Abstract
Background
Pathologic fractures occur in 5% to 10% of patients with osteosarcoma, and prior studies have suggested they are prognostically important. However, because they represent an uncommon event in the setting of an already rare disease, most studies fail to reach conclusive findings, and there is no agreement about how best to treat pathologic fractures.
Questions/purposes
(1) Is the occurrence of a pathologic fracture in patients with osteosarcoma associated with poorer overall survivorship? (2) Is the occurrence of a pathologic fracture in patients with osteosarcoma associated with poorer local recurrence-free survival or metastasis-free survival? (3) Is the surgical approach (amputation or limb salvage) associated with differences in local recurrence rates in patients with osteosarcoma with pathologic fractures?
Methods
This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Our study was registered in PROSPERO (ID: 380459). A search of the PubMed and Embase databases resulted in 625 and 747 titles, respectively. After application of the inclusion and exclusion criteria, 21 articles were finally included. Quality assessment of all studies was performed using the Newcastle-Ottawa Quality Assessment Scale. The Risk of Bias In Non-Randomized Studies of Interventions tool was used in the 11 articles that evaluated the effect of an intervention (amputation or limb salvage) on local recurrence rates. The relative risk (RR) was calculated to compare outcomes in patients with osteosarcoma with pathologic fractures and those without. Heterogeneity among studies was calculated using the I2 statistic. The pooled RR was calculated using the fixed-effects or random-effects model depending on study heterogeneity. The fragility index and the ratio between the fragility index and the total number of participants for each outcome was additionally calculated to assess the robustness of our results. A total of 7604 patients with osteosarcoma, 12% of whom (885) had pathologic fractures, were included in our analysis.
Results
Pathologic fractures in patients with osteosarcoma were associated with lower 3-year (RR 1.53 [95% CI 1.29 to 1.82]; p < 0.001) and 5-year overall survival (RR 1.27 [95% CI 1.16 to 1.40]; p < 0.001). No difference in recurrence rates was found between patients with osteosarcoma with pathologic fractures and those without (RR 1.22 [95% CI 0.91 to 1.64]; p = 0.18). However, having a pathologic fracture was associated with an increased risk of developing metastasis (RR 1.33 [95% CI 1.08 to 1.63]; p = 0.01). Treatment with limb salvage surgery was not associated with a higher rate of local recurrence (RR 1.58 [95% CI 0.88 to 2.85]; p = 0.13).
Conclusion
In light of these findings, surgeons should be aware that after appropriate case selection, patients with osteosarcoma and pathologic fractures undergoing limb salvage surgery may have similar rates of local recurrence to those undergoing amputation. Therefore, a pathologic fracture may no longer be an absolute contraindication for limb salvage surgery. Future studies adjusting for potential confounders such as tumor size, tumor location, and response to neoadjuvant therapy would provide further insight into the effect of pathologic fractures on our assessed outcomes.
Level of Evidence
Level III, therapeutic study.
Introduction
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, accounting for one-fifth of all primary bone cancers [23]. It is known for being extremely aggressive, showing high cellular activity and high rates of local invasion [1]. These characteristics, combined with biopsies, minor trauma, and necrosis after chemotherapy, produce susceptibility to pathologic fractures [28]. The incidence of pathologic fractures at diagnosis or during preoperative treatment for osteosarcoma has been reported to be between 5% and 10% [1]. Pathologic fractures in osteosarcoma have traditionally been considered a prognostic factor. The fracture supposedly causes the spread of tumor cells to surrounding joints and blood vessels (local recurrence) [13] or distant sites through micrometastases [23]. Therefore, the presence of a pathologic fracture used to be considered an immediate indication for amputation, while limb salvage surgery was not commonly performed [3, 7, 9].
The clinical importance of pathologic fractures as a prognostic factor is still debated because of conflicting evidence. Some studies have identified pathologic fractures as a risk factor for local recurrence and death [4, 21, 24, 25]. However, other studies did not find differences in local recurrence or survival rates [3, 8, 34]. Finally, a study reported no differences in recurrence but a lower survival rate in patients with a pathologic fracture [9].
We therefore performed a systematic review and meta-analysis to answer the following questions: (1) Is the occurrence of a pathologic fracture in patients with osteosarcoma associated with poorer overall survivorship? (2) Is the occurrence of a pathologic fracture in patients with osteosarcoma associated with poorer local recurrence-free survival or metastasis-free survival? (3) Is the surgical approach (amputation or limb salvage) associated with differences in local recurrence rates in patients with osteosarcoma with pathologic fractures?
