The incidence of secondary vertebral fracture of vertebral augmentation techniques versus conservative treatment for painful osteoporotic vertebral fractures: a systematic review and meta-analysis

Abstract

Background

Percutaneous vertebroplasty (PVP) and balloon kyphoplasty (BKP) are minimally invasive and effective vertebral augmentation techniques for managing osteoporotic vertebral compression fractures (OVCFs). Recent meta-analyses have compared the incidence of secondary vertebral fractures between patients treated with vertebral augmentation techniques or conservative treatment; however, the inclusions were not thorough and rigorous enough, and the effects of each technique on the incidence of secondary vertebral fractures remain unclear.

Purpose

To perform an updated systematic review and meta-analysis of the studies with more rigorous inclusion criteria on the effects of vertebral augmentation techniques and conservative treatment for OVCF on the incidence of secondary vertebral fractures.

Material and Methods

PubMed, MEDLINE, EMBASE, SpringerLink, Web of Science, and the Cochrane Library database were searched for relevant original articles comparing the incidence of secondary vertebral fractures between vertebral augmentation techniques and conservative treatment for patients with OVCFs. Randomized controlled trials (RCTs) and prospective non-randomized controlled trials (NRCTs) were identified. The methodological qualities of the studies were evaluated, relevant data were extracted and recorded, and an appropriate meta-analysis was conducted.

Results

A total of 13 articles were included. The pooled results from included studies showed no statistically significant differences in the incidence of secondary vertebral fractures between patients treated with vertebral augmentation techniques and conservative treatment. Subgroup analysis comparing different study designs, durations of symptoms, follow-up times, races of patients, and techniques were conducted, and no significant differences in the incidence of secondary fractures were identified (P > 0.05). No obvious publication bias was detected by either Begg’s test (P = 0.360 > 0.05) or Egger’s test (P = 0.373 > 0.05).

Conclusion

Despite current thinking in the field that vertebral augmentation procedures may increase the incidence of secondary fractures, we found no differences in the incidence of secondary fractures between vertebral augmentation techniques and conservative treatment for patients with OVCFs.

Keywords

Vertebral augmentation technique percutaneous vertebroplasty balloon kyphoplasty secondary vertebral fracture cement leakage

Introduction

As the population continues to age, the number of people with low bone mass and osteoporosis has risen, leading to skeletal fractures and the associated high morbidity and mortality. Osteoporotic vertebral compression fractures (OVCFs) are among the most common skeletal fractures, approximately 1.4 million new fractures occurring annually. These fractures are associated with pain and disability and increased mortality (1). The traditional management of OVCF has consisted of anti-osteoporotic medical treatment with a combination of calcium, vitamin D, miacalcin, and bisphosphonates, and pain management with analgesics, bed rest, and bracing (2). Although most patients with OVCFs respond well to conservative management, the pain can last for weeks or months; if conservative management fails, long-term care and hospitalization or even surgical interventions can be required (3). However, conventional open surgery for OVCFs is not optimal because of associated trauma, greater blood loss and difficulties achieving solid stabilization due to osteoporosis (4).

Percutaneous vertebroplasty (PVP), a minimally invasive vertebral augmentation technique (5), has been widely applied to treat OVCFs; this technique consists of injecting polymethylmethacrylate (PMMA) bone cement into the fractured vertebral body to intensify the vertebra and thereby reduce pain (6 –14). Balloon kyphoplasty (BKP), an improvement over PVP, can create a cavity in the vertebral body via an inflatable balloon tamp prior to the bone cement injection to correct the deformity, thus allowing for cement injection at a relatively low pressure aiming to reduce the incidence of cement leakages (6,15 –18).

Although both procedures have appeared encouraging for providing immediate pain relief and improved function in patients with OVCFs (19), complications still occur. The occurrence of secondary fractures following vertebral augmentation is one of the postprocedure risks that can influence therapeutic outcomes. However, it remains unclear whether vertebral augmentation techniques incur a higher risk of secondary vertebral fracture than conservative treatment. High-quality, large-scale, randomized controlled trials of patients with OVCF treated by either vertebral augmentation techniques or conservative treatment are rare. A recent meta-analysis compared the incidence of secondary vertebral fractures between patients treated with vertebral augmentation techniques with those who underwent conservative treatment (20); however, this meta-analysis included a study with malignancy-related vertebral fractures (17). Therefore, the purpose of the present study was to perform an updated systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective non-randomized controlled trials (NRCTs) with more rigorous inclusion criteria to compare the incidence of secondary vertebral fractures between patients with OVCF treated with vertebral augmentation techniques and those who underwent conservative treatment.

