Methods

Design: Single‐centre parallel group, two‐arm open‐label randomised controlled trial

Setting: Patients recruited from primary care centres, Spain

Timing: April 2006 to Jan 2010

Intervention: Percutaneous vertebroplasty and usual care versus usual care alone

Sample size: 64 patients required per group to have 80% power to detect a difference of at least 1.5 units on a 0‐10 VAS between groups in primary pain endpoint; overall type‐1 error rate was set at 5%

Analysis: Intention‐to‐treat analysis

Participants

Number of participants

• 219 patients screened for eligibility

• 94 excluded (55 did not meet inclusion criteria, 14 declined participation and 25 had other reasons)

• 125 randomised (64 to vertebroplasty and 61 to usual care)

• Data for 110 (54 (84%) for vertebroplasty and 56 (92%) for usual care) available at the 2‐month follow‐up

• Data for 95 (47 (73%) for vertebroplasty and 48 (79% for usual care) available at the final 12‐month follow‐up

Inclusion criteria

1. Acute, painful osteoporotic vertebral fracture from T4 to L5 with clinical onset < 12 months confirmed by spine radiograph and oedema present on MRI or positive bone scan if MRI contraindicated

2. Pain at least 4 on a 0‐10 VAS where higher scores indicated worse pain

Exclusion criteria

1. Untreatable coagulopathy

2. Active local or systemic infection

3. Current malignancy

4. Vertebral canal occupation by a fragment of the vertebral body

5. Non‐osteoporotic vertebral fracture

6. Active associated disorders such as fibromyalgia or spondyloarthropathies

7. Other disorders (such as dementia) that affect quality of life or pain assessment

Baseline characteristics

Vertebroplasty group (64 participants):

Mean (SD) age: 71.33 (9.95); 47 female, 17 male

Mean (SD) duration of back pain: 140.3 (96.09) days

Number (%) participants with symptom onset < 6 weeks: 2 (3%)

Number (%) participants with symptom onset < 4 months: 32 (50%)

Mean (SD) number of vertebral fractures at baseline: 3.55 (2.82)

Mean (SD) baseline pain score 7.21 (0.33) on a 0‐10 VAS (higher score indicates worse pain)

Mean (SD) QUALEFFO‐41 score: 65.19 (2.23) on a 0 to 100 scale (higher score indicates worse quality of life)

Usual care group (61 participants):

Mean (SD) age: 75.27 (8.53); 50 female, 11 male

Mean (SD) duration of back pain: 143.1 (130.33) days

Number (%) participants with symptom onset < 6 weeks: 4 (7%)

Number (%) participants with symptom onset < 4 months: 32 (52.5%)

Mean (SD) number of vertebral fractures at baseline: 3.02 (2.14)

Mean (SD) baseline pain score: 6.31 (0.35)

Mean (SD) QUALEFFO‐41 score: 59.17 (2.17)

Interventions

Vertebroplasty group

Percutaneous vertebroplasty was performed by an experienced interventional neuroradiologist.

A 25‐gauge needle was used to infiltrate the skin overlying the pedicle and to infiltrate the periosteum of the posterior lamina. Using a bilateral transpedicular approach a 10‐ or 13‐gauge needle was inserted posterolaterally relative to the eye of the pedicle, and through gentle tapping the needle penetrated the pedicle into the anterior two‐thirds of the fractured vertebrae and polymethylmethacrylate cement was injected. Following the procedure, participants were strictly rested in bed for 6 hours. Standardised analgesics were given as necessary and nasal calcitonin was given for the first month.

Usual care group

All participants received analgesics with a standardised format and nasal calcitonin for the first month. In case of no improvement in pain, the participant was considered for vertebroplasty (timing of decision not specified).

Both groups

When treatment in either group was ineffective (defined as pain 7 or more out of 10) or there was an intolerance to drug therapy, participants were offered rescue therapy consisting of an intrathecal infusion of 25 μg fentanyl and 1.5 mg buprivacaine.

After one month, both treatment groups began or continued treatment with bisphosphonates (or teriparatide or strontium ranelate if there was an intolerance to bisphosphonates), prescribed by the attending physician.

Outcomes

Participants were assessed at baseline, 2 weeks, and at 2, 6 and 12 months.

Outcomes

1. Pain measured on a 0 to 10 VAS (0 indicates no pain and 10 is maximum pain)

2. Number of participants with moderate (pain ≥ 4) or severe (pain ≥ 7) pain at 12 months

3. Quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO‐41), scores range from 0 to 100, with lower scores indicating a better quality of life

4. Analgesic consumption (nil, minor analgesics and/or NSAIDs, minor opioid derivatives, major opioid derivatives)

5. Radiologically apparent incident vertebral fractures measured at 6 and 12 months, defined as a reduction of 20% or more in the anterior, middle or posterior height of the vertebral body compared with adjacent undeformed vertebrae

6. Clinically apparent incident vertebral fractures confirmed on MRI at any time during follow‐up

7. Bone densitometry (dual X‐ray absorptiometry [DXA] measured at baseline and 12 months

8. Number of participants who received rescue therapy (intrathecal infusion with 25 μg and 1.5 mg bupivacaine)

9. Height

10. Weight (not reported in the paper)

11. Cement leakage during procedure

Outcomes included in this review

1. Pain

2. QUALEFFO

3. Incident vertebral fractures

Source of funding

Fundacio La Marato de TV3, the Spanish Society of Medical Radiology and the Catalan Society of Rheumatology

Notes

Trial registered on 13 Oct 2009 at ClinicalTrials.gov, registration number NCT00994032.

We extracted pain and quality of life data at 2 weeks, 2 months (pooled with the 3‐month outcome data from other trials), 6 and 12 months. These outcomes were reported in graphical format only; we extracted the mean and 95% confidence intervals from the graphs (http://plotdigitizer.sourceforge.net/) and converted 95% CI to SD.

Adverse events were only reported for vertebroplasty. It is not reported if any adverse events occurred with usual care.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Performed using a computer‐generated random list.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Neither participants nor personnel were blinded.

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

High risk

Participants assessed their pain and quality of life and were not blinded.

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

High risk

Rheumatologists who assessed radiographs and MRIs were not blinded.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

The proportion lost to follow‐up was similar between groups at the 12‐month follow‐up (17/64 or 27% from vertebroplasty and 13/61 or 21% from usual care), although the authors report that the losses may not have been random, but related to worse pain in the usual care group.

Selective reporting (reporting bias)

Unclear risk

Adverse events reported for vertebroplasty group; it is unclear if any adverse events occurred in the usual care group; mean pain and quality of life and confidence intervals were reported graphically only.

Other bias

Low risk

None apparent.

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

1. Back pain of no more than 12 months duration.

2. 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).

3. 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

1. Presence of more than two recent vertebral fractures.

2. Spinal cancer.

3. Neurologic complications.

4. 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.

5. Medical conditions that would make the patient ineligible for emergency decompressive surgery if needed.

6. Previous vertebroplasty.

7. Inability to give informed consent.

8. 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) RDQ: 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) RDQ: 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

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

1. Mean overall pain over the course of the previous week (0 to 10, 0 is no pain and 10 is maximum pain)

Secondary outcomes:

1. 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)

2. Assessment of Quality of Life (AQoL) questionnaire, (0 to 1 scale, 1 indicates perfect health)

3. European Quality of Life‐5 Dimensions (EQ‐5D) scale (0 to 1 scale, 1 indicates perfect health)

4. Pain are rest (0 to 10 scale, 0 is no pain)

5. Pain in bed at night (0 to 10 scale, 0 is no pain)

6. Roland‐Morris Disability Questionnaire (RDQ), modified 23‐item version (0 to 23 scale, higher scores indicate worse physical functioning)

7. 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.

8. Adverse events

9. Incident clinical fractures

10. Incident radiographic fractures (12 and 24 months)

11. Proportion with reduction in pain by ≥ 2.5 units (post‐hoc analysis requested by journal)

12. Timed up and go test (baseline, 12 and 24 months)

Outcomes included in this review:

1. Mean overall pain

2. Disability as measured by the RMDQ

3. Osteoporotic fracture‐specific Quality of Life as measured by the QUALEFFO EQ‐5D scale

4. Adverse events

5. 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

"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.

