour associated with mixing of PMMA, but the needle was not placed and PMMA was not infused. Follow‐up care Both groups of patients were monitored in the supine position for 1 to 2 hours before discharge.
Outcomes	Outcomes were reported 3 and 14 days, and 1 month (and 3 months for the primary outcomes) and at various times up to one year. Primary outcomes Modified Roland‐Morris Disability Questionnaire (RMDQ) (23‐item version, 0 to 23 scale, with higher scores indicating worse physical functioning Average back pain intensity during the preceding 24 hours (0 to 10 scale, with higher scores indicating more severe pain) Secondary outcomes Pain Frequency Index and the Pain Bothersomeness Index (0‐ to 4‐point scale, higher scores indicating more severe pain) Study of Osteoporotic Fractures‐Activities of Daily Living (SOF‐ADL) scale (0‐ to 18‐point scale, higher scores indicating more disability) European Quality of Life‐5 Dimensions (EQ‐5D) scale (‐0.1‐ to 1.0‐point scale, higher scores indicating better quality of life) Use of opioid medications Physical Component Summary (PCS) and Mental Component Summary (MCS) subscales of the Medical Outcomes Study 36‐Item Short‐ Form General Health Survey (SF‐36), version 2 (0‐ to 100‐point score, higher scores indicate better outcome) Proportion with clinically important improvement in pain (at least 30% improvement) Proportion with clinically important improvement in disability (at least 30% improvement) Adverse events Outcomes included in this review Mean pain Disability as measured by the RMDQ Quality of life as measured by the EQ‐5D Proportion with clinically important improvement in pain (at least 30% improvement) Adverse events
Source of funding	Supported by a grant (R01‐AR49373) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Notes	Trial registered at ClinicalTrials.gov, number NCT00068822. For this review, we only extracted outcomes at 2 weeks and 1 month (i.e. before cross‐over, and thus prior to the likely breaking of the randomisation schedule). After 1 month, significantly fewer participants in the vertebroplasty group crossed over into the alternate group (11 of 68 participants (16%)) compared with the placebo (sham) group (38 of 63 participants (60%), P = 0.001). At one year, difference in pain favoured the vertebroplasty group (MD 1.02 (95% CI 0.04 to 2.01); P = .042) but there was no evidence of an important difference in disability (MD in RMDQ 1.37 points (95% CI 3.62 to 20.88), P = .231). In the as‐treated analyses, participants treated with vertebroplasty did not differ from the placebo (sham) group in terms of either mean pain (MD 0.85 (95% CI 2.05 to 20.35), P = .166) or disability (RMDQ MD 0.66 (95% CI 3.30 to 21.98); P = .625).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocked randomisation (sizes ranging from 4 to 12 participants), stratified by study centre; sequences were generated by a random‐number generator.
Allocation concealment (selection bias)	Low risk	Allocation occurred just prior to the procedure using numbered opaque envelopes.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Group assignments were concealed from participants and study personnel. Before one month one participant in the vertebroplasty group and two participants in the sham group crossed over to the other treatment group. By three months more participants in the placebo group had crossed over (27/63, 36%) compared with the vertebroplasty group (8/68, 12%) and the reasons for the different cross‐over rate is unknown ‐ while it is possible that more participants in the control group had unsatisfactory pain outcomes, no difference in pain intensity was observed. 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). 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. As we only considered outcomes to one month, we judged this trial to be at low risk of bias up until one‐month follow‐up.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (e.g., pain, disability)	Low risk	Participants were blinded to treatment assignment.
Blinding of outcome assessment (detection bias) Objective outcomes (e.g., radiographic outcomes)	Low risk	No objective outcomes were assessed up to one‐month follow‐up.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and balanced across treatment groups.
Selective reporting (reporting bias)	Low risk	All outcomes measured to 3 months planned in the published protocol were reported.
Other bias	Low risk	None apparent.