This study investigates the effects of kyphoplasty on pain and mobility in patients with osteoporosis and painful vertebral fractures compared with conventional medical management.
Introduction: Pharmacological treatment of patients with primary osteoporosis does not prevent pain and impaired activity of patients with painful vertebral fractures. Therefore, we evaluated the clinical outcome after kyphoplasty in patients with vertebral fractures and associated chronic pain for >12 months.
Materials and Methods: Sixty patients with primary osteoporosis and painful vertebral fractures presenting for >12 months were included in this prospective, nonrandomized controlled study. Twenty-four hours before performing kyphoplasty, the patients self-determined their inclusion into the kyphoplasty or control group so that 40 patients were treated with kyphoplasty, whereas 20 served as controls. This study assessed changes in radiomorphology, pain visual analog scale (VAS) score, daily activities (European Vertebral Osteoporosis Study [EVOS] score), number of new vertebral fractures, and health care use. Outcomes were assessed before treatment and at 3 and 6 months of follow-up. All patients received standard medical treatment (1g calcium, 1000 IE vitamin D3, standard dose of oral aminobisphosphonate, pain medication, physical therapy).
Results: Kyphoplasty increased midline vertebral height of the treated vertebral bodies by 12.1%, whereas in the control group, vertebral height decreased by 8.2% (p = 0.001). Augmentation and internal stabilization by kyphoplasty resulted in a reduction of back pain. VAS pain scores improved in the kyphoplasty group from 26.2 ± 2 to 44.2 ± 3.3 (SD; p = 0.007) and in the control group from 33.6 ± 4.1 to 35.6 ± 4.1 (not significant), whereas the EVOS score increased in the kyphoplasty group from 43.8 ± 2.4 to 54.5 ± 2.7 (p = 0.031) and in the control group from 39.8 ± 4.5 to 43.8 ± 4.6 (not significant). The number of back pain-related doctor visits within the 6-month follow-up period decreased significantly after kyphoplasty compared with controls: mean of 3.3 visits/patient in the kyphoplasty group and a mean of 8.6 visits/patient in the control group (p = 0.0147).
Conclusions: The results of this study show significantly increased vertebral height, reduced pain, and improved mobility in patients after kyphoplasty. Kyphoplasty performed in appropriately selected osteoporotic patients with painful vertebral fractures is a promising addition to current medical treatment.
OSTEOPOROSIS IS AN INCREASING burden of an aging society, resulting in >400,000 vertebral fractures in the United States and >1 million vertebral fractures in Europe per year.(1–3) In addition to pain and a reduced quality of life,(4–8) vertebral fractures are also associated with increased cardiovascular mortality.(9,10) Braces are frequently used in conservative treatment, and in some cases, help patients to stay mobile, although controlled prospective trials showing effectiveness and patient benefit of most brace designs are rare.(11–13) Despite progress in medical prevention of osteoporotic fractures, patients who do have vertebral fractures may have severe pain. New techniques are needed for reducing pain and also for pain medication-dependent side effects. Previous reports described kyphoplasty as a minimally invasive procedure,(14,15) improving pain in patients with vertebral fractures. However, these results have not been confirmed by controlled studies. This paper presents the first prospective controlled study of kyphoplasty in patients with primary osteoporosis with painful vertebral compression fractures that were present for >12 months. Previously published reports on outcome after kypho- and vertebroplasty treatment included only patients with acute vertebral fractures present for <3 months. Morphological correction of the deformed vertebral bodies, new vertebral fractures, patient-reported pain, daily activities of the patients, and levels of health care use were assessed. The purpose of this study was to clarify whether patients with chronic pain caused by osteoporotic vertebral fractures benefit clinically from kyphoplasty.
MATERIALS AND METHODS
Study design and population
A prospective nonrandomized controlled study was undertaken in a single center. The study population consisted of consecutive patients with primary osteoporosis and painful vertebral fractures presenting at the outpatient clinic of the University of Heidelberg from May 2002 to September 2002.
