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Treatment of Chronic Symptomatic Vertebral Compression Fractures with Percutaneous Vertebroplasty

¹ All authors: Mallinckrodt Institute of Radiology, 510 S Kingshighway Blvd., Box 8131, St. Louis, MO 63110.

Received March 14, 2003; accepted after revision August 4, 2003.

 
Address correspondence to D. B. Brown (brownda{at}mir.wustl.edu).

Abstract

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OBJECTIVE. Most fractures treated with percutaneous vertebroplasty are subacute and less than 1 year old. We report our experience treating chronic vertebral fractures with vertebroplasty.

MATERIALS AND METHODS. Our database identified 41 patients with symptomatic fractures more than 1 year old. These patients were categorized into subgroups determined by fracture age: 12 months 1 day–24 months (n = 16) or more than 24 months 1 day (n = 25). Changes in pain and mobility for the study group were compared with those in 49 patients with fractures less than 1 year old.

RESULTS. Thirty-three (80%) of the 41 patients in the study group had improvement in pain—seven (17%) had complete and 26 (63%) had partial relief. Forty-five (92%) of the 49 control group patients had improvement in pain—24 (49%) had complete and 21 (43%) had partial relief. The number of patients achieving partial or complete relief of pain was not statistically different between groups (p > 0.05), although complete relief was significantly more frequent in the control group (p = 0.002). Twenty patients (49%) in the study group versus 34 patients (69%) in the control group had improved mobility after vertebroplasty (p = 0.047). Patients with fractures 12 months 1 day–24 months old had improvement in mobility similar to that in patients in the control group (p = 0.962). Fractures more than 24 months 1 day old were associated with significantly less improvement in mobility (p = 0.006).

CONCLUSION. Most patients with fractures more than 1 year old will experience clinical benefit from vertebroplasty. Complete relief of pain is more likely when less mature fractures are treated.

Introduction

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The current indications for percutaneous vertebroplasty are intractable pain caused by vertebral body fractures from osteoporosis, metastatic disease, or hemangiomas [1–6]. Treated patients usually have several weeks of symptoms that do not respond to conservative therapy [1–7]. Previous studies have described the successful treatment of more acute fractures [8, 9]. Treatment of long-standing fractures remains controversial. Previous authors have cast doubt regarding the value of treating older fractures [10, 11]. One trial has reported good results treating fractures with a mean age of 19 weeks [12], and another reported a mixed population with treatment of several fractures that were more than 2 years old [6]. Despite these preliminary reports, outcomes in patients with older fractures treated by percutaneous vertebroplasty remain undefined. Our group has taken an aggressive approach to treating patients with compression fractures of all ages when pain was referable to a specific fracture. The purpose of this article is to review our experience with percutaneous vertebroplasty in patients with fractures more than 1 year old and compare the resultant pain relief and changes in patient activity to a matched cohort of patients with fractures less than 1 year old.

Materials and Methods

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Our hospital's institutional review board approved this study. From September 1998 to July 2001, 219 patients underwent 242 sessions of vertebroplasty with 479 levels treated. The location and number of levels treated in each patient were documented, as was the duration of symptoms corresponding to a radiographically documented fracture. The primary indication for vertebroplasty was intractable, focal, intense pain thought to be related to the fracture. Patients were excluded from the procedure if there was an uncorrectable coagulopathy, unstable fracture involving the posterior elements, inability to provide informed consent, absence of a defined level of collapse or neurologic symptoms, or signs related to vertebral body collapse. The referring physician's neurologic assessment was verified by the radiologist performing the procedure.

Percutaneous vertebroplasty was performed with sterile technique using a C-arm angiographic unit (Angioskop D 33, Siemens Medical Systems, Erlangen, Germany). Mild to moderate conscious sedation was achieved using a combination of fentanyl citrate (Sublimaze, Abbott Laboratories, North Chicago, IL) and midazolam (Versed, Roche Pharmaceuticals, Manati, PR). After sterile preparation and draping, the area overlying the access site and the periosteum of the lamina posterior to the pedicle were anesthetized.

