Elsevier

The Lancet

Volume 388, Issue 10052, 1–7 October 2016, Pages 1408-1416
The Lancet

Articles
Safety and efficacy of vertebroplasty for acute painful osteoporotic fractures (VAPOUR): a multicentre, randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(16)31341-1Get rights and content

Summary

Background

We hypothesised that vertebroplasty provides effective analgesia for patients with poorly controlled pain and osteoporotic spinal fractures of less than 6 weeks' duration. The effectiveness of vertebroplasty, using an adequate vertebral fill technique, in fractures of less than 6 weeks' duration has not been specifically assessed by previously published masked trials.

Methods

This was a multicentre, randomised, double-blind, placebo-controlled trial of vertebroplasty in four hospitals in Sydney, Australia. We recruited patients with one or two osteoporotic vertebral fractures of less than 6 weeks' duration and Numeric Rated Scale (NRS) back pain greater than or equal to 7 out of 10. We used an automated telephone randomisation service provided by the National Health and Medical Research Council to assign patients (1:1; stratified according to age, degree of vertebral compression, trauma, corticosteroid use, and hospital) to either vertebroplasty or placebo, immediately before the procedure. Patients received conscious sedation. Vertebroplasty was done with the adequate vertebral fill technique and the placebo procedure with simulated vertebroplasty. Follow-up was for 6 months. Outcome assessors and patients were masked to treatment allocation. The primary outcome was the proportion of patients with NRS pain below 4 out of 10 at 14 days post-intervention in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01482793.

Findings

Between Nov 4, 2011, and Dec 5, 2014, 120 patients were enrolled. 61 patients were randomly assigned to vertebroplasty and 59 to placebo. 24 (44%) patients in the vertebroplasty group and 12 (21%) in the control group had an NRS pain score below 4 out of 10 at 14 days (between-group difference 23 percentage points, 95% CI 6–39; p=0·011). Three patients in each group died from causes judged unrelated to the procedure. There were two serious adverse events in each group, related to the procedure (vertebroplasty group) and the fracture (control group).

Interpretation

Vertebroplasty is superior to placebo intervention for pain reduction in patients with acute osteoporotic spinal fractures of less than 6 weeks' in duration. These findings will allow patients with acute painful fractures to have an additional means of pain management that is known to be effective.

Funding

Education grant from CareFusion Corporation.

Introduction

Osteoporotic vertebral fractures affect an estimated 1·4 million patients in the world annually.1Although most have mild symptoms, a subset of patients develop substantial pain and disability and some require admission to hospital.2 Standard therapy, consisting of rest, analgesia, and mobilisation, is often poorly tolerated in elderly people, with the adverse effects of analgesia and immobilisation leading to additional health problems, including poor cognition, increased risk of falls, constipation, and nausea.3

Vertebroplasty, the injection of polymethylmethacrylate (PMMA) into the fractured vertebral body, is frequently used for symptomatic osteoporotic fractures, and is based on the premise that fracture stabilisation can provide pain relief. Optimum timing for vertebroplasty is controversial. Because symptoms from painful vertebral fractures might improve over time, a common approach has been to allow the fracture to heal, a process spanning up to 12 months, and intervene only in patients with persistent pain. Two masked randomised controlled trials (RCTs)4, 5 have investigated this approach and found no significant benefit of vertebroplasty in patients with osteoporotic fractures of up to 12 months in duration when compared with a placebo. Early intervention was not assessed as a primary outcome in these trials, and the volume of cement used per patient was small, raising the question of whether vertebral stability was achieved.6

We hypothesise that vertebroplasty can effectively reduce pain if done with an adequate vertebral fill technique within 6 weeks of fracture onset. Evidence from open-label RCTs7, 8, 9 supports the premise of early intervention. However, evidence is deficient from the two masked trials10 because less than 25% (25 of 106) of vertebroplasty patients in pooled data had fractures of less than 6 weeks' duration.

To understand better the safety and effectiveness of vertebroplasty for patients with painful fractures of less than 6 weeks' duration, we undertook a study masked to patients and assessors comparing vertebroplasty with a placebo procedure—the Vertebroplasty for Acute Painful Osteoporotic fractURes (VAPOUR) trial.

Research in context

Evidence before this study

A systematic literature review by the Australian Medicare Services Advisory Committee in 2011 focused on three good quality randomised trials of vertebroplasty. Two masked trials (Kallmes and colleagues, Buchbinder and colleagues) enrolled patients with fractures up to 12 months' duration and found vertebroplasty no more effective than placebo in pain reduction. Subgroup meta-analysis of these masked trials (by Staples and colleagues) identified 57 patients with fractures of less than 6 weeks' duration, and found vertebroplasty no more effective than placebo in this acute fracture subgroup. Conversely, an open-label randomised trial (Klazen and colleagues) of patients with fractures of less than 6 weeks' duration showed that vertebroplasty was more effective than conservative care in reducing pain. The review concluded that the two masked trials were of superior methodological quality and provided evidence of lack of efficacy for vertebroplasty. However, the small representation of patients with uncontrolled pain and acute fractures of less than 6 weeks' duration in the masked trials caused uncertainty for the role of vertebroplasty in this subgroup. The review recommended a high quality placebo-controlled trial to specifically assess this patient group. This is such a trial.

Added value of this study

This randomised, parallel group, placebo-controlled trial, was designed to answer the question as to whether vertebroplasty compared with placebo improved pain measures, primarily, and disability measures, secondarily, in patients with fractures of less than 6 weeks' duration. There were 120 patients, twice the number of the subgroup meta-analysis of previous masked trials, thereby increasing the statistical power. Our findings show that vertebroplasty improved both pain and disability measures.

Implications of all the available evidence

Until now, there has been no evidence that vertebroplasty was more effective than placebo in the treatment of acute, painful, osteoporotic vertebral fractures, most notably for those in the thoracolumbar region. No masked studies have exclusively examined acute fractures of less than 6 weeks' duration but only in a subgroup analysis with small patient numbers. Our study will allow those people with acute painful fractures to have an additional modality of pain management that is known to be effective.

Section snippets

Study design and participants

This randomised, parallel group, placebo-controlled trial of vertebroplasty was done in four centres in Sydney, Australia. There was a 6-month follow-up period. The protocol, reported previously,11 is a modification of the protocol from the INVEST trial4 in which two of our authors were investigators.

Participants were referred to interventional radiology from primary care practitioners, medical specialists' consulting rooms, and hospital inpatient and emergency departments. The patient was

Results

Between Nov 4, 2011, and Dec 5, 2014, 120 patients were enrolled, randomly assigned, and all underwent the assigned intervention (figure 1). Baseline characteristics of both groups were similar (table 1). The mean PMMA volume injected per bone was 7·5 mL (SD 2·8). Minor PMMA extravasation occurred in 21 (34%) of 61 patients. 112 (93%) of 120 patients completed follow-up at 14 days and 102 (85%) had final assessment at 6 months.

In the intention-to-treat analysis, the proportion of patients with

Discussion

Vertebroplasty was used to control acute, severe pain in an elderly, fragile patient group and was more effective than placebo in reducing pain from osteoporotic fractures within 6 weeks of onset. Enrolment required severe NRS pain (defined as a score of ≥7 out of 10) and clear success from vertebroplasty was designated as low NRS pain (defined as <4 out of 10) at 14 days. The 23% advantage in this outcome was smaller than the 30% targeted in the study design, although this figure is within the

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