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.

Methods

Design: Single‐centre parallel group, two‐arm open‐label randomised controlled trial

Setting: Shanghai, China

Timing: Jan 2007 to Dec 2012

Interventions: Percutaneous vertebroplasty or usual care

Sample size:A priori sample size calculation not reported

Analysis: Completers' analysis

Participants

Number of participants

Numbers screened for eligibility and number excluded or declined to participate is not stated.

• 96 participants randomised (46 to vertebroplasty and 50 to usual care)

• Data for 89 (46 (100%) for vertebroplasty and 43 (86%) for usual care) available at 12‐month follow‐up although it is stated that 3 (6.5%) participants assigned to vertebroplasty group were lost to follow‐up.

• Four participants who were assigned to conservative care refused treatment and received vertebroplasty at the 3‐month follow‐up and another 3 were lost to follow‐up. These participants were excluded from the analysis.

Inclusion Criteria

1. Chronic osteoporotic compression spinal fractures on MRI (low signal on T1‐weighted and high signal on T2‐weighted scans) and persistent back pain for at least 3 months were enrolled. No other inclusion criteria were specified and no exclusion criteria were specified

Baseline characteristics:

Vertebroplasty group (n = 46):

Mean (SD) age: 64.6 (9.1) years; 32 female:14 male

Duration (SD) of back pain: 7.07 (3.00) months

Mean (SD) number of vertebral fractures at baseline 2.28 (1.00)

Mean (SD) baseline pain score: 6.5 (0.9)

N (%) use of osteoporotic drugs: 12 (26%)

Bone density T score (SD): ‐3.02 (0.80)

Usual care group (n = 43):

Mean (SD) age: 66.5 (9.1) years; 30 female:13 male

Duration (SD) of back pain: 6.81 (2.51) months

Mean (SD) number of vertebral fractures at baseline 2.00 (0.09)

Mean (SD) baseline pain score: 6.4 (0.9)

N (%) use of osteoporotic drugs: 18 (42%)

Bone density T score (SD): ‐3.00 (0.44)

Interventions

Percutaneous vertebroplasty performed by orthopaedic surgeons.

Vertebroplasty

All procedures were performed under local anaesthesia and undertaken on a single plane angiography system under fluoroscopic guidance in the operating theatre. The patient was placed in a prone position on the operating table. After local anaesthesia, a small incision was made with a scalpel blade. Thereafter, a bone puncture needle (13 G, Cook Medical, Bloomington, IN, USA) was placed transpedicularly in the fractured vertebra. After removal of the inner needle, commercially available polymethyl methacrylate (PMMA) (Osteo‐Firm, Cook Medical) was carefully injected into the fractured vertebra under continuous fluoroscopic monitoring via lateral and anteroposterior (AP) projections in order to ensure adequate lesion filling and to avoid PMMA leakage or migration into the venous system Injection was ceased when substantial resistance was met or when the cement reached the cortical edge of the fractured vertebral body; injection was also stopped if cement leaked into extraosseous structures or veins. In general, a total of 3–5 mL of PMMA was injected into the fractured vertebral body.
Post‐procedural fluoroscopic evaluation was obtained to show optimal filling of the lesion with no evidence of PMMA extravasation.

Vertebroplasty was also performed with one or more procedures on other fractures seen on MRI at adjacent levels above and below the chronic osteoporotic compression fractures to prevent new fractures. After the procedure, a CT scan of the treated vertebral bodies was done with 2 mm slices to identify the distribution of cement in the lesion, cement leakage outside the vertebral body, or other local complications.

Conservative care

Participants in the conservative care group were hospitalised and offered brace treatment, analgesia, general mobilising physiotherapy and treatment for osteoporosis including calcitriol and alendronate.

Outcomes

Outcomes were reported at 1 day, 1 week, and 1, 3, 6 and 12 months after treatment

Primary outcomes

1. Pain relief on a 0 to (no pain) to 10 (the worst pain imaginable) cm VAS scale.

Secondary outcomes

1. Capacity for walking, standing and sleeping, as measured by the Oswestry Low Back Disability Index (ODI) [range of total score not reported but presumably was 0 to 100 scale (0 is no disability)]

2. Physical function measured by the physical function items of the Roland Morris Questionnaire [range of total score not reported and trialists reported that this was a measure of quality of life]

3. Use of analgesia which was interpreted to mean 'incomplete pain relief' [no use of analgesia was interpreted to mean 'complete pain relief']

4. Hospital stay

5. Outpatient visits

6. Medical aids

7. Incidence of new symptomatic vertebral fractures (at 24 months)

8. AP and lateral spine radiographs at 1, 6 and 12 months ‐ reason not reported

9. Computed tomography scans 3 days after vertebroplasty to study cement distribution or extravasations

10. MRI at 3 and 12 months in all participants ‐ reason not reported

11. New vertebral fractures

12. Cement leakage in the vertebroplasty group and any clinical sequelae

Outcomes included in this review:

1. Mean pain

2. RMDQ

3. Vertebral fractures

Source of funding

Not reported.

Notes

There is no record of trial registration.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

The method of randomisation was not described and there was an uneven treatment allocation (46 participants allocated to receive vertebroplasty group and 50 participants allocated to receive conservative treatment) which was unexplained. 'Patients were randomly allocated to receive either vertebroplasty or conservative treatment.'

Allocation concealment (selection bias)

High risk

No information was provided about whether or not treatment allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants and investigators were aware of treatment allocation. It is not clear if participants in the percutaneous vertebroplasty group were offered treatment for osteoporosis.

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

High risk

Participants assessed their pain and function and were not blinded.

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

High risk

It is not stated who assessed the imaging outcomes. It is unlikely that they were blinded to treatment assignment as vertebroplasty cement is opaque and will be detected on imaging.

Incomplete outcome data (attrition bias)
All outcomes

High risk

No flow diagram is provided. Of the 50 participants allocated to receive conservative care, four refused conservative treatment and decided to have vertebroplasty at the 3 month follow‐up and an additional three were lost to follow‐up. Results are presented for only 43 participants. The authors state that of the 46 participants allocated to receive vertebroplasty, four were lost to follow‐up but they appear to perform the analysis on all 46 participants to 12 months.

Selective reporting (reporting bias)

Unclear risk

The one‐day outcomes are only reported for mean pain. Hospital stay, outpatient visits and medical aids were not reported. The trial does not appear to have been registered and no trial protocol is published.

Other bias

Unclear risk

It is not clear how many 'prophylactic' procedures were performed in the vertebroplasty group. The source of funding is not specified.

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

1. Over 21 years old

2. 1 to 3 acute painful vertebral fractures from T5 to L5 due to osteoporosis less than 6 months old

3. Oedema on MR imaging, uptake on radionuclide bone scans, or acute vertebral height loss within 6 months by CT, MRI imaging, or X‐ray.

4. Treatment of all target VCFs is technically feasible and clinically appropriate for both procedures (vertebroplasty and balloon kyphoplasty)

5. Pre‐treatment back pain score by numerical rating scale is > 4 (0‐10 scale)

6. Pre‐treatment Oswestry Disability Index is > 20 (0‐100 scale)

7. Stated availability for all visits

8. Participants understands the risks and benefits of participating in the trial and provides written consent

9. Mental capacity to follow protocol for up to 2 years

Exclusion criteria

1. Back pain not attributable to vertebral fracture (e.g., sacroiliac fracture, symptomatic degenerative disc disease, lumbar spinal stenosis)

2. Presence of more than three acute vertebral fractures

3. Vertebral fractures more than 6 months old

4. Fractures due to suspected or proven cancer or high‐energy trauma

5. Requiring other procedures for fracture stabilisation

6. Irreversible coagulopathy, bleeding disorder or known allergies to bone cement or contrast

7. Local or systemic infection

8. Any objective evidence of neurologic compromise at baseline

9. Previous vertebroplasty or kyphoplasty

10. Significant clinical comorbidity that may potentially interfere with long‐term data collection or follow‐up (e.g., dementia, severe comorbid illness

11. 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

1. 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

1. Physical function and quality of life measured by the SF‐36 Physical Component Summary

2. EuroQol‐5‐Domain (EQ‐5D) questionnaire

3. Numeric rating scale for back pain (scale 0‐10, 0 indicates no pain and 10 being worst pain ever) (also measured on day 7)

4. 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)

5. 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)

6. New clinical fractures (defined as subsequent painful vertebral fractures coming to clinical attention)

7. Post‐procedure CT through treated levels was performed to determine cement volume and leakage

8. All adverse events systematically classified into preferred terms and system organ class according to the Medical Dictionary for Regulatory Activities (MedDRA).