Material and Methods

Literature search

All of the listed authors contributed to the PRISMA-compliant literature search. Articles describing RCTs or prospective NRCTs comparing either PVP or BKP to conservative treatment or sham treatment for OVCF were identified and reviewed. Because the first study describing the use of vertebroplasty was published in 1987 (5), we searched PubMed, MEDLINE, EMBASE, SpringerLink, Web of Science, and Cochrane Library databases, for articles dating from 1987 to December 2013, using the combinations of the following terms: vertebroplasty, kyphoplasty, vertebral augmentation, secondary fracture, refracture, subsequent fracture, newly developed fracture, versus conservative treatment, non-surgical, and osteoporotic vertebral fracture. We also screened the references of the identified articles and reviews on this topic to avoid omitting any related articles. No limitations regarding the language of the article were imposed.

Selection of studies

Two of the authors (DS, BM) independently evaluated the potentially eligible studies. To be included, the studies were required to: (i) describe original RCTs or NRCTs; (ii) compare vertebral augmentation techniques (either PVP or BKP or both) to conservative treatment in patients with OVCF; and (iii) report the number of patients in both groups and the number of patients who experienced secondary vertebral fractures during the final follow-up of both groups. When multiple reports from the same center or trial were found, we selected the most thorough publication. The following studies were excluded: (i) retrospective studies, observational studies, and studies with no conservative treatment group or lacking key information; (ii) studies with no clear inclusion or exclusion criteria or with no clear description of the design; and (iii) studies including patients with severe cardiopulmonary co-morbidities, untreatable coagulopathies, systemic or local spine infections, suspected underlying malignant diseases, spinal-cord compression syndromes, or contraindications for magnetic resonance imaging. Full articles were obtained when the studies qualified or when it was difficult to judge whether the article would qualify based on the title and abstract. Any disagreements during the evaluations were resolved by discussion.

Data extraction

After selecting the studies, the same two authors extracted the relevant data from each qualified article. The following information was extracted independently: the first author’s last name, the year of publication, the country in which the study was conducted, the study design, the length of the patient enrollment period and follow-up period, the duration of symptoms before inclusion, the stage of symptoms, specific techniques, the numbers of cases and controls, and the mean ages of the patients in each group. A third reviewer was invited to resolve disagreements if agreement was not reached, and the opinion of the majority was applied to the further analysis.

Assessment of methodological quality

The same two authors independently assessed the methodological quality of the included studies. For RCTs, the “assessing the risk of bias” table, which is recommended by Cochrane Handbook for Systematic Review of Interventions, version 5.0 (21), was applied. For NRCTs, the Methodological Index for Non-randomized Studies (MINORS) (22), which consists of a list of 12 potential items, was applied for quality assessment. Each item on the MINORS has two scores, resulting in a total score of 24; a trial is considered high quality when the score is ≥16 points, whereas low quality is indicated by a score <16 points. Any disagreements were resolved by discussion, and if no consensus was reached, a third reviewer served as an adjudicator.

Statistical analysis

STATA software, version 11.0 (STATA Corporation, College Station, TX, USA) and RevMan software version 5.0 (The Cochrane Collaboration, Copenhagen, Denmark) were used for data analysis. Meta-analysis was performed in accordance with the recommendations of the Cochrane Collaboration (23). STATA software was used to compute the pooled RRs and 95% confidence intervals (CIs), generate forest plots, determine statistical associations, assess heterogeneity, perform subgroup and sensitivity analyses, and inspect for publication bias. A P value <0.05 was considered to be statistically significant. RevMan software was applied to generate the “assessing the risk of bias” table for RCTs.

The pooled risks ratio (RR) and the 95% confidence intervals (CIs) were calculated and compared using a random-effects model (23). Heterogeneity, which was assessed using Cochrane’s Q statistic and the I² statistic (24), was considered statistically significant with a P value <0.10. The I² statistic was used to evaluate the heterogeneity of the studies as follows: I²< 25% indicates low heterogeneity; I² value in the range of 25–50% indicates moderate heterogeneity; I²> 50% indicates high heterogeneity (24).

Sensitivity analyses were performed to investigate the influence of a single study on the overall risk estimate. Both Egger’s test and Begg’s test were performed to test for publication bias, with P < 0.05 indicating potential publication bias (19,25). Subgroup analyses by study design (RCT and NRCT), geographic region (western countries and eastern countries, as the ethnicity of patients was not clearly stated in every study), duration of symptoms before enrollment (acute and not acute), and specific techniques (PVP, BKP and PVP+BKP) were also applied. A cumulative meta-analysis was also applied to investigate the influence of the publication date and sample size (26).