Materials and Methods
Search Strategy
We performed a comprehensive search of the PubMed and Embase databases from inception to November 14, 2022. Our search strategy was conducted using the following terms: osteosarcoma AND (pathologic OR pathological) AND fracture. Additionally, references of the included studies were manually screened to identify potential studies that had been missed in our search. This review was submitted to PROSPERO (380459).
Eligibility Criteria
To be included in our analysis, articles had to report any of the following outcomes (3-year overall survival [OS], 5-year OS, local recurrence-free survival, or metastasis-free survival) in patients with osteosarcoma of the extremities and use a comparison group (patients with osteosarcoma without pathologic fractures).
The following exclusion criteria were applied: case reports, case series (without comparator groups), and other non-peer-reviewed publications such as conference proceedings and preprint servers; studies with data that were not displayed or not allowing for risk ratio and CI calculations; and nonhuman studies. No additional filters on language, patient age, or year of publication were applied.
Selection, Data Collection, and Extraction Process
A search query was separately conducted in each of the two databases and the resulting datasets were exported to Covidence™ (Veritas Health Information). After removing duplicates, two reviewers (MRG and AB) independently screened studies for eligibility. In case of disagreement, the senior author (SAL-C) was consulted to reach a consensus.
Data were extracted into a standardized sheet. For qualitative data synthesis, the following variables were collected: institutions where the study was performed, year of publication, study design, patient age, follow-up time, and outcomes reported. For continuous variables such as age and follow-up time, we collected mean or median values, according to how data were reported. The outcome measures of interest were 3-year and 5-year OS, local recurrence-free survival, and metastasis-free survival. For our quantitative analysis, we collected the number of events for a certain outcome in each of the groups (patients with osteosarcoma with and without pathologic fractures) and the total number of patients at risk in each group. When the number of events per treatment group was unavailable, we used GetData Graph Digitizer software to retrieve data from the Kaplan-Meier curves. This strategy was only applied to Kaplan-Meier curves that were accompanied by risk tables so the number of patients lost to follow-up before the event of interest could be identified. Data were then displayed in contingency tables for statistical analysis.
Study Selection and Characteristics
Our search strategy resulted in 625 and 747 articles from PubMed and Embase, respectively (Fig. 1). After removal of 595 duplicates, titles and abstracts of 777 unique studies were screened and 756 of them were excluded. Twenty-four articles were assessed for eligibility criteria. Twenty-one studies met our eligibility criteria and were finally included in our meta-analysis [1, 3, 4, 6-9, 13-16, 19, 22, 24-26, 29-32, 34].
Fig. 1.
This flowchart shows our study search and selection of relevant articles.
A total of 7604 patients with osteosarcoma, 12% of whom (885) had pathologic fractures, were included. The number of patients included in each study ranged from 15 [19] to 2847 patients. The most common location of the treatment centers was China [8, 15, 16, 31, 32, 34] and the United States [25, 26, 30]; one study was multicentric [13]. Most centers were tertiary care focusing on oncologic treatment. All articles were retrospective cohort studies published in English between 1992 and 2020. The reported median or mean age in most articles was in the first and second decade of life; one study reported a median age of 30 years [9] and another one of 66 years [29]. The median or mean follow-up ranged from 24 to 132 months (Table 1).
Table 1.