9. Serious adverse events (SAEs) included death, serious deterioration in health, life threatening injury/illness, hospitalisation or prolonged hospitalisation, or requiring medical or surgical intervention.

10. Rate of procedure/device related or possibly related serious adverse events at 30 days

11. Amount of analgesic use

Outcomes included in this review:

1. Mean pain

2. Modified Oswestry Disability Index

3. EQ‐5D

4. New radiographic vertebral fractures

5. New clinical vertebral fractures

6. 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 were terminated 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)

High 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 allocation 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.

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 health care 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.

Methods

Design: Two‐arm open‐label single centre quasi‐randomised controlled trial

Setting: Germany

Timing: Not stated

Interventions: Percutaneous vertebroplasty, balloon kyphoplasty or shield kyphoplasty

Sample size:A priori sample size calculation not reported

Analysis: Completers' analysis

Participants

Number of participants

• Numbers screened for eligibility and number excluded or declined to participate is not stated.

• 66 participants quasi‐randomised (22 to each of the three groups)

• Data for 59 (21/22 (%) for vertebroplasty, 20/22 (%) for balloon kyphoplasty and 18/22 (%) for shield kyphoplasty available at the 6‐month follow‐up.

• Two participants were deceased at the time of follow‐up and five refused to participate and these participants were excluded from the analysis.

Inclusion criteria

1. Patients with osteoporosis proven on DXA scan

2. Fresh painful single‐level vertebral fracture in middle and lower thoracic spin.

3. Symptom duration 6 weeks or less

4. Magnetic resonance imaging demonstrating oedema in the affected vertebral body

5. Conservative treatment (analgesics according to the WHO scheme, physiotherapy, physical therapy, orthotics adjustment) ineffective for at least 4 weeks

6. Provoked percussion pain in the spinous process agreed with the site of the radiologically proven compression fracture

Exclusion criteria

1. No painful vertebral deformation or considerable degenerative damage

2. Vertebral deformation (e.g. vertebra plana)

3. Tumour and metastasis

4. Local or systemic infection

5. Untreated clotting disorder

Baseline characteristics:

Vertebroplasty group (n = 21/22):

Mean (range) age: 71.3 (63‐77) years; 12 female:8 male (gender of one participant not specified)

Prevalent vertebral fractures at baseline: 1

Mean (SD) baseline pain score: 78.2 (9.36)

Mean (SD) baseline Oswestry Disability Index: 68.2 (5.7)

Balloon kyphoplasty (n = 20/22):

Mean (range) age: 63.3 (53‐77) years; 14 female:6 male

Prevalent vertebral fractures at baseline: 1.25 (range 1 ‐ 3)

Mean (SD) baseline pain score: 90.0 (7.07)

Mean (SD) baseline Oswestry Disability Index: 77.0 (4.2)

Shield kyphoplasty (n = 18/22):

Mean (range) age: 67.1 (47‐79) years; 14 female:4 male

Prevalent vertebral fractures at baseline: 1.14 (range 1‐2)

Mean (SD) baseline pain score: 88.16 (15.06)

Mean (SD) baseline Oswestry Disability Index: 75.7 (9.1)

Interventions

All procedures were performed by the same orthopaedic surgeon under biplane fluoroscopy and general anaesthesia.

Vertebroplasty

This was performed through a unipedicular transpedicular approach with one 13‐gauge bone biopsy needle (Stryker) placed in the anterior third of the vertebral body. Once the needle was in place, liquid and powder PMMA (high viscosity SpinePlex, Stryker, Germany) were mixed to toothpaste consistency. Under biplane guidance, the cement was injected through the needle until the vertebral body was filled in the posterior 25% or until there was leakage. No postural manoeuvre was performed to retain alignment before or during the procedure.

Balloon kyphoplasty

This was also performed through a unipedicular approach with a unilateral working cannula and standard kyphoplasty equipment (high viscosity KyphX HV‐R, Medtronic, Germany). A drill passing through the cannula created a tract for the 20‐mm balloon to be inserted in the centre of the vertebral body. Cement, mixed according to the manufacturer's recommendations, was injected as described for vertebroplasty. Injection was usually about 14 minutes after start of mixing.

Shield kyphoplasty

The Soteira shield kyphoplasty is a percutaneous minimally invasive system that enables a fractured vertebral body to be accessed through a unipedicular approach. The implant site was prepared by manually creating a cavity, and bone cement (Soteira, high viscosity) was delivered via an implantable cement director, the Shield Implant. This is a hollow, self‐expandable, coated implant that is marketed in a range of sizes and is attached to a disposable delivery system.

Follow‐up

All participants were discharged 2 days after surgery. All participants received daily standard doses of oral aminobisphosphonate, 1000 mg calcium and 1000 IU vitamin D3. In addition, physiotherapy and pain medication was prescribed as required.

Outcomes

Outcomes were reported immediately postoperatively and a mean of 5.8 months (range: 4 to 7 months) after treatment.

Primary outcomes

1. Mean pain, measured on a VAS scale (scale not specified but appeared to be on a 0 to 100 scale).

2. Mean disability, measured by the Oswestry Low Back Disability Index (ODI), 0 to 100 scale (0 is no disability)

Secondary outcomes

1. Beck Index (assesses vertebral height)

2. Surgery and fluoroscopy times

3. Dose‐area product (cGy x cm²)

4. Cement leakage

5. Incidence of new adjacent vertebral fractures

6. Other adverse events

Outcomes included in this review:

1. Mean pain

2. Disability as measured by the ODI

3. Incidence of new vertebral fractures

4. Adverse events

Source of funding

BioMedEs funded translation and copyediting. It is not reported whether or not other funding was received.

Notes

Trial registration: Not found.

The authors stated that there were no significant differences in baseline characteristics between groups but the review authors judged there to be significant pre‐treatment group differences: there were significant differences between groups with respect to age (mean age of participants in the vertebroplasty group was greater than the other groups) and participants allocated to the kyphoplasty groups appeared to have worse scores for pain and ODI at baseline compared with the vertebroplasty group.

We extract data to compared vertebroplasty to balloon kyphoplasty only.

We converted the 0 to 100 pain scale to a 0 to 10 pain scale for the purposes of pooling data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

'The included participants were distributed quasi‐randomly into three groups.'

Allocation concealment (selection bias)

Unclear risk

Quasi‐random method of allocation likely precluded concealment of sequence to the single investigator who allocated the participants to treatment as it was probably predictable.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Participants were blinded to treatment allocation. A single investigator who performed all procedures was not blinded to treatment allocation.

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

Low risk

Pain and disability was self‐assessed by participants who were unaware of their treatment allocation. Another orthopaedic surgeon not involved in the primary surgery performed the final follow‐up.

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

High risk

Images were analysed by the (unblinded) orthopaedic surgeon who performed the procedures, as well as by a radiologist. It is not reported whether or not the radiologist was blinded to treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Data were unavailable for 7 participants (two deaths and five participants who refused follow‐up: treatment group not specified, however data were not reported for 1 participant in the vertebroplasty, 2 in the balloon kyphoplasty group and 4 in the shield kyphoplasty group).

Selective reporting (reporting bias)

Unclear risk

Trial not registered and trial protocol was not published. All outcomes listed in the methods are reported.

Other bias

Unclear risk

Participants in the vertebroplasty group were older on average than participants in other groups (71.3 versus 63.3 and 67.1 years in the balloon and shield vertebroplasty groups respectively).

