VOPE 2015

Methods	Design: single centre two‐arm double‐blind randomised placebo‐controlled trial Setting: Denmark Timing: May 2011 to April 2014 Interventions: percutaneous vertebroplasty versus sham vertebroplasty (placebo). The thesis stated that cross‐over between groups was allowed after 3 months. Sample size:a priori sample size calculation of 80 participants based upon requiring 26 participants per group to detect a difference of 20 units in improvement in pain on a 0 to 100 VAS (SD 25 units), based on a two‐sided type 1 error rate of 5% and power 80% and allowing for dropouts. Sample size was reduced to 52 (26 per group) due to difficulties with recruitment (low willingness to participate). (NB unpublished manuscript in thesis differs to thesis text in sample size estimation. Unpublished manuscript indicates that sample size based upon requiring 23 participants per group to detect 20 units difference, SD 20 units). Analysis: completers' analysis (excluded 4 participants due to need for further spine surgery and 2 participants who were excluded prior to receipt of intervention due to malignant biopsies, treatment allocation not stated but based upon numbers four were from the vertebroplasty group and 2 were from the placebo group)
Participants	Number of participants 342 participants screened for eligibility 290 excluded (most due to unwillingness to participate in an RCT and symptom duration longer than 8 weeks) 52 randomised (26 to vertebroplasty and 26 to placebo) 46 participants (22 for vertebroplasty and 24 for placebo) 'eligible for statistical analysis' (2 excluded postoperatively due to malignant biopsies and 4 were excluded due to need for further spinal surgery during the first 3 months of follow‐up) Inclusion criteria (from trial registry) VCF on X‐ray of the spine (minimal 15% loss of height) level of VCF Th6 or lower Back pain ≤ 8 weeks at time of surgery ≥ 50 years of age Bone oedema on MRI of the fractured vertebral body Focal tenderness on VCF level Exclusion criteria (from trial registry) Severe cardio‐pulmonary condition Untreatable coagulopathy Systemic or local infection of the spine (osteomyelitis, spondylodisciitis) Suspected alternative underlying disease (malignancy) Radicular and/or cauda compression syndrome Contra‐indication for MRI Inclusion criteria (from thesis report) Vertebral fracture T6 to L5 Back pain less than 8 weeks Baseline pain at least 7 on a VAS score in either rest or activity MRI that included a STIR with oedema present Exclusion criteria (from thesis report) Previous malignant disease Age below 50 years Allergy of treatment substances Dementia evaluated by MMSE test (0‐30 points) with a cut‐off of 24 Fractures of other bones Unable to consent to the study Baseline characteristics Vertebroplasty group Mean (range) age: 70.59 (54 to 90) years; 18 female: 4 male Mean (SE) baseline pain score at rest: 40.55 (4.55) Mean (SE) baseline pain score with activity: 74.68 (4.55) BMD T‐score: ‐2.7 (0.25) Vertebral levels: T6 to L5, 27 levels treated Placebo group Mean (range) age: 69.33 (53 to 84) years; 22 female: 2 male Mean (SE) baseline pain score at rest: 53.04 (4.35) Mean (SE) baseline pain score with activity: 76.08 (4.35) BMD T‐score: ‐2.2 (0.254) Vertebral levels: T7 to L5, 28 levels treated
Interventions	Vertebroplasty All procedures were performed by spinal surgeons in the operating room. All vertebroplasties were performed under local anaesthesia using the V‐Max Mixing and Delivery System (DePuy Acromed, Leeds, England. Participants were placed prone on a Jackson table and lidocaine was used to anaesthetise the entry points. The 11‐gauge needles (Jamshidi needles) were then inserted in the fractured vertebral body via the pedicles under fluoroscopic guidance and a biopsy specimen was taken (not specified if uni‐ or bilateral pedicular approach). The PMMA cement was mixed and 2 mL of cement was injected into the pedicle under constant fluoroscopic guidance. The injection was stopped if the cement reached the posterior border of the vertebrae, showed signs of disc infiltration or the patient complained of leg symptoms. Placebo (sham vertebroplasty) The same procedure was performed for the placebo except that 2 mL of lidocaine (10 mg/mL) was injected into each Jamshidi needle (placed in the pedicle of the vertebral fracture as per the vertebroplasty group). The PMMA cement was mixed to create the odour similar to the vertebroplasty procedure. Both groups At inclusion, after a DEXA scan, all participants were commenced on treatment for osteoporosis. Prior to injecting either lidocaine of the PMMA, a needle biopsy was obtained (standard procedure at this site). Through the procedure, the staff in the operation room communicated minimally to ensure patients were unaware of the procedure performed.
