Buchbinder 2009

Methods	Design: multicentre (four sites), parallel group, two‐arm double‐blind randomised placebo‐controlled trial Setting: Melbourne, Australia Timing: April 2004 to October 2010 Interventions: percutaneous vertebroplasty versus sham vertebroplasty (placebo) Sample size: 24 participants per group required to detect at least a 2.5‐unit (SD 3) advantage of vertebroplasty over placebo in terms of pain (0 to 10 point scale), based on a two‐sided type 1 error rate of 5% and power 80%. Additional sample size calculation of 82 participants per group needed to show an increase by a factor of three in the risk of further vertebral fractures at 24 months. Original sample size was increased to 200 to allow for potential dropout. Trial enrolment terminated before reaching planned sample size for long‐term outcomes because it became evident that this sample size would not be achieved within an acceptable period of time and that the study’s power was sufficient to address the primary aim. This decision was made without knowledge of any outcome results. Analysis: intention‐to‐treat analysis
Participants	Number of participants 468 participants screened for eligibility 390 excluded (248 did not meet inclusion criteria; 141 declined to participate; 1 died) 78 randomised (38 to vertebroplasty and 40 to placebo) Data for 71 (35 (92%) for vertebroplasty and 36 (90%) for placebo) available at 6‐month follow‐up Data for 57 (29 (76%) for vertebroplasty and 28 (70% for placebo) available at the final 24‐month follow‐up Inclusion criteria Back pain of no more than 12 months duration. Presence of one or two recent vertebral fractures, defined as vertebral collapse of grade 1 or higher according to the grading system of Genant 1993 (in which vertebral collapse is graded on a scale of 0 to 3, with higher numbers indicating greater vertebral collapse). Bone oedema, a fracture line, or both within the vertebral body on magnetic resonance imaging (MRI) or positive bone scan if MRI contraindicated. Exclusion criteria Presence of more than two recent vertebral fractures. Spinal cancer. Neurologic complications. Osteoporotic vertebral collapse of greater than 90%, fracture through or destruction of the posterior wall, retropulsed bony fragment or bony fragments impinging on the spinal cord. Medical conditions that would make the patient ineligible for emergency decompressive surgery if needed. Previous vertebroplasty. Inability to give informed consent. Likelihood of noncompliance with follow‐up. Baseline characteristics Vertebroplasty group: Mean (SD) age: 74.2 (14.0) years; 31 female: 7 male Median (interquartile range (IQR)) duration of back pain: 9.0 (3.8 to 13.0) weeks Duration of back pain < 6 weeks: N = 12 (32%) Mean (SD) baseline pain score: 7.4 (2.1) Mean (SD) baseline QUALEFFO score: 56.9 (13.4) Mean (SD) RMDQ: 17.3 (2.8) Any medication for osteoporosis: N = 35 (92%); bisphosphonates: N = 31 (82%) Previous vertebral fractures: 18 (47%) Opioid use at baseline: 30 (79%) T score for bone mineral density (BMD) 2.5 or less at lumbar spine: 21/34; at femoral neck: 13/34 Placebo group: Mean (SD) age: 78.9 (9.5) years; 31 female: 9 male Median (IQR) duration of back pain: 9.5 (3.0 to 17.0) weeks Duration of back pain < 6 weeks: N = 13 (32%) Mean (SD) baseline pain score: 7.1 (2.3) Mean (SD) baseline QUALEFFO score: 59.6 (17.1) Mean (SD) RMDQ: 17.3 (2.9) Any medication for osteoporosis: N = 37 (92%); bisphosphonates: N = 32 (80%) Previous vertebral fractures: 21 (52%) Opioid use at baseline: 34 (85%)
Interventions	Percutaneous vertebroplasty or placebo (sham) procedure, performed by experienced interventional radiologists, who had formal training in vertebroplasty and appropriate certification. Vertebroplasty The left pedicle of the fracture site was identified with the use of a metallic marker. A 25‐gauge needle was used to infiltrate the skin overlying the pedicle and a 23‐gauge needle was used to infiltrate the periosteum of the posterior lamina. An incision was made in the skin, and a 13‐gauge needle was placed posterolaterally relative to the eye of the pedicle. Gentle tapping guided the needle through the pedicle into the anterior two thirds of the fractured vertebral body. Anterior‐posterior and lateral images were recorded with the needle in the correct position. Prepared PMMA (approximately 3 mL) was slowly injected into the vertebral body, infiltration of the vertebral body was confirmed radiographically. A bipedicular approach was used only if there was inadequate instillation of cement with the unipedicular approach. Injection was stopped when substantial resistance was met or when the cement reached the posterior quarter of the vertebral body; injection was also stopped if cement leaked into extraosseous structures or veins. All participants in the vertebroplasty group received cephalothin, administered intravenously immediately after PMMA injection. Sham procedure (placebo) The same procedures as those in the vertebroplasty group up to the insertion of the 13‐gauge needle to rest on the lamina. The central sharp stylet was then replaced with a blunt stylet. To simulate vertebroplasty, the vertebral body was gently tapped, and PMMA was prepared so that its smell permeated the room. Follow‐up care After the intervention, all participants received usual care. Treatment decisions were made at the discretion of the treating physician, who received up‐to‐date guidelines on the management of osteoporosis. Analgesia was given according to standard practice, and its use was recorded.