Participants in the kyphoplasty groups also appeared to have worse pain and disability scores at baseline compared to the vertebroplasty group (vertebroplasty: 78.2 and 68.2; balloon kyphoplasty: 90.0 and 77.0; and shield kyphoplasty 88.16 and 75.7 respectively).

It is not clear if BioMedEs had any role in the study other than funding translation and copyediting.

Methods

Design: Two‐arm open‐label randomised controlled trial; control group allowed to cross‐over into vertebroplasty group from one month (cross‐overs < 2 months = 4, < 6 months = 3, <12 months = 3, < 36 months = 10)

Setting: Iran

Timing: Sept 2004 to Jan 2009

Interventions: Percutaneous vertebroplasty or usual care

Sample size:A priori sample size calculation not reported

Analysis: Reported to be an intention‐to‐treat analysis

Participants

Number of participants

• 105 screened for eligibility

• 23 excluded (20 did not meet inclusion criteria and 2 declined to participate)

• 82 patients were randomised (40 to vertebroplasty and 42 to usual care)

• Data for 82 (40 (100%) for vertebroplasty and 42 (100%) for usual care) available at 6‐month follow‐up but 3 (7%) participants assigned to usual care received vertebroplasty before the 6‐month follow‐up

• Data for 76 (37 (93%) for vertebroplasty and 39 (93%) for usual care) available at the final 36‐month follow‐up but 10 (24%) participants assigned to usual care received vertebroplasty before the 36‐month follow‐up

Inclusion Criteria

1. Severe back pain refractory to analgesic medication (analgesics or NSAIDs) for at least 4 weeks and no longer than 1 year

2. Vertebral compression fracture with 10%–70% loss of vertebral body height on X‐ray of the spine

3. Focal tenderness on physical examination at the level of vertebral fracture

4. Vacuum phenomenon or bone marrow oedema of the vertebral fracture on MR imaging

5. Osteoporosis (T‐score less than ‐2.5) on bone densitometry

Exclusion Criteria

1. Uncorrected coagulopathy

2. Local or systemic infection

3. Secondary osteoporosis

4. Inability to give informed consent

5. Impaired cardio‐pulmonary function

6. Dementia

7. Posterior wall defect of the vertebral body on CT imaging

8. Spinal cancer

9. Traumatic fracture

10. Neurological complications

Baseline characteristics:

Vertebroplasty group (n = 40):

Mean (range) age: 72 (59 to 90) years; 30 female:10 male

Duration (range) of back pain: 30 (6 to 54) weeks

Previous vertebral fractures: 50

Mean (SD) baseline pain score: 7.2 (1.7)

Initial pain medication‐ paracetamol (acetaminophen) and codeine: 30 (75%); NSAIDs: 20 (50%)

Usual care group (n = 42):

Mean (range) age: 74 (55 to 87) years; 30 female:12 male

Duration (range) of back pain: 27 (4 to 50) weeks

Previous vertebral fractures: 56

Mean (SD) baseline pain score: 8.4 (1.6)

Initial pain medication‐ paracetamol (acetaminophen) and codeine: 30 (71%); NSAIDs: 32 (76%)

Interventions

Percutaneous vertebroplasty performed by neurosurgeons; usual care ('optimal medical therapy') delivered by a physician.

Vertebroplasty

Induction of conscious sedation (a combination of intravenous fentanyl and midazolam) in 10 (25%) participants and general anaesthesia in 30 (75%) participants. Patients were placed prone and single‐plane C‐arm equipment was used. Using sterile techniques, an 11‐gauge needle was inserted into the vertebral body via a unilateral parapedicular approach in 35 (87.5%) patients and via a bilateral transpedicular approach in 5 (12.5%) patients. A bilateral transpedicular approach was used only if there was inadequate instillation of cement with the unilateral approach under fluoroscopy. A polymethylmethacrylate mixture was injected into the vertebral body. Following the procedure, the patient remained supine in bed. During cement injection, fluoroscopic monitoring with a C‐arm unit was used in both planes. It is not stated whether or not participants in the vertebroplasty group could also receive analgesia and/or treatment of osteoporosis.

Usual care

The usual care group was prescribed 250 mg acetaminophen with codeine twice daily, 400 mg ibuprofen twice a day, 1000 mg calcium daily, 400 IU vitamin D daily, 70 mg alendronate orally once weekly, and 200 IU calcitonin daily. Analgesia could be increased by the treating physician as needed. Cross‐over to vertebroplasty was permitted after 1 month.

Follow‐up care

A change in lifestyle and physical treatment (undefined) was also suggested to participants in both groups.

Outcomes

Outcomes were reported at 1 week, and 2, 6, 12, 24 and 36 months after treatment

Primary outcomes

1. Mean pain in previous 24 hours, measured on a 1 to (no pain) to 10 (excruciating pain) VAS scale.

2. Mean disability, measured by the Oswestry Low Back Disability Index (ODI), 0 to 100 scale (0 is no disability)

Secondary outcomes

1. Ability to walk after one day

2. Incidence of new symptomatic vertebral fractures (at 24 months)

3. Radiographic measurement of vertebral body height (VBH, mm); and correction of spinal deformity (sagittal index, degrees) at 2, 6, 12, 24 and 36 months.

4. Adverse events

Outcomes included in this review:

1. Mean pain

2. Disability as measured by the ODI

3. Incidence of new symptomatic vertebral fractures

4. Adverse events

Source of funding

The vice‐chancellor for research affairs of Shiraz University of Medical Sciences and Apadana Tajhizgostar Co. (distributor of medical devices) provided grant support.

Notes

Trial registered retrospectively on 11 Oct 2009 at www.irct.ir, number IRCT138804252193N1.

All participants in the control group were permitted to undergo vertebroplasty after 1 month; 4 crossed over before 2 months, 3 before 6 months, 3 before 12 months and 10 before 36 months (total cross‐over 20/42 (47.6%)).

We included the 2‐month follow‐up data in the 3‐month analyses/meta‐analyses.

The trialists report epidural cement leakage in one participant receiving vertebroplasty, and no cases of venous emboli or infection. It is not reported if any adverse events occurred with usual care.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Generated by computerised random number generator

Allocation concealment (selection bias)

Low risk

The treatment assignment was kept in sealed envelopes. It is not clearly reported who prepared and opened the envelopes, but it is likely that allocation was concealed. "Neither the neurosurgeon (performing vertebroplasty) nor the physician (administering usual care) knew about the other study group and had no role in allocation."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants were unblinded. "Neither the neurosurgeon (performing vertebroplasty) nor the physician (administering usual care) knew about the other study group."

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

High risk

Participants self‐assessed pain and disability and were unblinded. "Two independent raters who were unaware of the study followed the patients. A third rater, who was likewise unaware of the study, verified the results. The raters were not involved in the care of the patients." "Follow‐up data were collected by raters."

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

High risk

It is not stated who assessed the imaging outcomes. It is unlikely that they were blinded to 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 groups (3/40 participants in the vertebroplasty group and 3/42 participants in the usual care group at the final 36 month follow‐up).

Selective reporting (reporting bias)

Unclear risk

Unclear if any additional outcomes were measured and not reported; e.g., incident fracture is not listed in the methods as an outcome but data are reported in the results for the 2‐year (but not end of study) follow‐up.

Other bias

Unclear risk

The trial was partially funded by Apadana Tajhizgostar Co., a distributor of medical devices and its role in the trial was not explicitly reported.