Results

Literature search

Fig. 1 shows a flow diagram describing the literature search and selection process. We initially identified a total of 80 relevant studies after a computerized search. Eventually, 13 articles, including eight RCTs (6 –8,11 –14,27) and five NRCTs (9,10,15,16,28), fulfilled all of the inclusion criteria. A total of 1459 patients were analyzed in all of these studies.

Fig. 1.

Flow diagram of the study selection process.

Characteristics and quality assessment

Table 1 summarizes the characteristics of the included studies. Three studies from Australia, two from China and one each from Taiwan, Denmark, Iran, the Republic of Korea, The Netherlands, both The Netherlands and Belgium, Slovenia, and Spain were included. We defined Iran as a western country because Iranians are different from the populations of eastern Asia. Therefore, nine studies were from western countries and four studies were from eastern countries. Ten studies focused on PVP alone, two studies focused on BKP alone, and one study investigated both PVP and BKP. The follow-up time was in the range of 3–80 months. Three studies had a mean follow-up time of less than 12 months, seven studies had a follow-up time of exactly 12 months, and three studies had a mean follow-up time of more than 12 months. Six studies stated that they included patients with OVCF in acute stages, five of which clearly stated that they enrolled patients who had experienced symptoms for less than 6–8 weeks before enrollment; however, one study (27) was excluded from the subgroup analysis because the time stage for less than 12 months was inaccurate. Three studies enrolled patients who had experienced symptoms at least 6–12 weeks prior to enrollment (i.e. not acute); because the remaining four studies did not clearly specify the duration of symptoms, we removed them from this subgroup analysis. Only eight studies were included in the subgroup analysis related to the duration of symptoms. The assessment of the methodological quality of the studies is illustrated in Fig. 2. The RCTs were evaluated using the “assessing the risk of bias” table, and the NRCTs were evaluated with the MINORS (Table 2).

Fig. 2.

Methodological quality assessment of the RCTs. “+” indicates a low risk of bias, “–” indicates a high risk of bias and “?” indicates unclear.

Table 1.

Characteristics of all the included studies in the meta-analysis.

First author	Year	Country in which conducted	Area of study	Design	Period of patient enrollment	Follow-up (months)	Follow-up time range (months)	Duration of symptom before inclusion	Stage of symptom	Specific technique	Case	Control	Total	Mean Age of PVP or BKP	Mean Age of Control
Yi X	2013	China	Eastern	RCT	2005–2009	36–80	>12	N/A	N/A	PVP/BKP	169	121	290	N/A	N/A
Chen D	2013	China	Eastern	RCT	2007–2012	12	=12	At least 3 months	Not acute	PVP	46	43	89	64.63	66.49
Blasco J	2012	Spain	Western	RCT	2006–2010	12	=12	Less than 12 months	N/A	PVP	64	61	125	71.33	75.27
Farrokhi M.R.	2011	Iran	Western	RCT	2004–2006	36	>12	At least 4 weeks and less than 1 year	Not acute	PVP	37	39	76	72	74
Klazen	2010	Netherlands and Belgium	Western	RCT	2005–2008	12	=12	Less than 6 weeks	Acute	PVP	91	85	176	75.2	75.4
Buchbinder R	2009	Australia	Western	RCT	2004–2008	6	<12	No more than 12 months	N/A	PVP	35	35	70	74.2	79.9
Rousing R	2009	Denmark	Western	RCT	2001–2008	3	<12	No more than 8 weeks	Acute	PVP	23	23	46	80	80
Voormolen M.H.	2007	Netherlands	Western	RCT	2003–2005	12	=12	At least 6 weeks and no longer than 6 months	Not acute	PVP	18	16	34	72	74
Lee H.M.	2012	Korea	Eastern	NRCT	2005–2009	12	=12	Acute severe back pain (time not mentioned)	N/A	BKP	82	149	231	76.8	66.2
Movrin I	2012	Slovenia	Western	NRCT	2007–2008	12	=12	Less than 6 weeks	Acute	BKP	46	61	107	67.8	73.8
Thillainadesan	2010	Australia	Western	NRCT	2004–2007	29	>12	Acute back pain (time not mentioned)	N/A	PVP	25	9	34	78.5	75.2
Wang HK	2010	Chinese Taiwan	Eastern	NRCT	2007–2008	12	=12	Less than 6 weeks	Acute	PVP	32	23	55	72.9	72.7
Diamond TH	2006	Australia	Western	NRCT	2000–2002	24	>12	Within 1–6 weeks	Acute	PVP	88	38	126	76.8	76.1

BKP, balloon kyphoplasty; Case, patients underwent PKP or BKP; Control, patients underwent conservative treatment or sham-operated; N/A, data not available; NRCT, non-randomized controlled trails; RCT, randomized controlled trails; PVP, percutaneous vertebroplasty.