Inclusion and exclusion criteria
Patients of both genders with primary osteoporosis with one or more painful osteoporotic vertebral fractures requiring chronic pain medication were eligible for participation. Vertebral fractures were present for >12 months before inclusion as analyzed by previous X-rays of the patients. Evaluation of suitability for kyphoplasty was performed as follows. (1) Pain localization was determined by pain triggering by applying pressure to the processus spinosi. Kyphoplasty was performed only if the patient was able to clearly localize the worst pain region along the spine and by knocking on the spinal processes that had to worsen the pain sensation at this spot. A thorough clinical examination determined the fractured vertebral body that was responsible for the chronic back pain—if the fractured vertebra was indeed the cause and not, for example, an intervertebral disc-related problem, (2) a team of endocrinologists, trauma surgeons, and radiologists analyzed the radiological status of each patient to ensure that kyphoplasty was technically feasible (absence of burst fractures, vertebra plana, degenerative osteophytes between vertebrae, and presence of clearly discernible pedicles), and (3) most importantly, the localization of the most severe back pain of the selected patients had to correspond to the technically treatable vertebrae (patient was able to clearly point to the fractured vertebrae as the pain source and the chronic pain could be exacerbated by knocking on the respective spinal processes). Among all the patients referred to our osteological center with chronic back pain, osteoporosis, and unresponsiveness to conventional pain treatment, <50% were selected as eligible for participation in the trial by the interdisciplinary Heidelberg team. All patients meeting the inclusion criteria were offered kyphoplasty and were asked to sign an informed consent form by the same investigator before the procedure, as required by the ethics committee of the University of Heidelberg, who approved the study. Patients were informed of risks and benefits of kyphoplasty and conservative management. Based on this informed consent, patients selected if they wanted to undergo kyphoplasty or control therapy with optimal medical treatment of osteoporosis, including physiotherapy and optimized analgesic treatment.
All participants in both groups received medical treatment (daily standard dose of oral aminobisphosphonate + 1000 mg calcium + 1000 IE vitamin D3) and a recommendation for supervised physiotherapy once a week for 6 months. All patients were hospitalized the day before kyphoplasty for premedication.
For patients undergoing kyphoplasty, two cannulae were inserted transpedicularly into the crushed vertebral body. Cavities of 4- to 5-ml volume were created by two balloon tamps inserted through the cannulae. After removal of the balloon tamps, bone cement polymethylmethacrylate (PMMA; KyphX; Kyphon and Cemex; Tecres) or calcium phosphate cement (Calcibon; BiometMerck, Darmstadt, Germany) was injected into the created cavities, where it hardens within minutes. PMMA cement and Calcibon were used in turns (first patient, PMMA cement; second patient, Calcibon; third patient, PMMA; etc.). All kyphoplasty patients were discharged 48 h after kyphoplasty.
Midline vertebral height, kyphosis angle, and new vertebral fractures:
Clinical study of the spine was assessed by evaluation of the lateral X-rays of the spine according to standard radiological analyses,(15–17) whereby the actual measurements of midline vertebral height and kyphosis angle were performed as described in detail by Lieberman et al.(15) Blinded radiographic assessment was not possible because the cement fillings are clearly discernible on the postkyphoplasty X-rays. However, blinded readings of radiographs have been shown to increase the frequency of errors in analyzing vertebral deformities.(18)
After 6 months, we also assessed new vertebral fractures of the thoracic and lumbar spine and of vertebrae directly adjacent to the treated (kyphoplasty group) or planned for treatment (control group) vertebral bodies. Standard definitions and procedures for the assessment of vertebral fractures(16) were used. A vertebral height reduction of 10% or more compared with the initial vertebral height (at study entry) of the posterior wall of the treated vertebrae or of the next adjacent intact vertebrae was defined as a new vertebral fracture.