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:

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 (RDQ) 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 RDQ (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

1. Age 50 years or older

2. One to three painful osteoporotic vertebral compression fractures between vertebral levels T4 and L5

3. Inadequate pain relief with standard medical therapy

4. A current rating for pain intensity of at least 3 on a scale from 0 to 10

5. Duration of pain less than one year

6. For fractures of uncertain age, bone oedema on MRI or increased vertebral‐body uptake on bone scan was required

Exclusion criteria

1. Neoplasm in the target vertebral body

2. Substantial retropulsion of bony fragments

3. Concomitant hip fracture

4. Active infection

5. Uncorrectable bleeding diatheses

6. Surgery within the previous 60 days

7. Lack of access to a telephone

8. Inability to communicate in English

9. 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 RDQ 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 RDQ 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

1. Modified Roland‐Morris Disability Questionnaire (RDQ) (23‐item version, 0 to 23 scale, with higher scores indicating worse physical functioning

2. Average back pain intensity during the preceding 24 hours (0 to 10 scale, with higher scores indicating more severe pain)

Secondary outcomes:

1. Pain Frequency Index and the Pain Bothersomeness Index (0‐ to 4‐point scale, higher scores indicating more severe pain)

2. Study of Osteoporotic Fractures‐Activities of Daily Living (SOF‐ADL) scale (0 to 18 point scale, higher scores indicating more disability)

3. European Quality of Life‐5 Dimensions (EQ‐5D) scale (‐0.1 to 1.0 point scale, higher scores indicating better quality of life)

4. Use of opioid medications

5. 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)

6. Proportion with clinically important improvement in pain (at least 30% improvement)

7. Proportion with clinically important improvement in disability (at least 30% improvement)

8. Adverse events

Outcomes included in this review

1. Mean pain

2. Disability as measured by the RMDQ

3. Quality of life as measured by the EQ‐5D

4. Proportion with clinically important improvement in pain (at least 30% improvement)

5. 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 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 (RDQ 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. It is also possible 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.

Methods

Design: Multicentre (6 centres), two‐arm open‐label randomised controlled trial; control group allowed to cross‐over to vertebroplasty at one week post intervention

Setting: Netherlands and Belgium

Timing:

Interventions: Percutaneous vertebroplasty or usual care

Sample size:A priori sample size calculation based on ability to detect a difference of 25% in significant pain relief with vertebroplasty compared with usual care based on a two‐sided type 1 error rate of 5% and power 80%.

Analysis: Intention‐to‐treat analysis

Participants

Number of participants

• 934 participants screened

• 732 were excluded (226 did not meet inclusion criteria, 229 met inclusion initially but then a decrease in pain during screening rendering them ineligible, 232 declined participation and 45 requested vertebroplasty)

• 202 patients were randomised (101 in percutaneous vertebroplasty, and 101 in conservative treatment)

• Data were available for 188 (96 (95%) for vertebroplasty and 92 (91%) for usual care) at the 1‐month follow‐up

• Data were available for 163 (86 (85%) for vertebroplasty and 77 (76%) for usual care) at the final 1‐year follow‐up

Inclusion Criteria

1. Acute back pain for 6 weeks or less

2. Pain on 0‐10 VAS of 5 or more

3. Focal tenderness at fracture level, as assessed by an internist on physical examination

4. Vertebral compression fracture on spine radiograph (minimum 15% height loss) at T5 or lower

5. Bone oedema of vertebral fracture on MRI

6. Decreased bone density (T scores ≤ 1)

Exclusion Criteria

1. Severe cardio‐pulmonary comorbidity

2. Untreatable coagulopathy

3. Systemic or local spine infection

4. Suspected underlying malignant disease

5. Radicular syndrome

6. Spinal‐cord compression syndrome

7. Contraindication for MRI

Baseline characteristics

Vertebroplasty Group:

Mean (SD) age: 75.2 (9.8) years; 70 female, 31 male

Mean (SD) duration of back pain: 29.3 (17.1) days

Number of VCFs at baseline: 2.4 (1.9)

Mean (SD) pain at baseline: 7.8 (1.5)

Mean (SD) RMDQ: 18.6 (3.6)

Mean (SD) QUALEFFO: 58.7 (13.5)

Bone density T score: ‐3.0 (1.17)

Usual care group

Mean (SD) age: 75.4 (8.4) years; 70 female, 31 male

Mean (SD) duration of back pain: 26.8 (16.0) days

Number of VCFs at baseline: 2.1 (1.5)

Mean (SD) pain at baseline: 7.5 (1.6)

Mean (SD) RMDQ: 17.2 (4.2)

Mean (SD) QUALEFFO: 54.7 (14.4)

Bone density T score: ‐3.0 (1.05)

Interventions

Percutaneous vertebroplasty

Percutaneous vertebroplasty was performed using a single or biplane angiography system under fluoroscopic guidance. After local analgesia, two 11‐ or 13‐gauge bone‐biopsy needles were placed transpedicularly in the fractured vertebral body. Polymethylmetacrylate bone cement (Osteo‐Firm, COOK Medical, Bloomington, IN, USA) was injected through bone‐biopsy needles under continuous fluoroscopic monitoring to identify local cement leakage or migration into the venous system towards the lung. In patients who had more than one fracture with bone oedema on MRI, all vertebral bodies were treated in one or more procedures. After the procedure, a CT scan of the treated vertebral bodies was performed with 2 mm slices to identify cement leakage or other possible local complications.

Usual care

'Optimal Pain Management (OPM)' consisted of the use of analgesics in ascending order:

1. Acetaminophen

2. Tramadol

3. Tramadol and acetaminophen

4. Morphine

5. Non‐steroidal anti‐inflammatory drugs (NSAIDs) for those already using or intolerant to opiate‐derivatives

Corrections in dose and classification of pain medication were made when necessary by the internist, and in most cases physiotherapy was prescribed.

Follow‐up care

All patients received osteoporosis medication, such as bisphosphonates together with supplemental calcium and vitamin D.

Outcomes

Outcomes were reported at baseline, 1 week, and 1, 3, 6 and 12 months. Pain diary ‐ pain VAS and use of analgesia recorded daily to 1 month.

Primary outcome

1. Mean pain on VAS ranging from 0 (no pain) to 10 (worst pain ever); clinically significant pain relief was defined as a decrease of 3 points or more in VAS score from baseline

Secondary outcomes

1. Pain‐free days were defined as days with a VAS score of 3 or lower

2. Cost‐effectiveness as costs per QALYs at one month and one year

3. Quality of life measured with the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO)(scores range from 0 to 100, with lower scores indicating a better quality of life)

4. Physical function: Roland‐Morris Disability Questionnaire (RMDQ)(modified 23‐item version, scores range from 0 to 23, with higher scores indicating worse physical functioning)

5. Quality of life: European Quality of Life‐5 Dimensions (EQ‐5D) scale, with a score range of 0 to 1

6. Use of analgesia

7. Incident radiographic vertebral fractures measured at 1, 3 and 12 months

8. Adverse events

Outcomes included in this review

1. Mean pain

2. Function RDQ

3. Quality of life measured with the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO)

4. Quality of life (EQ‐5D, scores range from 0 to 1, with 1 being best quality of life)

5. Proportion with incident radiographic vertebral fractures

Source of funding

The study was sponsored by ZonMw (Dutch organisation for health care research and innovation of care), project number 945‐06‐351 and an unrestricted grant from the COOK Medical (Bloomington, IN, USA).

Notes

Trial registered at ClinicalTrials.gov. Registration number NCT00232466. "VERTOS II"

Pre‐treatment group differences: participants allocated to vertebroplasty had worse scores for EQ5‐D; QUALEFFO and RDQ at baseline.

RDQ and QUALEFFO means only shown graphically in the trial report.

Dr Klazen provided mean (SD) data for the RDQ, EQ5D and QUALEFFO at all time points to 12 months.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation codes with a block size of six.

Allocation concealment (selection bias)

Low risk

Not explicitly reported, but as an independent telephone operator allocated participants by telephone, the allocation was likely concealed from the investigators.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants and study personnel were aware of treatment assignment.

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

High risk

Participants were not blinded to treatment assignment.

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

High risk

Radiologists were not blinded to treatment assignment.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

A greater number of participants completed one‐year follow‐up in the vertebroplasty group (86/101, 85%) compared with 77/101 (76%) in the usual care group. Fifteen (15%) participants in the usual care group received vertebroplasty.

Selective reporting (reporting bias)

Low risk

The trial authors published the planned outcomes in a trial protocol and provided results for each planned outcome.

Other bias

High risk

Quality of life and disability were worse at baseline in the vertebroplasty group which may have biased the results favouring the vertebroplasty group. The role of COOK Medical (Bloomington, IN, USA) in the trial is not explicitly reported.

