Dohm 2014

Methods	Design: multicentre, parallel group, two‐arm open randomised controlled trial including 75 sites Setting: USA and Canada Timing: October 2006 to May 2011 Interventions: percutaneous vertebroplasty versus balloon kyphoplasty Sample size: 1234 participants required to detect an 8.7% difference in subsequent radiographic fracture (40% in vertebroplasty, 31.3% in kyphoplasty), 20% withdrawal, 80% power and 5% type I error rate. Analysis: modified intention‐to‐treat analysis using all data available from the 381 participants randomised and treated (23 participants withdrew before receiving treatment, 15 assigned to vertebroplasty and 8 assigned to kyphoplasty)
Participants	Number of participants 3554 participants screened for eligibility 3150 excluded (2331 did not meet inclusion criteria; 412 declined to participate; 407 other reasons for being ineligible) 404 randomised (205 to vertebroplasty and 199 to kyphoplasty) 23 did not undergo treatment (15 vertebroplasty and 8 kyphoplasty) Data for 273 (143 (75%) for vertebroplasty and 130 (68%) for kyphoplasty) available at 12‐month follow‐up Data for 191 (100 (53%) for vertebroplasty and 91 (48% for kyphoplasty) available at the final 24‐month follow‐up Inclusion criteria Over 21 years old 1 to 3 acute painful vertebral fractures from T5 to L5 due to osteoporosis less than 6 months old Oedema on MRI, uptake on radionuclide bone scans, or acute vertebral height loss within 6 months by CT, MRI, or X‐ray. Treatment of all target VCFs is technically feasible and clinically appropriate for both procedures (vertebroplasty and balloon kyphoplasty) Pre‐treatment back pain score by NRS is > 4 (0‐10 scale) Pre‐treatment ODI is > 20 (0‐100 scale) Stated availability for all visits Participant understands the risks and benefits of participating in the trial and provides written consent Mental capacity to follow protocol for up to 2 years Exclusion criteria Back pain not attributable to vertebral fracture (e.g. sacroiliac fracture, symptomatic degenerative disc disease, lumbar spinal stenosis) Presence of more than three acute vertebral fractures Vertebral fractures more than 6 months old Fractures due to suspected or proven cancer or high‐energy trauma Requiring other procedures for fracture stabilisation Irreversible coagulopathy, bleeding disorder or known allergies to bone cement or contrast Local or systemic infection Any objective evidence of neurologic compromise at baseline Previous vertebroplasty or kyphoplasty Significant clinical comorbidity that may potentially interfere with long‐term data collection or follow‐up (e,g. dementia, severe comorbid illness Pregnant or wanting children within study period Baseline characteristics Vertebroplasty group: Mean (SD) age: 75.7 (10.5) years; 144 female: 46 male Duration of back pain: not stated Mean (SD) baseline pain score (from the trial registry website): 7.7 (1.8) out of 10 Mean (SD) baseline Oswestry Disability Index score (from the trial registry website): 57.8 (16) out of 100 Bisphosphonate use: N = 65 (34.2%) Opioid use at baseline: 126/169 (74.6%) T score for bone mineral density (BMD) less than ‐1: N = 133 (83.2%) Kyphoplasty group: Mean (SD) age: 75.5 (10.3) years; 151 female: 40 male Duration of back pain: not stated Mean (SD) baseline pain score (from the trial registry website): 7.8 (1.8) out of 10 Mean (SD) baseline Oswestry Disability Index score (from the trial registry website): 59 (17.5) out of 100 Bisphosphonate use: N = 75 (39.3%) Opioid use at baseline: 122/165 (73.9%) T score for bone mineral density (BMD) less than ‐1: N = 138 (83.6%)
Interventions	Specialist training of those performing the procedures was not reported. Investigator requirements were 50 lifetime procedures or 20 in the last year for each procedure. If an investigator only qualified for one of the procedures, they could participate as a team with an investigator qualified in the other technique. Tools and polymethylmethacrylate bone cement used were approved or cleared by the FDA for treating vertebral fractures by using kyphoplasty and vertebroplasty, respectively. Vertebroplasty Procedures were performed according to local practices and was not standardised across centres. Balloon kyphoplasty The procedure was performed by using a bilateral approach. Kyphon Osteo Introducer Systems, Inflatable Bone Tamps, HV‐R Bone Cement, Bone Filler Devices, and other balloon kyphoplasty devices were manufactured by Medtronic Spine, Sunnyvale, California. Both treatment groups In the results it is stated that investigators were to attempt vertebral deformity correction regardless of treatment; 142/189 (75.!%) participants in the vertebroplasty group and 154/191 (80.6%) participants in the kyphoplasty group had perioperative postural reduction.
Outcomes	Outcomes were reported at 7 days, 1, 3, 12 and 24 months after treatment Primary outcomes New radiographic vertebral fractures (including any new or worsening index fracture) according to the method of Genant 1993 at 12 and 24 months (Standing lateral spine radiographs baseline, post‐operatively, 3, 12, 24 months) Secondary outcomes Physical function and quality of life measured by the SF‐36 Physical Component Summary EuroQol‐5‐Domain (EQ‐5D) questionnaire Numeric rating scale for back pain (scale 0‐10, 0 indicates no pain and 10 being worst pain ever) (also measured on day 7) Back function measured by the modified Oswestry Disability Index (Section 8, regarding sexual activity was removed) ( score ranges from 0‐100. The best score is 0 (no disability) and worst is 100 (maximum disability) Vertebral kyphotic angulation by quantitative morphometry (angle formed by lines drawn parallel to the caudal and cranial fractured vertebral body endplates determined the kyphotic angulation) New clinical fractures (defined as subsequent painful vertebral fractures coming to clinical attention) Post‐procedure CT through treated levels was performed to determine cement volume and leakage All adverse events systematically classified into preferred terms and system organ class according to the Medical Dictionary for Regulatory Activities (MedDRA). Serious adverse events (SAEs) included death, serious deterioration in health, life‐threatening injury/illness, hospitalisation or prolonged hospitalisation, or requiring medical or surgical intervention. Rate of procedure/device related or possibly related serious adverse events at 30 days Amount of analgesic use Outcomes included in this review Mean pain Modified Oswestry Disability Index EQ‐5D New radiographic vertebral fractures New clinical vertebral fractures Serious other adverse events thought to be device/procedure/anaesthesia‐related
Source of funding	Medtronic Spine sponsored the study and contributed to study design, data monitoring, statistical analysis and reporting of results and paid for independent core laboratory and data safety‐monitoring board services.
