Participants
Participants will be recruited from general practitioners, specialists who manage acute osteoporotic vertebral fractures and hospital inpatient and emergency departments. To increase awareness of the trial, we will advertise in local media, include regular updates in relevant medical organisation newsletters, and send regular newsletters to our referral base.
All potential participants will be screened to determine eligibility according to the following inclusion and exclusion criteria. Participants will have back pain of no more than 12 months duration. Osteoporotic spinal fractures will be confirmed by thoracic and lumbar spine radiograph and, if not already obtained, all participants (unless contraindicated) will have an MRI examination of the thoracic and lumbar spine to determine the position, extent, age and stability of the vertebral fracture and to ensure no exclusion criteria exist. Only participants with one or two recent vertebral fractures, defined as vertebral collapse and oedema or fracture line within the vertebral body, will be included. When an MRI is unable to be performed, a CT scan, to determine the position and extent of the vertebral fracture/s, and bone scan, to determine the presence of increased uptake in a distribution compatible with recent vertebral fracture will be required.
Exclusion criteria will be: the presence of more than two recent spinal fractures; presence of malignant disease in the spine; neurological complications; osteoporotic vertebral collapse of > 90%; fracture through or destruction of posterior wall; retropulsed bony fragment or bony fragments impinging on the spinal cord; discitis; osteomyelitis; uncontrolled sepsis; non-correctable coagulation disorder; medical conditions that make the patient ineligible for emergency decompressive surgery should it be necessary to treat a procedure complication (e.g. severe heart and/or lung disease, renal failure); current malignancy; dementia; previous vertebroplasty; inability to give informed consent; an/or likelihood of non-compliance with follow up.
Interventions
All procedures will be standardised across sites. Patients will be positioned prone on the angiographic table and preliminary screening will be performed to identify the fracture level. A 25G intravenous cannula will be inserted into the dorsum of the hand or forearm and neurolept sedation/analgesia of midazolam and fentanyl (doses appropriate for weight and height) will be given as required during the procedure by the radiologist performing the procedure. A cardiac monitor clip will be placed on the other hand. For all patients, the skin will be prepared with an iodine-based solution and a drape will be placed over the body. All procedures will be standardised with care taken to preserve blinding in the event that patients do not have total amnesia. Throughout the procedure, blood pressure, heart rate, oxygen saturation and neurological status will be monitored. Procedures will be performed in hospitals with neurosurgical or orthopaedic surgical support in case of unforeseen complications and patients will be monitored for 4 hours following the procedure in the Day Procedure Ward prior to being discharged. Analgesia as required will be given following the procedure.
Percutaneous Vertebroplasty
The left pedicle of the fracture site will be identified with a metallic marker and a 25G needle will be used to infiltrate the skin overlying the pedicle. A longer 23G needle will be used to infiltrate the periosteum of the posterior lamina. A scalpel will be used to make a small incision in the skin. A 13G needle (Cook, USA) with a bevelled edge will be placed posterolateral relative to the eye of the pedicle. Gentle tapping using a hammer will be performed to guide the needle through the pedicle down into the anterior two thirds of the fractured vertebral body. Bi-plane imaging if available will guide needle placement, alternatively the image intensifier screen will be rotated from the A-P to the transverse planes and back again to monitor the progress of the needle as it passes through the bone. Both A-P and lateral images will be recorded with the needle in the correct position. Intravertebral contrast injection venography will be optional. Some operators find the localisation of veins to be useful. Ten ml dilute contrast will be injected through connecting tubing into the needle to assess filling of epidural veins with digital subtraction radiography if venography is used.
At the nursing trolley, the pre-packaged PMMA with radio-opacifier will be mixed to an appropriate consistency. This will be poured into a 20 ml syringe from which several 1 ml syringes will be filled. The stylet will be removed from the 13G needle transfixed within the vertebral body and approximately 3–4 millilitres PMMA will slowly be injected into the vertebral body rotating the needle in order to direct the passage of bone cement to the affected area. The working time for the injection is approximately 2 minutes. Having confirmed satisfactory infiltration of the vertebral body with bone cement in both A-P and lateral planes (with the image intensifier), the needle will be slowly removed by rotation. A unilateral approach will be used unless there is inadequate instillation of cement, in which case a bipedicular approach will be used. Extreme care will be taken to ensure that no leakage of cement occurs either into a vein or outside the bone. The injection will be stopped when significant resistance is met, or when the cement reaches the posterior quarter of the vertebral body or when there is escape into extraosseous structures or veins. All patients in the active group will receive 1 gram cephalothin IV as prophylaxis against infection.