Characteristics of all studies included in the meta-analysis
| Author | Sample, n | Pathologic fracture, n | No pathological fractures, n | Age in years | Follow-up, months | Outcomes assessed |
| Kelley et al. [13] | 2847 | 321 | 2526 | PF: 17.7 ± 12.6 No PF: 17.1 ± 8.5 |
130b | 5-year OS, LRFS |
| Puri et al. [22] | 552 | 31 | 521 | 19a (3-64) | 72a (36-132) | 5-year OS |
| Schlegel et al. [24] | 127 | 32 | 95 | 17 (3-79) | 51b | 3-year OS, 5-year OS, LRFS |
| Yin et al. [32] | 39 | 13 | 26 | 16 (5-39) | 32 (8-167) | 3-year OS, 5-year OS |
| Chung et al. [7] | 268 | 34 | 234 | PF: 23.5 ± 19.1 No PF: 22.8 ± 15.2 |
PF: 45 (1-200.4) No PF: 52 (0.7-277.7) |
5-year OS, LRFS |
| Deng et al. [8] | 982 | 95 | 887 | PF: 16a (8-51) No PF: 17a (4-75) |
PF: 27a (1-223) No PF: 30a (1-214) |
3-year OS, 5-year OS, LRFS |
| Liu et al. [16] | 148 | 30 | 118 | 18 (6-66) | 48.1a (36-83) | 3-year OS, 5-year OS |
| Malagelada et al. [19] | 15 | 15 | 0 | PF: 25.6a (8-66) | PF: 84.3a (24-348) | LRFS (PF group) |
| Lee et al. [15] | 15 | 5 | 10 | PF: 13.1a (9.2-14.9) No PF: 13.3a (9-14.7) |
NA | 5-year OS, LRFS |
| Zuo et al. [34] | 65 | 15 | 50 | PF: 23.2 ± 8.0 No PF: 21.8 ± 12.2 |
34.7a (8-47) | 3-year OS, LRFS, MFS |
| Xie et al. [31] | 199 | 28 | 171 | 14 (6-30) | 40.7a (9-108) | 3-year OS, 5-year OS, LRFS, MFS |
| Cho et al. [6] | 377 | 38 | 339 | 18.6a (3-63) | 84 (6-204) | MFS |
| Ferguson et al. [9] | 232 | 31 | 201 | 30 (11-82) | NA | 3-year OS, 5-year OS, LRFS (PF group) |
| Kim et al. [14] | 384 | 37 | 347 | NA | PF: 43 (10-228) | LRFS, MFS |
| Vermesan et al. [29] | 22 | 12 | 10 | 66.5b | 30 (18-72) | 5-year OS |
| Bramer et al. [4] | 484 | 56 | 428 | 16 (4-57) | 117a (7-252) | LRFS (PF group) |
| Weiss et al. [30] | 21 | 9 | 12 | 15.7 (3.2-23) | NA | 5-year OS |
| Bacci et al. [3] | 735 | 46 | 689 | NA | 132 (36-240) | 5-year OS, LRFS |
| Scully et al. [25] | 107 | 52 | 55 | PF: 23.5 ± 17.4 No PF: 22.0 ± 13.6 |
54a (6-152) | LRFS |
| Abudu et al. [1] | 40 | 40 | 0 | 18 (2-46) | 55 (8-175) | LRFS (PF group) |
| Scully et al. [26] | 16 | 16 | 0 | 18a (11-68) | > 24 in all patients | LRFS (PF group) |
Data presented as mean ± SD or median (range). If different measures are displayed, they are noted by a for mean and b for median. PF = pathologic fracture; LRFS = local recurrence-free survival; OS = overall survival; NA = not available.
Seven studies with 244 patients with pathologic fractures and 1548 patients without pathologic fractures were included to compare 3-year OS outcomes [8, 9, 16, 24, 31, 32, 34] (Table 2). Thirteen studies, including 687 patients with osteosarcoma with pathologic fractures and 5500 without pathologic fractures reported 5-year OS [3, 7-9, 13, 15, 16, 22, 24, 29-32]. Information on local recurrence-free survival was available in 11 articles, totaling 721 patients with pathologic fractures and 5492 without pathologic fractures [3, 4, 7, 8, 13-15, 24, 25, 31, 34]. Four studies, including 118 patients with pathologic fractures and 907 patients without pathologic fractures, were included to compare metastasis-free survival among patients with osteosarcoma [6, 14, 31, 34]. Eleven articles assessed local recurrence-free survival in 415 patients with pathologic fractures caused by osteosarcoma, including 138 patients treated with amputation and 277 with limb salvage surgery [1, 3, 4, 8, 9, 14, 15, 19, 25, 26, 34].
Table 2.