Pain was evaluated in patients by a visual analog scale (VAS) spine score that has been validated for patients undergoing spinal surgery.(19) Some minor modifications of the VAS score had to be implemented because the patients were too old and too fragile to answer questions regarding sex life, jogging, weight lifting, and traveling.
The general complaints and impairments of the activities of daily life associated with osteoporotic fractures were evaluated in patients using the EVOS questionnaire, which had been validated for the European Vertebral Osteoporosis Study.(20) The questionnaire consisted of 23 questions addressing physical functioning. Given the number and specificity of the individual questions, it did not seem appropriate to present them separately within the scope of this paper.(21)
Pain medication and health care contacts:
We evaluated the patients' self reports of required pain medication in the month before kyphoplasty and 6 months after the procedure by assessing patients' charts. Pain medication usage was classified according to WHO standards.(22) In addition, we assessed the number of the patients' health care contacts because of any complaint and particularly caused by back pain-related complaints within the 6-month follow-up period. The above outcomes were assessed before (baseline) and 3 and 6 months after kyphoplasty.
Establishing kyphoplasty at our center, two adverse events occurred among the first nine cases. One patient experienced a penetration of the spinal cord, leading to permanent paresis and paresthesia of one leg. In another case, we observed an epidural hematoma in the spinal canal after 24 h. After these two adverse events during the learning phase, 35 procedures were performed without any adverse events. After establishing kyphoplasty as safe, the study was submitted to the local ethics committee, and all patients were treated after the ethics committee had approved the study.
During the study we assessed neurological symptoms and procedural adverse events by evaluating postkyphoplasty CT scans with regards to cement leakages.
Kyphoplasty and control group outcomes were compared at 3- and 6-month follow-up using multivariate generalized linear regression modeling. Group comparisons were adjusted for baseline outcome values alone and baseline characteristics (age, sex, and number of preoperative fractures). Baseline characteristics were compared using independent two-group t-test and Fischer's exact test for continuous and binary outcomes, respectively. Pearson correlation coefficient was used to examine the association between morphometry and both EVOS and VAS scores.
Subgroup analysis was undertaken by examining the treatment effect interaction at 6-month follow-up in EVOS and VAS total scores. Three subgroups were predefined: (1) biocement versus PMMA, (2) number of preoperative fractures (one to three fractures versus more than three fractures), and (3) baseline VAS and EVOS scores.
Where necessary, missing outcome values were imputed by the “last value brought forward” replacement method (i.e., missing values were replaced with the outcome value for that case collected at the previous assessment point). To assess the potential impact of missing values, sensitivity analysis was used to compare outcome results with and without missing value replacement by imputation.
All analyses were undertaken according to intention-to-treat, and results are expressed as means and SD or as mean differences with 95% CIs. All data analysis was undertaken using Strata V.6.
Two hundred eleven patients with primary osteoporosis and chronic back pain caused by vertebral fractures for >12 months were identified during the study period. BMD, as evaluated by DXA measurements (Hologic 4500 Discovery) of the spine and left total hip, was comparable in all patients included in this study (controls: BMD spine, 0.803 g/cm2; BMD total hip, 0.661 g/cm2; kyphoplasty group: BMD spine, 0.790 g/cm2; BMD total hip, 0.635 g/cm2; spine: p = 0.73; hip: p = 0.42).
Ninety-seven patients were offered kyphoplasty, and of these, 60 patients responded and returned to our clinic. Forty patients chose to undergo kyphoplasty, whereas the remaining 20 patients elected not to undergo kyphoplasty and were taken as a control group (Fig. 1).
There was no evidence of a statistically significant difference in the characteristics of the kyphoplasty and control groups at entry to the study (Tables 1 and 2).
Table Table 1.. Demographic and Clinical Characteristics of Study Population
Table Table 2.. Anatomical Distribution of Fractured Vertebrae in the Control and Kyphoplasty Group
Midline vertebral height and kyphosis angle
Vertebrae treated by kyphoplasty exhibited a relatively constant kyphosis angle during follow-up, whereas there was a significant increase of the kyphosis angle in the controls after 6 months (p < 0.0001), indicating further fracturing of the anterior vertebral wall in the controls. The midline vertebral height was significantly greater (p < 0.0001 at both 3 and 6 months) in the kyphoplasty group compared with the control group (Table 3; Figs. 2A and 2B).