Outcomes	Outcomes were reported at baseline, 6 hours, every week to 3 months, and 12 months The primary outcome was specified to be pain relief at 1 day, 1‐12 weeks, and 12 months. Both VAS and NRS were specified in the clinical trial registry. The thesis specifies both pain at rest and pain with activity on a VAS but not which was the primary endpoint. Outcomes (from the published thesis) Mean pain at rest on a VAS score (0 to 100), in a pain diary Mean pain during forward bending resembling a patient in activity on a VAS score (0 to 100), in a pain diary (not at 6 hours) Use of pain medication (opioids and frequency during the day and week) Danish version of SF‐36 (baseline, 3 and 12 months) Danish version of EQ‐5D (baseline, 3 and 12 months) Vertebral height of the fractured vertebrae from full standing spine radiographs, lateral view (baseline, 3 and 12 months) Kyphosis of the fractured vertebrae (baseline, 3 and 12 months) Number of new radiographic vertebral fractures (12 months) Major complications Additional outcomes in the trial registration: Lung capacity (spirometer) at 3 and 12 months Outcomes used in the review Mean pain during forward bending resembling a patient in activity (we used this outcome for the main comparison as overall pain was not measured and this outcome was specified in our a priori hierarchy of pain measures after unspecified pain) Quality of life: EQ‐5D Number of new radiographic vertebral fractures as 12 months
Source of funding	The primary sponsor was Sygehus Lillebaelt, Denmark (Hospital). The secondary sponsor was Odense University Hospital.
Notes	Trial registration: NCT01537770 and EUCTR2010‐024050‐10‐DK Abstract (no numerical data reported): http://journals.sagepub.com/doi/abs/10.1055/s‐0036‐1582763, Global Spine J 2016; 06 ‐ GO106 Thesis cited: http://www.forskningsdatabasen.dk/en/catalog/2371744560; full text copy of the thesis provided by the author. No participants crossed over between treatment groups during this study. As SF‐36 physical function may be conceptually different to RMDQ and other back‐specific disability measures we did not combine it with other disability measures in our meta‐analysis. However no between‐groups differences were reported for SF‐36 at any time point. The amount and frequency of opioid use also did not differ between groups over time.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomisation was a block randomisation design using 52 envelopes". No further details were reported.
Allocation concealment (selection bias)	Low risk	The randomisation envelope was opened after the bone biopsy had been taken.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants were blinded to treatment allocation. Throughout the procedure there was minimal communication with the participants and operating room staff. The primary investigator of the trial (EH) performed all screening procedures and follow‐up examinations and was blinded to the participant's assigned treatment arm throughout the study period. Success of blinding was not assessed. The biostatistician was also blinded to treatment allocation when performing the analysis.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (e.g., pain, disability)	Low risk	Participants were unaware of treatment assignment.
Blinding of outcome assessment (detection bias) Objective outcomes (e.g., radiographic outcomes)	High risk	Radiologists who assessed follow‐up radiographs at 3 and 12 months were aware of treatment assignment as vertebroplasty cement is opaque and will be detected on imaging.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Six of the 52 participants were not included in the analysis (4/26 (6.5%) in the vertebroplasty group and 2/26 (3.3%)in the placebo group. Of these, 2 were excluded due to malignant biopsies and 4 were excluded due to the need for further spinal surgery during the period of follow‐up but their treatment allocation was not reported.
Selective reporting (reporting bias)	Unclear risk	NRS pain data and spirometry were not reported. It is not clear whether pain at rest or with forward bending to resemble a patient in activity was the primary endpoint.
Other bias	Unclear risk	Thesis published in 2015 and includes an unpublished manuscript. Baseline pain at rest in the vertebroplasty group was lower than in the placebo group (40.55 (SE 4.55) compared with 53.04 (SE 4.35), P = 0.0476, although pain with activity was similar between groups (vertebroplasty 74.68 (SE 4.55), placebo 76.08 (SE 4.35)).