Reported outcomes by studies included in our meta-analysis
| Author | 3-year OSa | 5-year OSa | LRFSa | MFSa | Total patients undergoing surgery (limb salvage surgery or amputation)b | Patients with recurrence (limb salvage surgery or amputation)b | Recurrence rate (limb salvage surgery or amputation)b |
| Kelley et al. [13] | 63%/70.6% | 89.9%/92.8% | |||||
| Puri et al. [22] | 55%/59% | ||||||
| Schlegel et al. [24] | 65%/86% | 59.4%/83% | 75%/88% | ||||
| Yin et al. [32] | 53.8%/64% | 53.8%/57.1% | |||||
| Chung et al. [7] | 37%/50% | 76.5%/78.2% | |||||
| Deng et al. [8] | 61.4%/68.2% | 59.4%/63.1% | 89.5%/87.9% | 59/36 | 5/1 | 8.5%/2.8% | |
| Liu et al. [16] | 66.7%/83% | 66.7%/81.4% | |||||
| Malagelada et al. [19] | 6/8 | 3/1 | 50%/12.5% | ||||
| Lee et al. [15] | 40%/80% | 80%/80% | 2/3 | 1/1 | 50%/33.3% | ||
| Zuo et al. [34] | 66.7%/75.3% | 73.3%/86% | 73.3%/68% | 10/5 | 3/1 | 30%/20% | |
| Xie et al. [31] | 50.5%/71% | 45.5%/61.9% | 85.7%/91.2% | 50%/62.6% | |||
| Cho et al. [6] | 49.3%/65.1% | ||||||
| Ferguson et al. [9] | 44%/70% | 41%/60% | 19/12 | 2/0 | 10.5%/0% | ||
| Kim et al. [14] | 89.2%/94.6% | 47.8%/60.8% | 33/4 | 4/0 | 12.1%/0% | ||
| Vermesan et al. [29] | 50%/79% | ||||||
| Bramer et al. [4] | 86%/86% | 44/12 | 6/2 | 14%/17% | |||
| Weiss et al. [30] | 55.6%/66.7% | ||||||
| Bacci et al. [3] | 65%/67% | 95.7%/95.2% | 34/11 | 1/1 | 2.9%/9.1% | ||
| Scully et al. [25] | 75%/96% | 30/22 | 7/4 | 23.3%/18% | |||
| Abudu et al. [1] | 27/13 | 5/0 | 19%/0% | ||||
| Scully et al. [26] | 10/6 | 3/0 | 30%/0% |
The values displayed in these columns refer to patients with osteosarcoma with pathologic fractures (first number) and without pathologic fractures (second number).
Values displayed in these columns refer only to the subgroup of patients with pathologic fractures. OS = overall survival; LRFS = local recurrence-free survival; MFS = metastasis-free survival.
Assessment of Study Quality Assessment and Risk of Bias
Two reviewers (MRG and AB) independently conducted quality assessments using the Newcastle-Ottawa Quality Assessment Scale (Supplemental Table 1; http://links.lww.com/CORR/B104). Items in the selection and exposure groups were assigned a score of 0 or 1 star; the item comparability of cases and controls was the only one that could be assigned a score of 0, 1, or 2 stars. Studies with a total score of 7 or more were considered high-quality and included in the analysis, as reported [23, 28, 33]. All studies assessed obtained a score of 7 or higher and were therefore included. In addition, because one of our study questions evaluated the effect of an intervention (limb salvage surgery or amputation) on an outcome (local recurrence), we used the Risk of Bias In Non-Randomized Studies of Interventions to assess the risk of bias. The Risk of Bias In Non-Randomized Studies of Interventions is a widely used tool recommended by the Cochrane Collaboration to assess the risk of bias in nonrandomized (observational) studies of interventions [27]. All 11 studies that assessed local recurrence rates according to intervention were subject to this assessment.
The evaluation of each risk of bias domain was performed using the robvis online visualization tool [20]. Bias was mainly found on Domain 1 (bias from confounding) and Domain 5 (bias from missing data). Among the 11 studies assessed, we found that nine studies [3, 4, 8, 9, 14, 19, 25, 26, 34] had an intermediate risk of bias and two [1, 15] had a high risk (Supplemental Figure 1; http://links.lww.com/CORR/B105).
Statistical Analysis
We used risk ratios (RRs) to compare outcomes between the retrospective cohort studies found in each of the articles. Heterogeneity among studies was calculated using the I2 statistic. Values of I2 > 50% or p < 0.05 indicated significant heterogeneity between studies, and a random-effects model was chosen; otherwise, a fixed-effects model (weighted with inverse variance) was used. All our studies had an I2 value < 50% and a p > 0.05, so the analysis was conducted using fixed-effects methods. The only outcome with an I2 greater than 0% was 3-year OS, which had an I2 of 6.7%.
A fixed-effects meta-analysis assumes that the true effect size underlies all of the studies included in the analysis. Under this model, a meta-analysis attributes greater weight to effect sizes (results from each study) with higher precision. The degree of precision, and thus the weight of each study, is determined using the inverse of the variance of each effect size.