Methods

Design: Single centre, two‐arm, randomised controlled trial

Setting: Taichung, Taiwan

Timing: Not stated

Interventions: Percutaneous vertebroplasty versus kyphoplasty

Sample size:A priori sample size calculation not reported

Analysis: Type of analysis (completers or intention‐to‐treat) not reported

Participants

Number of participants

• Number screened not reported

• 100 participants randomised (50 in each group)

• Loss to follow‐up not explicitly reported

• Data may have been available for all participants at the final 6‐month follow‐up

Inclusion Criteria

1. Confirmed osteoporotic vertebral compression fracture at the thoraco‐lumbar junction (T12‐L1)

Exclusion Criteria

1. None reported

Baseline characteristics

Vertebroplasty Group:

Mean (SD) age: 74.3 (6.4) years; 38 female, 12 male

Mean (SD) duration between 'injury' and treatment: 15.8 (6.7) days

Location: 12 T12, 38 L1

Mean (SD) pain at baseline: 7.9 (0.7)

Kyphoplasty group

Mean (SD) age: 72.3 (7.6) years; 39 female, 11 male

Mean (SD) duration between 'injury' and treatment: 17.0 (7.7) days

Location: 11 T12, 39 L1

Mean (SD) pain at baseline: 8.0 (0.8)

Interventions

Percutaneous vertebroplasty

The surgical procedures involved IV general anaesthesia (Propofol) and 2% xylocaine injected locally. A special bone biopsy needle (Angiotech, USA) was passed percutaneously and slowly through each side of the pedicle into the vertebral body. The bone filler PMMA (Zimmer) was prepared and mixed with both gentamicin, to reduce risk of infection, and powder containing barium, allowing X‐ray visualisation. An optimal amount of bone filler was injected into the vertebral body via the needles on both sides. All procedures were performed under a mobile C‐arm X‐ray.

Balloon kyphoplasty

The same anaesthesia was employed. Using image guidance, two small incisions were made, a probe was placed into the vertebral space at the fracture site. The bone was drilled and a balloon (VCF‐X CentralMedical Tech., Taiwan) , called a bone tamp, was inserted on each side. The balloons were then inflated with contrast medium (to facilitate image guidance X‐rays) and expanded to the desired height and removed. The spaces created by the balloons were then filled with PMMA (prepared as for vertebroplasty) to bind the fracture.

Follow‐up

All participants undertook an orally administered treatment regimen to protect their bone density after surgery (details not reported).

Outcomes

Outcomes were reported at baseline, 3 days and 6 months.

Primary outcomes

1. Measurement of vertebral body height

2. Measurement of kyphotic wedge angle (to evaluate kyphosis)

3. Pain, measured on a 10‐point VAS

Outcomes included in this review

1. Mean pain

Source of funding

Grant from Chung‐Shan Medical University Hospital (CS08110)

Notes

Trial registration: Not found.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomly assigned according to permuted block randomisation which was likely to be adequate.

Allocation concealment (selection bias)

Unclear risk

Whether or not treatment allocation was concealed is not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Whether or not participants and investigators were blinded to treatment allocation is not reported.

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

Unclear risk

Whether or not participants were blinded to treatment allocation is not reported.

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

Unclear risk

'Radiographic measurement was made by technicians 'blind' to treatment group status, with variability controlled via inter‐ and intra‐observer comparisons'. No details of the inter‐ and intra‐observer comparisons are reported.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

It is stated that the minimum follow‐up period was six months. Completeness of follow‐up not explicitly reported.

Selective reporting (reporting bias)

Unclear risk

Trial not registered and trial protocol was not published. All outcomes listed in the methods are reported.

Other bias

Low risk

None apparent.

Methods

Design: Single‐centre, parallel group, two‐arm open‐label randomised controlled trial

Setting: Denmark

Interventions: Percutaneous vertebroplasty or usual care

Timing:

Sample size:A priori sample size of 16 participants per group was calculated, based on being able to detect a difference in pain of 2 points on a 0‐10 VAS (SD set to 2 points) with 80% power and type 1 error rate of 0.05; increased to 20/group to allow for unpredictable patient exclusions and other unexpected events

Analysis: Completers' analysis

Participants

Number of participants

• Number of participants who were screened is not reported

• 50 participants randomised (26 in percutaneous vertebroplasty and 24 in usual care)

• Data were available for 24 (92%) in vertebroplasty group and 23 (96%) in usual care group at the 3‐month follow‐up

• Data were available for (22 (85%) in vertebroplasty group and 22 (92%) in usual care group at the final 12‐month follow‐up

Inclusion criteria

1. Intractable pain because of either acute (< 2 weeks, 40 participants) or subacute (between 2 and 8 weeks, 10 participants) osteoporotic vertebral fractures

2. Plain radiographs confirmed vertebral fracture

3. If there was only one vertebral fracture on plain radiograph and relevant acute/subacute pain, no further tests were performed. If there was more than one vertebral fracture. MRI scan or bone scan was performed to differentiate new from old fractures and fractures showing bone oedema on MRI or increased burn turnover on bone scan were accepted as new fractures

Exclusion Criteria

1. Age under 65 years

2. Uncorrected therapeutic anticoagulation

3. Senile dementia, impaired cognitive function or other cerebral disease

4. Infection in the spine or the overlying skin

5. Malignant disease

6. Bone metabolic disease

7. Fracture of tubular bone

8. Allergy to radiopaque agents

Baseline characteristics

Vertebroplasty Group (n = 25, baseline data of one participant who declined follow‐up was excluded):

Mean (range) age: 80 (65 to 96) years; 19 female, 6 male

Mean (95% CI) duration of fracture: 8.4 (3.7 to 13.0) days

Mean (95% CI) pain at baseline: 7.5 (60.6 to 8.4) based upon 19 participants

Mean (95% CI) physical function at baseline (SF‐36 PCS): 36.7 (30.0 to 43.4) based upon 17 participants

Mean (95%) CI) EQ‐5D: 0.356 (0.196 to 0.516) based upon 17 participants

Usual care group (n = 24)

Mean (range) age: 80 (71 to 93) years; 21 female, 3 male

Mean (95% CI) duration of fracture: 6.7 (21. to 11.4) days

Mean (95% CI) pain at baseline: 8.8 (8.2 to 9.3) based upon 17 participants

Mean (95% CI) physical function at baseline (SF‐36 PCS): 33.4 (26.2 to 40.7) based upon 17 participants

Mean (95%) CI) EQ‐5D: 0.083 (‐0.151 to 0.317) based upon 16 participants

Interventions

Vertebroplasty

Percutaneous vertebroplasty was performed by orthopaedic surgeons specialised in spine surgery. Most patients were mildly sedated and all patients were prepared for general anaesthetic in case of complications. Under biplane fluoroscopic control and with the patients in a prone position 11‐ to 13‐gauge needles were placed using a uni or bilateral transpedicular approach. Bone cement (PMMA) was injected under continuous fluoroscopy. In cases of extra vertebral cement leakage, the injection was terminated. Monitoring during the procedure included electrocardiogram, oxygen saturation, and blood pressure. After the procedure, the patients remained in a prone position for 30 minutes and then lay supine for a further 90 minutes.

Usual care 

Patients offered brace treatment in addition to pain medication and physiotherapy.

Follow‐up care

Both groups were hospitalised and offered pain medication and physiotherapy until discharge.

Outcomes

Outcomes were reported at 3 and 12 months.

Outcomes

1. Mean pain, measured on a 0 cm to 10 cm scale, where 0 is no pain and 10 is worst pain possible.

2. Quality of life, measured using the Short‐Form health survey (SF‐36), 0 to 100 scale, where a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability. Only measured for participants with pain < 2 weeks (40/50 participants).

3. Pain, measured using the Dallas Pain Questionnaire (DPQ), a 16‐item instrument that assesses four aspects of daily living affected by chronic back pain (day‐to‐day activities, work and leisure activities, anxiety and depression and social interest), measured as a percentage of pain interference in each of the four aspects (0% is no pain and 100% is pain all the time). Only measured for participants with pain < 2 weeks (40/50 participants).