After a small skin incision, an 11-gauge Jamshidi trochar needle (MDTech, Gainesville, FL) was advanced. Using rotational fluoroscopy, we advanced the needle by the transpedicular approach into the anterior third of the vertebral body. We performed intraosseous venography using 1–3 mL of iohexol (Omnipaque 180, Nycomed, Princeton, NJ) to exclude direct venous communication, detail venous drainage, and assess vascularity [13]. We repositioned the needle if necessary to opacify trabeculae before filling venous structures.

We mixed the methyl methacrylate powder (Osteobond copolymer bone cement, Zimmer, Warsaw, IN) with 5 mL of sterilized barium sulfate (Zimmer) [14]. The liquid methylmethacrylate monomer was then added to the powder and mixed to toothpastelike consistency. We injected the polymethylmethacrylate mixture in the lateral projection using a series of 1-mL syringes or a 10-mL syringe with a metal adapter [15]. Injection continued until the polymethylmethacrylate reached the posterior quarter of the vertebral body or it started passing into the disk space or paravertebral tissues. If the polymethylmethacrylate reached the contralateral pedicle, we deemed a second needle unnecessary [16]. When filling the vertebral body was thought to be insufficient, we placed a second transpedicular needle (Fig. 1A,1B,1C,1D,1E).

View larger version (126K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —74-year-old woman with osteoporotic compression fracture of L4 vertebral body. Lateral radiograph obtained in 1997 shows anterosuperior compression of L4.

View larger version (116K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —74-year-old woman with osteoporotic compression fracture of L4 vertebral body. Lateral radiograph obtained in November 1998 reveals further collapse.

View larger version (138K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1C. —74-year-old woman with osteoporotic compression fracture of L4 vertebral body. Sagittal T2-weighted image (TR/TE, 4,000/117) obtained 18 months after B shows no increase in signal in affected vertebral body. Note asymptomatic hemangioma in L2 vetebra.

View larger version (124K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1D. —74-year-old woman with osteoporotic compression fracture of L4 vertebral body. Frontal radiograph after injection of left pedicle shows inadequate filling of right vertebral hemibody.

View larger version (151K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1E. —74-year-old woman with osteoporotic compression fracture of L4 vertebral body. Frontal radiograph after placement of second needle, which led to good final result.

After the procedure, we obtained follow-up by telephone calls to patients 2 weeks, 1 month, 3 months, 6 months, 1 year, and then annually after the final procedure. Patients were asked if their pain was gone, improved, the same as, or worse than before vertebroplasty. We considered patients with complete elimination of or improvement in pain at the final time to have achieved clinical benefit from percutaneous vertebroplasty. Patients also were asked whether their current level of activity had improved, was the same, or was worse since undergoing vertebroplasty. Forty-one patients had symptoms more than 1 year old; these individuals comprised the study group. No patients were refused treatment on the basis of the duration of symptoms. The study group was further subdivided as to whether symptoms had been present for 12 months 1 day–24 months or 24 months 1 day or more. Subgrouping in the study group was performed to further evaluate different fracture ages. As a control, 49 patients with symptoms less than 1 year old who underwent vertebroplasty during the same time period and agreed to follow-up were tracked. These patients were similar in age (study group: mean age = 68 years, range = 40–87 years; control group: mean age = 73 years, range = 44–88 years), cause of fracture, and percentage of female patients (study group vs control group, 78% vs 70%). We compared complete elimination of pain as well as the total of patients achieving improvement in symptoms after percutaneous vertebroplasty between groups.

Results

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The 41-patient study group underwent 44 vertebroplasty sessions on 77 vertebral levels. The indication for vertebroplasty was osteoporotic compression fracture in all 41 patients. Forty-three thoracic and 34 lumbar levels were treated as follows: T3 (n = 2), T4 (n = 2), T5 (n = 1), T6 (n = 2), T7 (n = 4), T8 (n = 4), T9 (n = 4), T10 (n = 7), T11 (n = 7), T12 (n = 10), L1 (n = 15), L2 (n = 8), L3 (n = 5), L4 (n = 5), and L5 (n = 1). The mean number of procedures performed on all patients with chronic fractures was 1.1. The mean number of levels treated per patient was 1.9. Sixteen patients with fractures from 12 months 1 day to 24 months old underwent 16 procedures involving 30 levels. Twenty-five patients with fractures of 24 months 1 day or older underwent 28 procedures involving 47 levels. The mean and median fracture ages for the entire study group were 40.4 and 28 months, respectively. The three patients who underwent multiple procedures had the second vertebroplasty a mean of 10.1 months and median of 10 months after the initial vertebroplasty. Two of these patients initially had pain relief and developed new fractures.