For meta-analysis results, we also calculated the fragility index and the ratio between the fragility index and the total number of participants for each outcome. The fragility index is defined as the minimum number of patients from one or more studies included in the meta-analysis for whom an event-status modification (changing an event to nonevent or vice versa) would make the results no longer statistically significant (p > 0.05) [2]. The statistical analyses were performed with StataSE 14 (StataCorp).
Publication Bias
Publication bias was assessed using a funnel plot analysis, in which the event rate is plotted against the inverse of the standard error (Supplemental Fig. 2; http://links.lww.com/CORR/B106). A funnel plot was created for each of the three study questions. No severe asymmetry was visualized in any of the funnel plots, indicating that publication bias was not significantly present.
Clinical Importance
It is difficult to determine the clinical significance of the difference in relative risk between two groups: pathologic fractures and nonpathologic fractures. This is because of the lack of agreement among studies with a specific threshold value to determine clinical significance. However, we think that a relative risk of 1.3 reflects a finding that is most likely clinically relevant because this describes a 30% likelihood that a particular outcome will occur. As mentioned, this is an arbitrary benchmark.
Results
Association Between Pathologic Fracture and Overall Survival
The presence of a pathologic fracture was associated with an increased risk of overall death at 3 years (RR 1.53 [95% CI 1.29 to 1.82]; p < 0.001) (Fig. 2A). The fragility index and ratio were 19 and 1% (19 of 1792), respectively. The 5-year OS rate was lower for patients with osteosarcoma with a pathologic fracture (RR 1.27 [95% CI 1.16 to 1.40]; p < 0.001) (Fig. 2B). The fragility index and ratio were 34 and 0.5% (34 of 6187), respectively.
Fig. 2.
These forest plots show studies assessing the relative risk for (A) 3-year overall survival and (B) 5-year overall survival in patients with osteosarcoma with and without pathologic fractures.
The fragility index and ratio refer to the number and percentage of observed events that would need to change in order for the finding (in this case, the association between pathologic fracture and death) to no longer be statistically significant. A modification of event status (that is, changing an event to a nonevent or a nonevent to an event) in 19 patients (1% of the sample) would be necessary to make the effect of a pathologic fracture on 3-year OS no longer statistically significant. For 5-year OS, the change in event status needed would be in 34 patients (0.5% of the sample). This highlights the robustness of our findings.
Association Between Pathologic Fracture and Survival Free From Local Recurrence and Metastasis
Having a pathologic fracture in patients with osteosarcoma was not associated with a higher rate of local recurrence (RR 1.22 [95% CI 0.91 to 1.64]; p = 0.18) (Fig. 3A). However, pathologic fractures in patients with osteosarcoma were associated with a higher risk of developing a metastasis than in those without pathologic fractures (RR 1.33 [95% CI 1.08 to 1.63]; p = 0.01) (Fig. 3B). The fragility index and ratio were 4 and 0.4% (4 of 1025), respectively.
Fig. 3.
These forest plots represent studies assessing the relative risk for (A) local recurrence-free survival and (B) metastasis-free survival in patients with osteosarcoma with and without pathologic fractures.
A modification of event status in four patients (0.4% of the sample) would be necessary to make the effect of a pathologic fracture on metastasis-free survival no longer statistically significant.
Surgical Approach (Amputation or Limb Salvage) and Local Recurrence Rates
Limb salvage surgery to treat pathologic fractures in patients with osteosarcoma was not associated with a higher risk of local recurrence than amputation (RR 1.58 [95% CI 0.88 to 2.85]; p = 0.13) (Fig. 4)
Fig. 4.
This forest plot represents studies assessing the relative risk of recurrence in patients with osteosarcoma with pathologic fractures treated with amputation or limb salvage.
Discussion
Whether pathologic fractures are associated with poorer survival and a higher risk of tumor recurrence in patients with osteosarcoma has been the subject of debate for a long time. Understanding the association between pathologic fractures and survival, local recurrence, and the development of metastasis is critical, because it has not been established whether a different therapeutic approach is called for after a pathologic fracture occurs. Although several systematic reviews have been published on the topic, they were limited by a much smaller sample than the one in our systematic review and missed several landmark studies published in the past 5 years [23, 28, 33]. Moreover, only the first systematic review by Salunke et al. [23] conducted a subanalysis in patients with pathologic fractures to compare local recurrence rates by treatment (limb salvage or amputation). With 7604 patients with osteosarcoma, including 885 with pathologic fractures, our systematic review has almost twice the sample size of a previous study by Zhou et al. [33]. In our study, pathologic fractures in patients with osteosarcoma were associated with poorer OS and an increased risk of metastasis, but not with an increased risk of local recurrence. Furthermore, based on our results, a pathologic fracture may no longer be an absolute contraindication for limb salvage surgery.