4. Adverse events

5. Incident radiographic fractures at 3 months

The following additional measures were added after commencement of the trial and only measured in 17 participants in each group.

1. European Quality of Life‐5 Dimensions (EQ‐5D) scale, with a score range of 0 to 1, where 1 indicates perfect health

2. Activities of daily living measured using the Barthel Index, 0 to 20 score, higher score indicates more independence, or better daily function

3. Cognitive status, measured using the mini‐mental status examination (MMSE), 30 questions, with 'impaired cognitive function' defined as a score less than 24/30 correct answers

4. Physical tests: tandem test to measure time able to maintain balance; timed up‐and‐go (time taken to rise from chair, walk 3 metres and return); and the repeated chair test to assess muscle power (number of repeated chair stands in 30 seconds). These tests were only performed at 3 months

Source of funding

Foundation and Danish government funds. The authors stated that no commercial party received benefits from the study.

Notes

Trial registration: Not found.

Baseline pain score was higher in the usual care group (8.8 versus 7.5, P = 0.02) and mean stay in hospital was significantly longer in the usual care group (11.7 days vs 7.6 days, P = 0.01).

We calculated the SD for pain, SF‐36 Physical Function and EQ‐5D outcomes from the reported 95% CIs.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Sealed envelopes containing the treatment assignment 'were prepared beforehand by the investigating surgeon and sorted randomly'.

Allocation concealment (selection bias)

Unclear risk

'The type of treatment was unknown to the patient and the investigators until after the patient had given written consent.' 'Enrolment of patients and randomization were performed by the surgeons involved in the study or the responsible PhD investigator.' It is not stated whether or not envelopes were opaque and whether steps were taken to ensure use of consecutive envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants and investigators were aware of treatment allocation.

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

High risk

Participants were aware of treatment assignment.

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

High risk

Radiologists were aware of treatment assignment.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Baseline data are not included for one participant in the vertebroplasty group as they did not contribute follow‐up data (refused to attend for 3‐month follow‐up). An additional single participant in each group did not contribute outcome data as they died before the 3‐month follow‐up and an additional single participant in each group did not contribute 12‐month outcome data as they died sometime after the 3‐month follow‐up. Additional outcomes were added after the trial started (EQ5D, Barthel, MMSE, three physical tests) and were not collected for all participants.

Baseline pain data were also either not collected and/or not reported for 6 (24%) participants in the vertebroplasty group and 7 (29%) participants in the usual care group and other baseline data were not collected and/or not reported for up to 13/25 participants in the vertebroplasty group and up to14/24 participants in the usual care group depending upon outcome.

Three‐month follow‐up outcome data were either not collected and/or not reported for up to 14/24 participants in the vertebroplasty‐treated group and 9/23 participants in the usual care group depending upon outcome.

Twelve‐month follow‐up outcome data were either not collected and/or not reported for up to 10/22 participants in the vertebroplasty‐treated group and 9/22 participants in the usual care group depending upon outcome.

Selective reporting (reporting bias)

Unclear risk

Trial not registered and trial protocol was not published. All outcomes listed in the methods are reported.

Other bias

Unclear risk

Baseline pain was higher in the usual care group (8.8 versus 7.5) (although it was only measured in 17/24 and 19/25 participants in the usual care and vertebroplasty‐treated groups respectively.

Participants receiving usual care were hospitalised for longer (11.7 days versus 7.6 days); it is unclear if more pain medication and physiotherapy was offered, and how this would affect outcomes.

Methods

Design: Multicentre, two‐arm, randomised controlled trial

Setting: Germany (3 centres) USA (1 centre)

Timing: March 2008 to Sept 2009

Interventions: Percutaneous vertebroplasty versus kyphoplasty

Sample size:A priori sample size calculation not reported

Analysis: Completers' analysis

Participants

Number of participants

• Number of participants who were screened is not reported

• 78 participants randomised 1:2 (28 (39 levels) in the percutaneous vertebroplasty and 49 (65 levels) in the cement directed kyphoplasty system groups respectively)

• Data were available for 23 (82%) in vertebroplasty group and 37 (76%) in kyphoplasty group at the 3‐month follow‐up

• Data were available for 19 (68%) in vertebroplasty group and 28 (57%) in the kyphoplasty group at the final 12‐month follow‐up

Inclusion criteria

1. Up to three painful vertebral compression fractures between T4 and L5 unresponsive to at least 6 weeks of conservative treatment or were admitted to hospital for acute back pain

2. Confirmed diagnosis of osteoporosis or osteopenia

Exclusion Criteria

1. Burst fractures

2. Planar collapse

3. Vertebral bodies having inadequate space between endplates for cavity creation

4. Infection

5. Current cancer treatment at the affected level

6. Multiple myeloma

7. Prior cement at the affected level

Baseline characteristics

Vertebroplasty Group (n = 25, baseline data of one participant who declined follow‐up were excluded):

Mean (SD) age: 74 (11.5) years; 19 female, 9 male

Mean (SD) pain at baseline: 8.49 (1.18)

Usual care group (n = 24)

Mean (range) age: 80 (71 to 93) years; 21 female, 3 male

Mean (SD) pain at baseline: 8.31 (1.12)

Interventions

Percutaneous vertebroplasty

The procedure was performed using a bipedicular cement injection in accordance with each participating physician's standard technique. The same cement was used for both procedures (Spineplex, Stryker Instruments, Kalamazoo, MI).

Cement directed kyphoplasty system

The kyphoplasty system was provided by Soteira Inc, Natick, MA. The surgical procedure began with access gained through a unilateral intrapedicular or extrapedicular approach. The curved design of the cavity creation instrument allowed the physician to drill a curved path from one pedicle, crossing the sagittal midline and stopping with the contralateral anterior quadrant of the vertebral body. The drill converted to a cavity cutting reamer in situ, which created a 10‐mm diameter cylindrical cavity. The cement directing implant consisted of a non load‐bearing, hollow, passively self‐expanding cylindrical device manufactured from a textile composite of nitinol wire, polyethylene teraphthalate fibre, and polycarbonate urethane. The implant was 10mm in diameter and 15‐, 20‐ or 25‐mm long. The size of the implant was chosen to match the length of the cavity. The implant was designed to contain initially injected cement then regulate and direct cement flow into surrounding cancellous bone. Because the cavity was created by cutting, in contrast to bone compaction as in a balloon kyphoplasty, cement was able to penetrate into the bone beyond the boundaries of the cavity. Cement injection into the implant and directed through openings in its wall created a cement mantle in the anterior vertebral body, which extended towards the endplates and stabilised the fracture by filling cracks and voids, interdigitating with viable cancellous bone. Device placement in a centrally located cavity provided bilateral cement flow with the vertebral body, crossing both sides of the sagittal midline using a unipedicular approach. The nitinol‐based implant is expanded prior to cement injection to create a barrier to limit posterior cement flow into the basivertebral vein and spinal canal, while still allowing cement to permeate the vertebral body.

Outcomes

Patient follow‐up occurred at 3 and 12 months. Plain radiographs and CT scans were taken within 24 hours of the procedure and at 3 months, and plain radiographs were also taken at 12 months.

Outcomes

1. Cement leakage rates based primarily on postoperative CT scans, supplemented by A/P and lateral radiographs

2. Cement leakage location using a newly developed leak location classification method (1. anterior, 2. lateral, 3. neuroforamen, 4 spinal canal or 5. superior or inferior endplate leaks).

3. Changes in vertebral height determined by comparing CT scans obtained postoperatively and at 3 months

4. Long‐term stability of the cement mantle

5. Presence of new fractures at treated or adjacent level

6. Pain intensity on a visual analogue scale (VAS) (not reported in the published paper but referred to in a congress abstract of the same trial reported in German)

7. Disability assessed by the Oswestry Disability Index (ODI) were measured but these data are not presented in this paper (not reported in the published paper but referred to in a congress abstract of the same trial reported in German)

Outcomes included in this review

1. Presence of new fractures at treated or adjacent level

Source of funding

Funding provided by Soteira Inc. (Natick, MA)

Notes

Trial reported to be registered with ClinicalTrials.gov with ID: NCT00576546 but this could not be verified.