Placebo treatment
Many patients who undergo vertebroplasty recall the tapping sensation against the vertebra. For this reason, subjects assigned to placebo will undergo the same procedures to insertion of the 13G needle to rest on the lamina. At that point, the central sharp stylet will be removed and replaced by a blunt ended stylet. To simulate vertebroplasty, gentle tapping with a hammer will be performed sufficient to generate enough noise and vibration to be heard and felt by the patient. The blunt ended stylet will be less likely to penetrate the bone during tapping with a hammer. At regular intervals the image intensifier will be rotated into the lateral planes and then back to the AP plane. At the nursing trolley, some PMMA will be reconstituted with barium and saline such that the smell permeates throughout the room. Several 1 ml syringes will be filled as for the active group and injection will be simulated.
All participants receive usual care according to the discretion of their treating doctor. Analgesia use is unrestricted and its use will be recorded at baseline and follow up. All treating physicians receive an information sheet about the trial as well as a copy of the most up-to-date guidelines for management of osteoporosis. Management of osteoporosis is at the discretion of the participants' treating physicians.
Outcome Assessment
The same blinded assessor will assess all participants at baseline. Baseline data will include gender, date of birth, height, weight, risk factors for osteoporosis including use of certain medications such as corticosteroids and anticonvulsants, smoking and alcohol use, medications for osteoporosis, usual level of exercise, fracture history, current therapy for vertebral fracture. If not already available, plain films of the thoracic and lumbosacral spine will be obtained. If not performed within the previous year, bone mineral density measurement will also be performed.
All participants will be evaluated after the procedure at 1 week, 1, 3, 6, 12 and 24 months using mailed questionnaires. Reply-paid envelopes will be provided to maximise response rates.
The following outcomes will be assessed at each time point:
Overall pain, pain at rest, and pain in bed at night (over the last week) will be measured on a 0–10 numerical scale comprising a vertical line labelled "no pain" at the bottom (0) and "maximal imaginable pain" at the top (10) [
28].
A range of standardised, self-report quality of life measures will be used:
The Assessment of Quality of Life (AQoL) is a health-related quality of life instrument comprising 15 items in 5 dimensions (Illness, Independent Living, Social Relationships, Physical Senses, and Psychological Well-being) [
29,
30]. It is well validated, responds to rapid changes in health status and is sensitive to changes in the frail elderly [
29]. The AQoL incorporates utility weights that have been derived from an Australian population sample using time-trade off (TTO). The range of scores is between 0.00 (death) and 1.00 (perfect health), with higher scores representing better health-related quality of life. The utility score can be used in cost-utility analyses and calculation of Quality-Adjusted Life Years.
The quality of life questionnaire of the European Foundation for Osteoporosis (QUALEFFO) is an osteoporosis-specific measure comprising 41 items organised in five domains (Pain, Physical Function, Social Function, General Health Perception and Mental Function) [
31]. Each domain score and QUALEFFO total scores are expressed on a 100-point scale, with lower scores corresponding to better health-related quality of life. It has demonstrated reliability between patients with and without vertebral fracture and QUALEFFO scores have been shown to increase progressively with increasing numbers of vertebral fractures [
32].
The EQ-5D is a standard general quality of life instrument, measuring five domains (Mobility, Self Care, Usual Activities, Pain/Discomfort and Anxiety/Depression), with three levels in each, ranging in severity from no problem, some problem to extreme problem [
33]. Respondents are then classified into one of 243 (3
5) health states, with the best imaginable health state representing someone who reports the highest level of functioning in each domain. This instrument has been used in studies of patients with and without vertebral fractures [
34,
35].
The Roland Morris Disability questionnaire measures physical disability due to low back pain [
36] but has also been shown to be an effective tool in evaluating vertebroplasty outcomes [
37]. The original questionnaire consisted of 24 questions and was derived from the Sickness Impact Profile (SIP), with qualification 'because of my back pain' added to each question [
36]. We will use a modified version comprising 28 items, modified to reduce the redundancy of some of the questions and to add items that better reflect changes in the patient [
37]. Items are scored from 0 (no disability) to 28 (maximum disability). An additional question regarding the use of wheelchairs has been added and is scaled from 1 (no disability) to 4 (maximum disability).