Limitations
First, our analysis focused only on pathologic fractures in patients with osteosarcoma and did not consider additional factors that might be related to exposure (pathologic fracture) and outcome (OS, local recurrence-free survival, or metastasis-free survival). Because some of these factors might not be evenly distributed between the groups of patients with and without pathologic fractures, they might act as confounders. Although controlling for potential confounders would solve this issue, only three studies performed a regression analysis to adjust for certain variables [6, 13, 22]. Readers should be aware of the presence of potential confounders (older age, location of the fracture, and comorbidities) that might partially explain the worse outcomes associated with pathologic fractures.
Second, all studies included in the assessment of our third research question (association of treatment type with local recurrence) were observational. This meant that the type of treatment was not randomly allocated and was rather selected based on a set of preoperative findings. Preoperative findings such as large tumors, large hematomas, and poor neoadjuvant chemotherapy response might have favored more aggressive surgeries (amputation) and resulted in an important selection bias. In this light, important baseline differences between patients treated with amputation and those treated with limb salvage are expected.
Third, completeness of follow-up between groups (patients with and without pathologic fractures) was not reported in any study. Readers should be aware of this limitation because a different length of follow-up between groups can lead to an overestimation or underestimation of our reported findings. Although publication bias can always be present, our funnel plot analysis did not show important asymmetry along the central axis, ruling out overt publication bias.
Lastly, we used a fixed-effects model to determine the effect size. As mentioned, this model assumes all results to be true, weighting each study according to sample size and precision. This approach is not favored because it does not fully identify or account for differences such as clinical heterogeneity. However, most I2 values in the studies included in this systematic review were null, confirming there was very small heterogeneity among these studies. Therefore, our approach is valid because the statistical tool was not affected or limited, given the intrinsic lack of heterogeneity between the included studies. Still, some differences between the included studies do exist.
Association Between Pathologic Fracture and Overall Survival
We found that OS rates were lower for patients with a pathologic fracture at both the 3-year and 5-year intervals. Our findings are supported by multiple studies reporting worse OS for patients with osteosarcoma with pathologic fractures [4, 9, 13, 24, 25]. Among them, a multicenter study including 2847 patients with osteosarcoma, 321 of them with pathologic fractures, reported 63% and 70.6% 5-year OS for patients with and without pathologic fractures, respectively [13]. Despite the most recent studies indicating a worse prognosis after a pathologic facture, additional articles have not shown worse overall survivorship after a pathologic fracture [3, 8, 34]. High heterogeneity among study populations, including different distributions of potential confounders between groups, might explain the divergence of results. For this purpose, Kelley et al. [13] performed a multivariate analysis adjusted for age, sex, tumor site, tumor size, type of surgery, and response to neoadjuvant chemotherapy and found that pathologic fractures were an independent predictor of OS in patients with osteosarcoma. Although this study supports the association of pathologic fractures and worse OS, we suggest that future studies about this topic should focus on controlling for potential confounders that might bias results. We suggest future studies do propensity score matching between groups (patients with and without pathologic fractures) before an analysis of risk factors. By matching patients based on demographic and clinical characteristics and treatment variables (such as response to chemotherapy or type of surgery), the distribution of potential confounders would be similarly distributed between study groups.
Association Between Pathologic Fracture and Survival Free From Local Recurrence and Metastasis
We found no differences in rates of local recurrence between patients with and without pathologic fractures. Based on the assumption that a pathologic fracture will lead to seeding of tumor cells into the surrounding tissue, some authors have advocated for amputation [10, 12, 17]; our findings suggest otherwise, indicating that pathologic fractures are not associated with a higher risk of recurrence. Unlike the results for OS, most studies assessing local recurrence agreed that pathologic fractures were not associated with a higher risk of local recurrence in patients with osteosarcoma [1, 3, 4, 7-9, 11, 15, 30, 31, 34]. A single-center retrospective study reported a higher local recurrence rate in patients with osteosarcoma with pathologic fractures (24%) than in those without (7%) (p = 0.02) [24]. However, only 9% of patients with pathologic fractures underwent amputation in this study, compared with reported rates of 20% to 60% [3, 4, 9, 15, 25]. This represents an important deviation from the amputation rates described in most studies and might explain the difference in results.