Notes	Trial registered on 5 May 2006, registration number: NCT00323609. Known as ‘KAVIAR’ trial. Due to higher than anticipated withdrawal rate (38%), low patient enrolment, and patient/investigator willingness for randomisation, the sponsor terminated the study before reaching the planned sample size after enrolling 404 participants. This decision was made without knowledge of any outcome results. Enrolled participants left the study without additional follow‐up except that any not reaching the 1‐month visit were followed to collect 30‐day safety data. Outcomes reported in the published report differ from planned outcomes according to trial registration. Outcomes not reported in the published paper include SF‐36 Mental Component Summary, quality of life questionnaire (mini‐OQLQ), ambulatory status, change in vertebral body height; change in sagittal vertical axis; vertebral fracture‐related health care utilisation. Time to new clinical fracture reported in results but not listed as outcome in trial registration. We extracted the reported denominators for number of participants with new radiographic fractures at 12 and 24 months in each treatment group, which differed from the number of participants with complete follow‐up at these time points as reported in the flow diagram.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised by computer using a dynamic minimisation technique stratified by the number of prevalent vertebral fractures, aetiology and study centre. It is not clear how participants were stratified by aetiology as the inclusion criteria specified that participants have osteoporotic fractures (and people with fractures due to cancer or high‐energy trauma were excluded).
Allocation concealment (selection bias)	Unclear risk	It is not reported whether or not the random sequence was concealed from investigators prior to allocating a participant to treatment.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Treatment was not concealed from participants or investigators.
Blinding of outcome assessment (detection bias) Self‐reported outcomes (e.g., pain, disability)	High risk	Participants were told of their treatment group immediately following randomisation, this way may have influenced their assessment of self‐reported outcomes.
Blinding of outcome assessment (detection bias) Objective outcomes (e.g., radiographic outcomes)	High risk	It is not stated who assessed the imaging outcomes but it is unlikely that they were blinded to treatment assignment as both procedures will be detected on imaging. An independent radiologist determined cement volume and was not blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Loss to follow‐up was small and equal across treatment groups for short‐term outcomes. Follow‐up was completed at 1 month for 181/190 who underwent vertebroplasty (5 withdrew, 1 lost, 1 other medical reason, 1 logistical reasons, 1 died) and 180/191 who underwent kyphoplasty (4 withdrew, 1 lost, 1 other medical reason, 4 other reason, 1 died). However loss to follow‐up was greater for the primary endpoints measured at 12 and 24 months. At 12 months there was complete follow‐up for 130/190 (68%) in the vertebroplasty group (20 withdrew, 4 lost, 3 logistical reason, 2 other medical reason, 3 other reason, 1 due to unrelenting pain, 14 died, 13 sponsor terminated study) and 143/191 (75%) in the kyphoplasty group (11 withdrew, 4 lost, 3 other medical reason, 4 logistical reasons, 1 due to unrelenting pain, 5 other reason, 10 died, 10 sponsor terminated study). At 24 months, 91/190 (48%) participants in the vertebroplasty group had completed follow‐up (23 withdrew, 10 lost, 5 logistical reason, 7 other medical reason, 3 other reason, 1 due to unrelenting pain, 21 died, 29 sponsor terminated study), and 100/191 (52%)participants in the kyphoplasty group completed follow‐up (13 withdrew, 9 lost, 3 other medical reason, 9 logistical reasons, 1 due to unrelenting pain, 11 other reason, 16 died, 29 sponsor terminated study). Overall, the reasons for the losses were similar except a higher proportion who received their assigned treatment withdrew from the vertebroplasty group (20/190; 11%) compared to the kyphoplasty group (11/191; 6%). It is unclear if the reasons for withdrawal were systematically different. In the methods it is stated that seven participants who received vertebroplasty and 4 who received kyphoplasty underwent the alternate treatment for a subsequent vertebral fracture but the timing was not stated. It is stated that for any participant having surgery for a new vertebral fracture, the last observation before surgery was carried forward to later visits. In the results it is stated that 70/88 (79.5%) participants with a new clinically recognised fracture underwent a subsequent vertebral augmentation but these data are not presented by treatment group and the timing of further vertebral augmentation is not specified.
Selective reporting (reporting bias)	Low risk	All outcomes planned at trial registration were reported although on the trial registration site primary and secondary outcomes were modified after the trial was completed. Some outcomes not reported in the published paper (e.g. SF‐36 Mental Component Summary, quality of life questionnaire (mini‐OQLQ), ambulatory status, change in vertebral body height; change in sagittal vertical axis; vertebral fracture‐related healthcare utilisation) were reported in the trial registration report but not the published paper. Time to clinical fracture (in days) was reported but was not listed as an outcome in the trial registration.
Other bias	Unclear risk	The trial was sponsored by a device company. The company also contributed to study design, data monitoring, statistical analysis and reporting of results including manuscript authorship, paid for independent core laboratory and data safety‐monitoring board services, and terminated the study early.