The 49-patient control group underwent 55 vertebroplasty procedures on 98 vertebral levels. Indication for vertebroplasty in this group was osteoporotic compression fracture. In the control group 50 thoracic and 48 lumbar levels were treated as follows: T5 (n = 2), T6 (n = 6), T7 (n = 8), T8 (n = 6), T9 (n = 3), T10 (n = 1), T11 (n = 7), T12 (n = 18), L1 (n = 19), L2 (n = 11), L3 (n = 5), L4 (n = 10), and L5 (n = 3). The mean number of procedures per patient was 1.1, and the mean number of levels treated was 2.0. The six patients who underwent multiple procedures had the second vertebroplasty a mean of 3.7 and median of 4 months after the first procedure. Three of these patients had pain relief with development of new fractures. These values were not significantly different from the study group. No complications of significance occurred in either group.

All patients were treated within 1 month of their most recent imaging study. Followup in the study group ranged from 6 to 28 months with mean and median durations of 15.8 and 12 months, respectively. Follow-up in the control group ranged from 4 to 27 months with mean and median durations of 13.2 and 12 months, respectively. No patients in either group were lost to follow-up.

Changes in pain and mobility after percutaneous vertebroplasty in both groups are outlined in Table 1. No patients in either group described worsening of their pain. In the study group, seven (17%) of the 41 patients reported complete eradication of pain, although 26 (63%) had improvement after vertebroplasty. Clinical benefit was present in 33 (80%) of the 41 patients in the study group. Compared with the control group patients, significantly fewer patients in the study group had complete relief of pain (p = 0.002). The difference between the study group and the control group in achieving clinical benefit was not statistically significant (p > 0.05). Subgroup analysis showed a significantly greater proportion of patients achieving complete pain relief in the control group than in the group with fractures 12 months 1 day–24 months old (p = 0.010) or in the group with fractures 24 months 1 day old or older (p = 0.016). The proportion of patients achieving clinical benefit was not significantly different in any fracture age group. Even though fractures more than 1 year old were less likely to be pain-free after percutaneous vertebroplasty, 80% of patients still reported improvement or eradication of pain.

Twenty patients (49%) in the study group had improved mobility after percutaneous vertebroplasty compared with 34 (69%) in the control group. The difference between groups was statistically significant (p = 0.047). Patients in the group with fractures 12 months 1 day–24 months old had an increase in mobility similar to the control group patients (p = 0.962). In patients with fractures 24 months 1 day old or older, the improvement in mobility was statistically worse than in the control group (p = 0.006).

All three patients in the study group with a decrease in their baseline activity had fractures that were 3 years old or older. One patient had developed new lower spine radiculopathy requiring epidural steroid injection several months after percutaneous vertebroplasty at a level separate from her vertebroplasty. She reported an improvement of her pain at the percutaneous vertebroplasty site before the steroid injection. A second patient had a knee injury after vertebroplasty that was the cause of her limited activity. The pain at her vertebroplasty site had completely disappeared. The third patient had worsening of her chronic obstructive lung disease that limited her mobility.

Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Vertebral compression fractures have a prevalence of 26% in women more than 50 years old [17]. More than 84% of these injuries are associated with pain. Resultant limitations in mobility lead to significantly impaired functional status when compared with healthy cohorts [18]. Although many patients recover with conservative therapy, a significant number continue to have pain that is refractory to such measures. Traditional immobilization techniques such as bed rest and bracing may create a vicious cycle in which decreased activity leads to worsened bone density with resultant fracture formation and more pain. Long-term consequences are physically and psychologically devastating and include physical deconditioning, difficulty breathing and sleeping, depression, fear of additional fracture, and distorted body image [17, 19]. The cause of chronic longer-lasting pain in these patients is poorly understood; suggested mechanisms include structural changes, osteoarthritis, and nerve irritation resulting in complex regional pain syndrome [20].