Outcomes	Outcomes were reported at 1 week, and 1, 3, 6, 12 and 24 months. Primary endpoint was 3 months. Primary outcome Mean overall pain over the course of the previous week (0 to 10, 0 is no pain and 10 is maximum pain) Secondary outcomes Quality of life, measured using the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) (0 to 100 scale, with lower scores indicating a better quality of life) Assessment of Quality of Life (AQoL) questionnaire, (0 to 1 scale, 1 indicates perfect health) European Quality of Life‐5 Dimensions (EQ‐5D) scale (0 to 1 scale, 1 indicates perfect health) Pain are rest (0 to 10 scale, 0 is no pain) Pain in bed at night (0 to 10 scale, 0 is no pain) Roland‐Morris Disability Questionnaire (RMDQ), modified 23‐item version (0 to 23 scale, higher scores indicate worse physical functioning) Participant global assessment of pain, fatigue and overall health, measured on 7‐point ordinal scales, ranging from a 'great deal worse' to a 'great deal better'; treatment success' defined as responses of “moderately better” or “a great deal better” were classified as successful outcomes. Adverse events Incident clinical fractures Incident radiographic fractures (12 and 24 months) Proportion with reduction in pain by ≥ 2.5 units (post‐hoc analysis requested by journal) Timed up‐and‐go test (baseline, 12 and 24 months) Outcomes included in this review Mean overall pain Disability as measured by the RMDQ Osteoporotic fracture‐specific Quality of Life as measured by the QUALEFFO EQ‐5D scale Adverse events Proportion with incident clinical fractures
Source of funding	The study was supported by grants from the National Health and Medical Research Council of Australia (284354), Arthritis Australia, the Cabrini Education and Research Institute, and Cook Australia. Cook Australia had no role in the design of the trial, the collection or analysis of the data, the preparation of the manuscript, or the decision to submit the manuscript for publication.
Notes	Trial registered at anzctr.org.au, number ACTRN012605000079640 on 5 August 2005.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocked randomisation (in permuted blocks of 4 and 6) were generated by computer‐generated random numbers; stratified according to treatment centre, sex and duration of symptoms (< 6 weeks or ≥ 6 weeks).
Allocation concealment (selection bias)	Low risk	Quote: "To ensure concealment of the assigned intervention, the treating radiologist received the opaque, sealed envelope containing the assigned intervention just prior to the procedure."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The participants and investigators, other than the treating radiologists, were unaware of treatment assignments. At 24 months 55 participants completed the assessment of blinding question. In the vertebroplasty group 16/29 believed they had received vertebroplasty, 2 believed they had received placebo and 11 were unsure; in the placebo group 8/26 believed they had received vertebroplasty, 7 believed they had received placebo and 11 were unsure. The Blinding Index was 0.59 (95% CI, 0.47–0.71), indicating adequate blinding at the end of the study.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (e.g., pain, disability)	Low risk	Participants (who assessed their pain, disability, quality of life and treatment success) were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Objective outcomes (e.g., radiographic outcomes)	High risk	Assessment of the timed up‐and‐go test was performed by a blinded outcome assessor at 12 and 24 months. Radiologists who assessed follow‐up radiographs and MRIs after 24 months were aware of treatment assignment as vertebroplasty cement is opaque and will be detected on imaging.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was small and equal across treatment groups for shorter‐term outcomes. There was complete follow‐up at one month for 35/38 from the vertebroplasty group (3 did not return questionnaire) and 38/40 from the sham group (2 did not return questionnaire); at 6 months this was 35/38 from the vertebroplasty group (2 died for reasons considered unrelated to the trial and 1 did not return their questionnaire), and 36/40 from the sham group (2 died for reasons considered unrelated to the trial and 2 did not return their questionnaires). Loss to follow‐up was greater for longer‐term outcomes. At two years, 29/38 (76%) participants in the vertebroplasty group had completed follow‐up (5 had died, 1 withdrew due to dementia and 3 did not return questionnaires), and 28/40 (70%) participants in the sham group completed follow‐up (7 had died, 1 withdrew due to illness and 4 did not return questionnaires).
Selective reporting (reporting bias)	Low risk	All outcomes planned in the published protocol were reported.
Other bias	Low risk	None apparent.