Table 2.

The MINORS appraisal scores for the studies of NRCT.

			MINORS methodological criteria
Study	Year	Design	1	2	3	4	5	6	7	8	9	10	11	12	Total
Lee HM	2012	NRCT	2	0	2	2	2	2	1	0	1	2	2	2	18
Movrin I	2012	NRCT	2	2	2	2	2	2	1	0	1	2	2	2	20
Thillainadesan	2010	NRCT	2	0	2	1	1	1	1	0	1	2	2	2	15
Wang HK	2010	NRCT	2	2	2	2	1	2	1	0	1	2	2	2	19
Diamond TH	2006	NRCT	2	2	2	2	2	2	1	0	2	2	2	2	21

The numbers represent the following items from MINORS methodological criteria as: 1, a clearly stated aim; 2, inclusion of consecutive patients; 3, prospective data collection; 4, endpoints appropriate to the aim of the study; 5, unbiased assessment of the study endpoint; 6, a follow-up period appropriate to the aims of the study; 7, loss to follow-up <5%; 8, prospective calculation of the sample size; 9, an adequate control group; 10, contemporary groups; 11, baseline equivalence of groups; and 12, adequate statistical analyses.

The items are scored as follows: 0 (not reported); 1 (reported but inadequate); or 2 (reported and adequate). The total score is 24; high quality is indicated when the score is ≥16 points, while low quality is indicated when the score is <16 points.

Results of the meta-analysis

Fig. 3 shows the RRs and 95% CIs comparing the incidence of secondary vertebral fractures between patients treated with vertebral augmentation and those who underwent conservative treatment. The summary RR of the eight RCTs studies was 0.841 (95% CIs = 0.521–1.357, P for heterogeneity = 0.133, I²= 37.1%) and the summary RR of five NRCTs was 0.961 (95% CIs = 0.529–1.745, P for heterogeneity = 0.256, I²= 24.8%) the pooled RR for the RCTs and NRCTs was 0.879 (95% CIs = 0.617–1.252, P for heterogeneity = 0.161, I²= 28.2%). No statistically significant differences in RR were observed among the different study designs. The I² was in the range of 25–50%, indicating moderate heterogeneity. No statistically significant differences in RR were found among the following subgroups: study design, geographic region, follow-up time, specific technique, and stage of symptoms (Table 3).

Fig. 3.

Forest plot depicting the incidence of secondary vertebral fractures in RCTs and NRCTs.

Table 3.

Subgroup analysis between vertebral augmentation techniques and conservative treatment.

		Meta-analysis
	Subgroups	Study numbers	Pooled RR (95% CI)	P (Q statistic)	I²
1	Study design
	RCT	8	0.841 (0.521–1.357)	0.133	37.1%
	NRCT	5	0.961 (0.529–1.745)	0.256	24.8%
	Total	13	0.879 (0.617–1.252)	0.161	28.2%
2	Geographic region
	Western	9	0.906 (0.590–1.393)	0.203	27.1%
	Eastern	4	0.879 (0.416–1.859)	0.138	45.6%
	Total	13	0.879 (0.617–1.252)	0.161	28.2%
3	Follow-up time (months)
	Less than 12	3	0.689 (0.385–1.234)	0.373	0.0%
	Exactly 12	7	1.032 (0.562–1.894)	0.055	51.4%
	More than 12	3	0.827 (0.456–1.473)	0.455	0.0%
	Total	13	0.879 (0.617–1.252)	0.161	28.2%
4	Specific techniques
	PVP	10	1.002 (0.643–1.564)	0.151	32.1%
	BKP	2	0.701 (0.251–1.959)	0.209	36.6%
	Total	12	0.942 (0.638–1.390)	0.172	27.7%
5	Stage of symptom
	Acute	5	0.929 (0.491–1.757)	0.126	44.3%
	Not acute	3	0.576 (0.217–1.530)	0.320	12.2%
	Total	8	0.811 (0.490–1.343)	0.184	30.6%

Sensitivity analysis and publication bias

The results of Egger’s test (P = 0.373 > 0.05) were consistent with Begg’s test (P = 0.360 > 0.05), indicating no statistically significant evidence of publication bias (Fig. 4). The results from the sensitivity analysis are shown in Fig. 5. The cumulative meta-analysis revealed no trend in RR with publication year or sample size.

Fig. 4.