Previous authors have pointed out that the duration of conservative therapy and the timing of vertebroplasty after fracture vary widely among studies [12]. The significance of fracture age relevant to treatment success remains undefined. Considering the low complication rate and high efficacy of vertebroplasty in other trials, it is reasonable to treat chronic fractures in this patient group with limited available options. Additionally, because vertebroplasty is still coming of age in the United States, patients with long-standing symptoms are likely to be referred as treatment becomes regionally available and physician awareness of percutaneous vertebroplasty increases.

Our success at improving or completely eliminating pain (80%) is similar to many reports based on acute fractures and in keeping with other publications [2, 4–6, 16, 21]. Cotton et al. [1] stated that 90% of patients would experience relief after treatment of osteoporotic compression fractures. In the current study, clinical benefit was greater in the subgroup with fractures that were 12 months 1 day–24 months old than for fractures 24 months 1 day or older (87% vs 76%, respectively). Zoarski et al. [3] tracked long-term results as they treated 30 patients with follow-up of 15–18 months. These researchers found vertebroplasty to be durable over longterm follow-up with 96% of the patients satisfied with the result of the treatment. The clinical benefit described in this study was at final follow-up in all patients.

Other groups of researchers have anecdotally described poor results after treatment of fractures more than 6 [11] or 12 [10] months old. There remains a relative paucity of peer-reviewed data in patients with chronic pain. Barr et al. [6] reported complete elimination of symptoms in 63% of their patients 48 hr after treatment. Many patients in that trial had "well-documented pain and fractures more than 2 years old." The study by Kaufmann et al. [12] is closest to ours in terms of patient population. The mean fracture age in the trial of these researchers was 19 weeks, and follow-up was 1 month after treatment. Kaufmann et al. reported a significant improvement in pain and mobility for the entire patient group. Fracture age was not independently associated with symptom relief after vertebroplasty, which mirrors our findings. A number of complementary differences between the two trials exist. Our study includes a control group to evaluate relative efficacy to our study group. The median fracture age (28 months) in this trial indicates fractures are more chronic and the follow-up is longer (mean, 15.8 months) than in the other study. Nevertheless, both studies show considerable benefit to patients treated with this technique, justifying treatment of patients with pain from chronic fractures.

Our data show that most older fractures respond to vertebroplasty, although there may be fewer complete responses. Clinical benefit is still present in 76% of fractures that are 24 months 1 day old or older, although treatment success is less than that with less mature fractures. Overall improvement in mobility was similar with less acute fractures, having a trend toward greater mobility. Many of our patients had fractures diagnosed at an outside institution by physicians unaware of the procedure, and patients were referred as their pain persisted and treating clinicians became aware of the procedure. The lesser improvement in pain and increase in mobility in patients with older fractures suggest that the disabling spiral that starts with ineffectual conservative treatment has long-term adverse outcomes even after vertebroplasty. Results were positive enough that we believe percutaneous vertebroplasty is an effective treatment for persistent pain related to chronic fractures. However, treating patients earlier is still preferable because they are more likely to have complete eradication of pain and may retain more mobility.

This study has some weaknesses. One is its retrospective nature. A separate weakness is the absence of a formal validated questionnaire, which might have provided more quantitative information.

The findings of this study show that chronic vertebral compression fractures can be safely and efficaciously treated with percutaneous vertebroplasty. Although the quantity of pain relief and improvement in mobility may be slightly lower than in the acute fracture setting, measurable improvement in symptoms was noted in 80% of treated patients.