No efficacy outcomes were reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were randomised into vertebroplasty or cement‐directed kyphoplasty in a ratio of 1:2 but the method of generating the random sequence was not reported.

Allocation concealment (selection bias)

Unclear risk

Whether or not treatment allocation was concealed is not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Participants were blinded but investigators were not blinded.

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

Low risk

Participants were blinded to treatment allocation.

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

High risk

Cement leakage, changes in vertebral body height and the incidence of new fractures measured by investigators using radiographs were assessed by the investigators who were aware of treatment assignment.

Incomplete outcome data (attrition bias)
All outcomes

High risk

A completers' analysis was performed. Data were available for 23 (82%) and 37 (76%) in vertebroplasty and kyphoplasty groups respectively at the 3‐month follow‐up and 19 (68%) and 28 (57%) at the final 12‐month follow‐up. It is unclear it this is significantly different and the reasons for missing data are not reported.

Selective reporting (reporting bias)

High risk

A Congress abstract of the same trial is reported in German (https://www.thieme‐connect.com/products/ejournals/abstract/10.1055/s‐0031‐1279397), and indicates that pain intensity on a visual analogue scale (VAS) and disability assessed by the Oswestry Disability Index (ODI) were measured but these data are not presented in this paper.

Other bias

Unclear risk

The role of Soteira Inc. (Natick, MA) in the trial, other than supply of the Cement Directed Kyphoplasty System, is not explicitly reported.

Methods

Design: Multicentre (three hospitals), two‐arm open‐label randomised controlled trial; control group allowed to cross‐over to vertebroplasty at two weeks

Setting: Netherlands and Belgium

Timing:

Interventions: Percutaneous vertebroplasty or usual care

Sample size:A priori sample size calculation not reported

Analysis: Completers' analysis

Participants

Number of participants

• Number of participants who were screened is not reported but it is stated that approximately one in four of those screened initially consented to participate

• 46 participants randomised but 10 did not receive the assigned treatment (6 in the usual care group wanted to receive vertebroplasty and 2 in the vertebroplasty group wanted to be treated with usual care)

• 38 received treatment (18 treated with vertebroplasty, 16 treated with usual care and 4 unknown)

• Data were available for 34 participants at 2 weeks (18 for vertebroplasty and 16 for usual care) as 4 participants who were treated with unknown therapy did not complete 2‐week follow‐up and were excluded from the analysis

Inclusion criteria

1. Patient age 50 years or older

2. Back pain due to vertebral fracture refractive to medical therapy for at least 6 weeks and no longer than 6 months

3. Focal tenderness on physical examination related to the level of the vertebral fracture

4. Height loss of the vertebral body of a minimum of 15% on plain radiograph of the spine

5. Bone density T‐scores less than ‐2.0, 5

6. Bone oedema of the affected vertebra on MRI

 Exclusion criteria

1. Poor cardio‐pulmonary condition

2. Untreatable coagulopathy

3. Ongoing systemic infection or local infection of the spine (osteomyelitis, spondylodiscitis)

4. Radicular and/or cord compression syndrome

5. Indication of other underlying disease than osteoporosis

6. No informed consent

Baseline characteristics

Vertebroplasty group:

Mean (range) age: 72 (59 to 84) years; 14 females, 4 males

Mean (range) duration of back pain (units not reported, assumed as days): 85 (47 to 138) days

Mean (range) number of pre‐existing vertebral compression fractures: 3.3 (1 to 8) at T5 to L5

Mean (range) baseline pain: 7.1 (5 to 9)

Mean (range) baseline disability, RMDQ: 15.7 (8 to 22)

Mean (range) baseline quality of life, QUALEFFO: 60 (37 to 86)

No pain medication: 2 (11%)

Paracetamol: 4 (22%)

NSAIDs: 6 (33%)

Opioids: 6 (33%)

Usual care group:

Mean (range) age: 74 (55 to 88) years; 14 females, 2 males

Mean (range) duration of back pain (units not reported, assumed as days): 76 (46 to 141) days

Mean (range) number of pre‐existing vertebral compression fractures: 3.1 (1 to 8) at T5 to L5

Mean (range) baseline pain: 7.6 (5 to 10)

Mean (range) baseline disability,RMDQ: 17.8 (9 to 24)

Mean (range) baseline quality of life, QUALEFFO: 67 (38 to 86)

No pain medication: 1 (6%)

Paracetamol: 7 (44%)

NSAIDs: 3 (19%)

Opioids: 5 (31%)

Interventions

Vertebroplasty 

Percutaneous vertebroplasty was performed under local anaesthesia on a biplane (in 2 hospital departments) or monoplane (in 1 hospital department) angiographic unit. In most cases, a bilateral transpedicular approach was used. Under continuous fluoroscopy, PMMA bone cement (Osteopal V; Biomet Merck, Ried B. Kerzers, Switzerland) was injected manually using 1.0‐mL syringes and 11‐ or 13‐gauge bone biopsy needles (Cook Europe Bjaeverskov, Denmark). Immediately after the PV, a CT scan with multiplanar reconstructions of the treated levels was performed to assess the cement deposition and to identify possible extra cement leakage or other local complications that might not have been noted under fluoroscopy.

Usual care

Participants were treated with the following medications, in ascending order.

1. Paracetamol (acetaminophen)

2. Non‐steroidal anti‐inflammatory drugs (NSAIDs)

3. Opioids

The dose per day of prescribed analgesics was regulated, and the class of pain medication was adjusted as needed.

Outcomes

Outcomes were reported at 1 day and 2 weeks

Outcomes

1. Mean pain on a 0 to 10‐point scale ranging from 0 (no pain) to 10 (worst pain in the patient's life)

2. Type of analgesic use (ordinal variable from 0 (no analgesic use) to 3 (use of opioids)

3. Disability: Roland‐Morris Disability Questionnaire (RMDQ), 0 to 23 point scale, with higher scores indicating worse disability

4. Quality of life: Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO), scores range from 0 to 100, with lower scores indicating a better quality of life

5. Adverse events

6. Incident clinical vertebral fractures

Outcomes included in this review

1. Mean pain

2. Disability measured by the RDMQ

3. Vertebral fracture‐specific quality of life (QUALEFFO), scores range from 0 to 100, with lower scores indicating a better quality of life) at 2 weeks.

Source of funding

None reported.

Notes

Trial registration: not found.

Standard deviations not reported for pain, disability or quality of life in the trial report but were provided by Dr Voormolen.

The trial authors report that the original protocol was to follow participants for up to 12 months with outcome assessments at 1 day, 2 weeks and 3, 6, and 12 months. Participants randomised to usual care who still had severe pain after two weeks could cross over to receive vertebroplasty. As the majority of participants receiving usual care crossed over to vertebroplasty after two weeks, the authors stopped the study early, and did not collect outcome data beyond two weeks.

There were two adjacent incident vertebral fractures in the vertebroplasty group within the two week follow‐up period, but it is unclear if there were any incident fractures in the usual care group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The method of generating the random sequence was not reported.

Allocation concealment (selection bias)

Unclear risk

An independent central operator allocated participants to treatment but whether or not treatment allocation was concealed is not reported.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Participants and investigators were not blinded to treatment assignment.

Blinding of outcome assessment (detection bias)
Self‐reported outcomes (e.g., pain, disability)

High risk

Participants were not blinded to treatment assignment.

Blinding of outcome assessment (detection bias)
Objective outcomes (e.g., radiographic outcomes)

High risk

Radiologists were not blinded to treatment assignment.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Four participants were excluded from the analysis (refused to complete 2‐week follow‐up). The treatment group of these participants is not reported.

Selective reporting (reporting bias)

Unclear risk

Trial protocol is not published. The number of participants with an incident clinical vertebral fracture is only reported for the vertebroplasty group. Measures of variance were not reported for continuous outcomes.

Other bias

Unclear risk

Eight participants withdrew after randomisation as they were not assigned to their preferred treatment (2 in the vertebroplasty group and 6 in the usual care group).

The source of funding is not reported.