Table Table 3.. Radiographic Outcomes at 3 and 6 Months Follow-up
New vertebral fractures
The incidence of further vertebral fractures in patients with osteoporosis increases significantly after the first vertebral fracture occurred.(23) Thus, we analyzed the number of new vertebral fractures. Six new vertebral fractures occurred in five patients (12.5%) after kyphoplasty, and eight new vertebral fractures occurred in six (30%) control patients (χ2 = 1.46, p = 0.227). In the control group, among the 41 adjacent vertebrae, 5 vertebrae (12%) exhibited a new fracture, whereas in the kyphoplasty group, 5 new vertebral fractures occurred among 84 (6%) adjacent vertebrae (p = 0.323).
At 3 and 6 months, the kyphoplasty group exhibited a significant improvement of total VAS scores compared with controls (p = 0.012 and p = 0.007; Tables 4 and 5; Fig. 2C).
Table Table 4.. Clinical Outcomes at 3- and 6-Month Follow-up
Table Table 5.. Evaluation of the VAS-Score Questionnaire Before (T0) and 6 Months After (T6) Kyphoplasty (Rx) vs. Control (Con) Group
The beneficial effect of kyphoplasty on patients' complaints seems to be accompanied by improved daily activity as determined by the EVOS score. At 6 months, the kyphoplasty group exhibited a significant improvement in EVOS scores compared with controls (p = 0.031; Table 4; Fig. 2D).
Relation of clinical outcome to radiomorphometrical changes
To address the hypothesis that reheightening of the radiomorphological appearance of the treated vertebrae is associated with decrease in pain and improvement of daily activity, we assessed changes of vertebral height in comparison with changes in pain and activity scores. For this analysis, the radiomorphometric changes (i.e., midvertebral heights) after kyphoplasty were correlated to the clinical scores. There was no significant correlation between the change in midline vertebral height after kyphoplasty and the obtained clinical benefit regarding pain and activity (baseline to 6 months change in VAS score versus baseline to 6-month change in vertebral height; r = 0.273, p = 0.124; baseline to 6-month change in EVOS score versus baseline to 6-months change vertebral height; r = 0.139, p = 0.565). Furthermore, there was no evidence of a difference in the treatment effects for VAS and EVOS scores across subgroups.
Pain medication usage and health care contacts
After kyphoplasty, there was a reduction in the percentage of patients requiring opiates from 67.5% to 55%, whereas in the controls, the percentage of patients requiring opiates reduced from 70% to 65% (data not shown). There were also significantly fewer back pain-related doctor visits in the kyphoplasty group (p = 0.015; Fig. 3).
There were no complications of neurological, embolic, or cardiovascular symptoms during or after kyphoplasty in any patient. In 72 treated vertebral bodies, seven cement leakages (9.7%) were observed, which is comparable with observed rates of clinically asymptomatic cement leakages.(24)
This prospective, nonrandomized controlled study supports the use of kyphoplasty in addition to medical therapy as an effective method to improve and stabilize deformities of fractured osteoporotic vertebrae, resulting in reduction of pain, improvement of daily activity, and reduction of health care use. These findings apply only to a subgroup of patients with severe and disabling chronic pain who were unresponsive or not eligible for conventional treatment and surgery. The inclusion of patients with long-lasting pain caused by osteoporotic fractures indicates that a self-healing capacity resulting in pain reduction plays no role in this subgroup. The fact that fewer doctor visits were observed in patients compared with the controls is supportive of a beneficial effect of kyphoplasty. However, with regard to cost-effectiveness, a formal cost-effectiveness study is required to confirm a potential reduction in downstream health resources with kyphoplasty.(25,26) Other treatment options for pain caused by vertebral fractures such as brace treatment have also yet to be evaluated with regard to costs in a prospective controlled study.(27,28)
Kyphoplasty may induce new vertebral fractures, particularly in adjacent vertebrae, because of the increased strength of the stabilized vertebral bodies in an osteoporotic spine with an initially already present 35-fold increased vertebral fracture risk, considering that 73% of the patients in this study had initially more than three fractured vertebrae.(23,29) However, no significant difference in adjacent vertebral fracture rate was observed between kyphoplasty and controls in this study. Kyphoplasty increases the number of patients exhibiting an improved activity, and thus, an enhanced mobility and an altered loading pattern of the entire spine after kyphoplasty may restore the physiological microdeformation of bone architecture that is perceived and translated by osteoblastic cells into antiresorptive and osteoanabolic signals, preventing further vertebral fractures.(30) Future work with greater numbers of patients and a longer follow-up period are needed to clarify the impact of kyphoplasty on vertebral fracture incidence.