References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Cotton A, Boutry N, Cortet B, et al. Percutaneous vertebroplasty: state of the art. RadioGraphics1998; 18:311 –320[Abstract]
2. Jensen ME, Evans AJ, Mathis JM, Kallmes DF, Cloft HJ, Dion JE. Percutaneous polymethylmethacrylate vertebroplasty in the treatment of osteoporotic vertebral body compression fractures: technical aspects. AJNR 1997;18:1897 –1904[Abstract]
3. Zoarski GH, Snow P, Olan WJ, et al. Percutaneous vertebroplasty for osteoporotic compression fractures: quantitative prospective evaluation of long-term outcomes. J Vasc Interv Radiol2002; 13:139 –148[Medline]
4. Mathis JM, Barr JD, Belkoff SM, Barr MS, Jensen ME, Deramond H. Percutaneous vertebroplasty: a developing standard of care for vertebral compression fractures. AJNR2001; 22:373 –381[Free Full Text]
5. Weill A, Chiras J, Simon JM, Rose M, Sola-Martinez T, Enkaoua E. Spinal metastases: indications for and results of percutaneous injection of acrylic surgical cement. Radiology1996; 199:241 –247[Abstract/Free Full Text]
6. Barr JD, Barr MS, Lemley TJ, McCann RM. Percutaneous vertebroplasty for pain relief and spinal stabilization. Spine2000; 25:923 –928[Medline]
7. Mathis JM, Petri M, Naff N. Percutaneous vertebroplasty treatment of steroid-induced osteoporotic compression fractures. Arthritis Rheum 1998;41:171 –175[Medline]
8. Grados F, Depriester C, Cayrolle G, Hardy N, Deramond H, Fardellone P. Long-term observations of vertebral osteoporotic fractures treated by percutaneous vertebroplasty. Rheumatology2000; 39:1410 –1414[Abstract/Free Full Text]
9. Cyteval C, Sarrabere MP, Roux JO, et al. Acute osteoporotic vertebral collapse: open study on percutaneous injection of acrylic surgical cement in 20 patients. AJR1999; 173:1685 –1690[Abstract]
10. Jensen ME, Dion JE. Percutaneous vertebroplasty in the treatment of osteoporotic compression fractures. Neuroimaging Clin N Am 2000;10:547 –568[Medline]
11. Maynard AS, Jensen ME, Schweickert PA, Marx WF, Short JG, Kallmes DF. Value of bone scan imaging in predicting pain relief from percutaneous vertebroplasty in osteoporotic vertebral fractures. AJNR 2000;21:1807 –1812[Abstract/Free Full Text]
12. Kaufmann TJ, Jensen ME, Schweickert PA, Marx WF, Short JG, Kallmes DF. Age of fracture and clinical outcomes of percutaneous vertebroplasty. AJNR 2001;22:1860 –1863[Abstract/Free Full Text]
13. McGraw JK, Heatwole EV, Strnad BT, Silber JS, Patzilk SB, Boorstein JM. Predictive value of intraosseous venography before percutaneous vertebroplasty. J Vasc Interv Radiol2002; 13:149 –153[Medline]
14. Leibold RA, Gilula LA. Sterilization of barium for vertebroplasty: an effective, reliable, and inexpensive method to sterilize powders for surgical procedures. AJR2002; 179:198 –200[Free Full Text]
15. Schallen EH, Gilula LA. Vertebroplasty: reusable flange converter with hub lock for injection of polymethylmethacrylate with screw-plunger syringe. Radiology2002; 222:851 –855[Abstract/Free Full Text]
16. Kim AK, Jensen ME, Dion JE, Schweickert PA, Kaufmann TJ, Kallmes DF. Unilateral transpedicular percutaneous vertebroplasty: initial experience. Radiology2002; 222:737 –741[Abstract/Free Full Text]
17. Silverman SL. The clinical consequences of vertebral compression fracture. Bone1992; 13[suppl]:S27 –S31
18. Lyles KW, Gold DT, Shipp KM, Pieper CF, Martinez S, Mulhausen PL. Association of osteoporotic vertebral compression fractures with impaired functional status. Am J Med1993; 94:595 –601[Medline]
19. Lukert BP. Vertebral compression fractures: how to manage pain, avoid disability. Geriatrics 1994;49 : 22–26[Medline]
20. Forderreuther S, Schurmann M, Beyer A. When fracture pain does not subside: recognizing complications [in German]. MMW Fortschr Med 2001;143:29 –32
21. Cotton A, Dewatre F, Cortet B, et al. Percutaneous vertebroplasty for osteolytic metastases and myeloma: effects of the percentage of lesion filling and the leakage of methyl methacrylate at clinical follow-up. Radiology1996; 200:525 –530[Abstract/Free Full Text]

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This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brown, D. B. Articles by Shimony, J. S. Search for Related Content PubMed PubMed Citation Articles by Brown, D. B. Articles by Shimony, J. S. Social Bookmarking                      What's this? Hotlight (NEW!) What's Hotlight?