Participants' perceived recovery with respect to pain, fatigue and overall health will be measured on 7-point ordinal scales ranging from 'a great deal worse' to 'a great deal better' at all follow up time points. It will be used to classify participants with a successful outcome, defined as 'moderately better' or ''a great deal better' across each indicator.
At baseline, 12 and 24 months, all participants will be assessed by the same blinded assessor who will administer the timed 'Up and Go' test [
38]. This measures the time it takes a person to rise from a standard arm chair, walk to a line on the floor 3 metres away, turn around, return to the chair and sit down again. It is a widely used functional measure in older people and has good reliability and validity.
To determine the incidence of new vertebral fractures radiologically, all participants will undergo plain film examination of the thoracic and lumbosacral spine at 12 and 24 months. Regular serial follow-up films are recommended standard care following vertebroplasty to evaluate the treated vertebrae and to look for fractures in untreated vertebrae [
25]. Two independent blinded radiologists will read the radiographs using the well-validated and reliable Genant semi quantitative method for identifying and gauging the severity of the fracture [
39]. A new vertebral fracture will be defined as an increase in deformity grade (equivalent to a decrease of >15% in any vertebral height) from the baseline radiograph to the end of the study; or a new fracture in an existing prevalent fracture if there is progression to a higher grade of deformity (equivalent to a further vertebral height reduction of >15%) [
39].
Success of blinding will be assessed at the end of the study by asking participants to indicate their treatment group. Five response options will range from 'I am definitely in placebo group', through to 'I am definitely in the vertebroplasty group', with 'don't know' as the central option.
Sample size
The primary outcome will be overall pain at 3 months. Very large effects (e.g. >7 on a 10 point scale) have been reported for improvement in pain scores for individual patients. People who undergo conventional treatment will also tend to have some improvement as some acute symptoms subside. To detect a large (i.e. at least a 2.5 unit) advantage of vertebroplasty over placebo in pain score (SD = 3.0, α = 0.05, β = 0.80, 2-tailed t-test) we would require only 24 participants per group. At 12 and 24 months we expect smaller differences to exist between the groups due to the natural course of the disease (i.e. improvements in the placebo group and likely adjustment to the illness) and possibly a greater frequency of vertebral fracture in the vertebroplasty group. Using the same assumptions as above but considering a 15% advantage in the vertebroplasty group (mean vertebroplasty improvement = 4.0 units, mean placebo improvement = 2.5 units) we would require 64 people in each group.
The most relevant adverse event from vertebroplasty may be further vertebral fractures. A reasonable estimate for the one year incidence of new fractures in women with at least one fracture and not on preventive treatment is about 20% based on new vertebral fractures observed in the first year for the placebo arm of four risedronate clinical trials [
21]. Many participants in our trial are likely to be on treatment for osteoporosis, which may theoretically reduce the risk of further vertebral fracture by 50% to around 10% [
21,
40,
41]. In the two controlled before-after studies there was between a zero and 3 fold increase in the 1 year new fracture risk [
42,
20]. The risk of fracture in the second year is unknown but likely to be less than in the first year. With 82 people in each group we will have 80% power to detect a 3-fold excess in fractures in the vertebroplasty group (alpha = 0.05, 2-tailed Log rank test). While this study is not specifically designed to assess small group differences related to infrequent events, if medium to large excesses in adverse events are present, the study is adequately powered.
Health-related Quality of Life (AQoL utility score) is an important global secondary outcome at 2 years. This is a complex mix of benefits such as vertebral-specific reduction in pain and decreased distress, but may also involve adverse events such as vertebral re-fracture or hip fracture. The AQoL is an ideal generic instrument to capture broad health-related changes – incorporating a mix of health declines and improvements. With a sample size of 82, there will be 80% power to detect a 0.13 change in Health -related Quality of Life (utility). For example, the improvement in the placebo group may be 0.10 units compared with 0.23 in the vertebroplasty group (sd = 0.3, α = 0.05, 2-tailed t-test). Compared with the disease-specific outcomes noted above, this magnitude of change can be regarded as relatively small but clinically relevant [
43]; hence the study is powered to detect even modest overall benefits of vertebroplasty. To allow for attrition, we will increase the sample by 20% to 100 patients per group.