The principle limitations of this study were its nonrandomized design and lack of a formal sample size calculation. Given that patients were not allocated to kyphoplasty and control randomly, we cannot discount the possibility of selection bias and confounding. However, we did not observe a significant difference in baseline characteristics between the two groups. In addition, to minimize the potential of confounding, we undertook statistical analysis adjusting for baseline score and characteristics. Nevertheless, we cannot completely discount the possibility of differences between groups because of nonmeasured confounders. Given the lack of data at the onset of study on the potential differences in outcome that might exist between the two groups, we could not formally estimate sample size. It is therefore possible that our failure to detect differences in some of the outcomes between the kyphoplasty and control group may reflect a limitation of statistical power.
The observed improvements in pain reduction and mobility after kyphoplasty is support for its use in patients with painful vertebral fractures who profit not only with respect to the percentage of patients whose complaints are improved but also with respect to the quantity of improvement seen in the kyphoplasty group. Furthermore, reported inevitable side effects of long-term analgesic medication(31) in patients with chronic pain can be avoided. However, our results require confirmation by randomized controlled trials. Additionally, there remain unresolved questions about kyphoplasty, e.g., why do some patients treated by kyphoplasty not exhibit satisfactory clinical improvement in pain and activity?
Several reports show a substantial height restoration of the fractured vertebrae after kyphoplasty.(15,32,33) Kyphoplasty may reheighten the crushed vertebral body by 33-65%,(15,32,34) whereby the quantitative differences in height restoration are merely caused by different methods of calculating vertebral height and different ages of the treated fractures. Determining regain-of-lost-height results in somewhat greater vertebral height restorations(15,32,34) than determining height restoration in relation to an adjacent intact vertebral body.(14,35) Particularly in vertebral fractures <4 weeks old, dynamic fracture mobility may allow a significant restoration of vertebral height already when putting the patient for kyphoplasty on his chest and iliac crests in hyperlordosis.(35,36) In this study, we observed a small but significant effect of kyphoplasty on height restoration (∼15%) in our osteoporotic patients with old vertebral fractures.(37) There was no significant correlation between the degree of height restoration and the observed improvement of pain or mobility. Internal stabilization and thus prevention of permanent microfracturing may also cause pain reduction,(38) because previous retrospective observations of patients after vertebroplasty with no effect on vertebral morphology also showed a significant reduction of pain.(25,26,34,39,40)
In summary, in this prospective nonrandomized controlled study, we observed a positive effect of kyphoplasty on vertebral morphology and patient's pain, level of activity, and health care use after 6 months. Therefore, kyphoplasty performed in appropriately selected osteoporotic patients with severely painful vertebral fractures is a promising addition to current pharmacological treatment. These findings require confirmation by randomized controlled trials.
We are grateful for the support of this study by Biomet Merck Darmstadt, Germany, Kyphon Europe, Deutsche Forschungsgemeinschaft (Ka 682/7-1), and from the Havemann Family, Germany.