Plots of Begg’s test and Egger’s test. (a) Begg's funnel plot with pseudo 95% confidence limits, (b) Egger's publication bias plot.

Fig. 5.

Sensitivity analysis comparing the incidence of secondary vertebral fractures among patients undergoing vertebral augmentation and patients undergoing conservative treatment.

Discussion

PVP and BKP provide more rapid relief of pain and improvement of function than conservative treatment (7 –9,11,14,16,17,20). However, complications such as cement leakage or secondary vertebral fractures can reduce the therapeutic effects of these techniques. Because most of the previous studies were retrospectively designed, it was difficult to distinguish clinical sequelae resulting from the procedure itself from the natural consequences of osteoporosis, which could also contribute to the future fractures. Concomitant osteoporosis treatment regimens, the number and severity of prevalent fractures and clustering effects could also have influenced the results, unless these factors were accounted for in well-designed, prospective RCTs comparing vertebral augmentation techniques and conservative treatment (29). The purpose of the current study was to update and supplement previous studies on this topic with more rigorous inclusion criteria. Our meta-analysis showed that there were no statistically significant differences in the incidence of secondary vertebral fractures among patients treated with vertebral augmentation techniques and patients treated with conservative treatment. These findings were consistent with most of the included studies and with those of previous studies (6 –16,20,28) indicating that vertebral augmentation techniques were preferred over conservative management, as the former can achieve immediate pain relief and functional improvement. In contrast, Blasco et al. (27) found that PVP was associated with a higher incidence of vertebral fractures than conservative treatment. They found that PVP resulted in a 2.78-fold increased risk of radiological vertebral fractures relative to conservative treatment, and they attributed this difference to the following explanations: (i) more vertebrae were treated with PVP in their study (mean of 2.46 vertebrae); (ii) patients experienced increased mobility after the PVP; (iii) cement leakages into discs after PVP increased the risk of secondary fractures. As previously reported, because patients who undergo PVP or BKP experience a rapid improvement in symptoms, they are prone to becoming more physically active and therefore more likely to sustain trauma (30). An intervertebral cement leakage, a procedure-related complication, can also contribute to the incidence of fractures (31). These two factors were related, as multiple authors have reported that secondary vertebral fractures could result from the increased stiffness and ultimate failure load of the treated vertebral body or from the weakness of the surrounding local spinal segment of the treated vertebrae due to osteoporosis (7 –17,28,29). When cement leaks into the disc, the hard cement creates a strong mechanical pressure that can cause adjacent endplate fracture. Because most patients who undergo PVP or BKP experience clear pain relief and functional improvement, they tend to increase their daily physical activities, which can place additional stress on the vertebrae (31).

With the exception of a meta-analysis directly comparing PVP and BKP, meta-analyses comparing the effects of vertebral augmentation and conservative treatment on the incidence of secondary vertebral fractures are relatively rare. Even though PVP has been considered associated with a higher incidence of secondary fractures than conservative treatment, Anderson et al. also observed no significant differences in the incidence of secondary vertebral fractures among patients treated with the two treatments (20). We excluded a study by Wardlaw et al. (18) from our meta-analysis, as this study enrolled patients with OVCF and patients with multiple myeloma or osteolytic metastatic tumors, which might have biased the conclusion. Our meta-analysis also included three new RCTs (7,8,29); however, the results remained similar. In a previous meta-analysis, Zou et al. studied the long-term incidence of subsequent vertebral body fractures following vertebral augmentation or conservative treatment and found no evidence of an increased incidence of fractures of adjacent vertebral bodies after the procedure (32). However, only two RCTs were included in their study, which limited the power of the analysis. Nevertheless, their results were similar to ours, even when we conducted subgroup analyses with different follow-up times.

Limitations of this present study were stated as follows: (i) the demographics and co-morbidities of all of the included study participants were not reported; (ii) data on the specific segments of the secondary vertebral fracture sites were not well recorded in all of the included studies – thus, a comparison of the incidence of fractures at different levels was not possible; (iii) few RCTs and NRCTs comparing OVCF patients who underwent BKP alone with OVCF patients undergoing conservative treatment have been conducted, we therefore included only two trials investigating BKP among the analyzed studies (15,16); (iv) although we detected no statistically significant evidence of publication bias in the current meta-analysis, publication bias may have influenced our findings nevertheless.

In conclusion, no differences in the incidence of secondary fractures in patients who underwent vertebral augmentation techniques and patients who underwent conservative treatment were observed. Additional RCTs, especially trials comparing the incidence of secondary vertebral fractures at different levels, trials comparing BKP and conservative treatment and trials identifying risk factors for secondary fractures, should be conducted.

Footnotes

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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