In contrast, we found that pathologic fractures in patients with osteosarcoma were associated with an increased risk of metastasis. This finding is extremely important because the association between pathologic fractures and increased risk of metastasis might explain the lower OS we found in the group with pathologic fractures. This is especially true in a disease such as osteosarcoma, which mainly targets young people and where OS rates closely resemble disease-free survival rates. The mechanism for this event has traditionally been proposed to be the formation of a hematoma after a pathologic fracture, which leads to seeding of cancer cells into the systemic circulation from damage to the microcirculation [24]. However, our group has proposed and validated a different explanation for this association in which the pathologic fracture is not a causative agent but simply another manifestation of the biologic aggressiveness of a given osteosarcoma. Our group evaluated the micro-RNA profile differences between patients with osteosarcoma who either had or did not have pathologic fractures [18]. Known markers of low disease survival and increased risk of metastasis were more prevalent in that study’s group of patients with pathologic fracture than in this study, confirming that poorer survival and increased risk of metastasis are a product of the biologic aggressiveness of the tumor because it is the fracture and not a product of the fracture. We think future clinical studies should control for potential confounders so the effect of a pathologic fracture on patient outcomes can be individualized, whereas basic science studies should focus on RNA sequencing and methylation to identify mutations of and genetic characteristics contributing to lower survival and a higher risk of local recurrence and metastatic disease, which, as mentioned, are more likely to be present in patients with pathologic fractures.
Surgical Approach (Amputation or Limb Salvage) and Local Recurrence Rates
No differences were found in the risk of local recurrence between groups of patients with osteosarcoma who were treated with amputation and those treated with limb salvage surgery. Based on our results, a pathologic fracture may no longer be an absolute contraindication for limb salvage surgery. Although many authors reported no differences in survival and local recurrence rates between treatments [1, 4, 5, 8, 9, 15, 25, 34], one study reported that amputation was associated with a lower local recurrence rate [26]. The limitations of this study include the small sample size (18 patients) and being more than two decades old, before most modern limb salvage techniques were perfected. However, we must emphasize the important selection bias that is behind treatment choice. Patients deemed eligible for limb salvage surgery often show a positive response to chemotherapy and have no evident red flags such as wide contamination of surrounding tissue, a tumor location that is difficult to access, large tumor size, or large hematoma. We think that with careful patient selection, limb salvage surgery is a more favorable option. It will provide the patient with similar survival and recurrence rates without the associated morbidity of an amputation.
Conclusion
Our study showed that pathologic fractures in patients with osteosarcoma were associated with lower OS. Local recurrence-free survival was not different between patients with and without pathologic fractures, but metastasis-free survival was lower in patients with a pathologic fracture. In patients with a pathologic fracture caused by osteosarcoma, no difference in local recurrence rates was seen between patients treated with amputation and those treated with limb salvage surgery. Based on these findings, we believe that a pathologic fracture may no longer be an absolute contraindication to limb salvage surgery. Future studies should focus on identifying the effect of pathologic fractures on these outcomes by controlling for potential confounders such as tumor size, location, and response to neoadjuvant therapy, among others.
Supplementary Material
Footnotes
Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members.
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.
This work was performed at the Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA, USA.
Contributor Information
Marcos R. Gonzalez, Email: mgonzalez52@mgh.harvard.edu.
Angad Bedi, Email: adbedi@mgh.harvard.edu.
Daniel Karczewski, Email: dkarczewski@bwh.harvard.edu.
References
- 1.Abudu A, Sferopoulos NK, Tillman RM, Carter SR, Grimer RJ. The surgical treatment and outcome of pathological fractures in localised osteosarcoma. J Bone Joint Surg Br. 1996;78:694-698. [PubMed] [Google Scholar]
- 2.Atal I, Porcher R, Boutron I, Ravaud P. The statistical significance of meta-analyses is frequently fragile: definition of a fragility index for meta-analyses. J Clin Epidemiol. 2019;111:32-40. [DOI] [PubMed] [Google Scholar]
- 3.Bacci G, Ferrari S, Longhi A, et al. Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand. 2003;74:449-454. [DOI] [PubMed] [Google Scholar]
- 4.Bramer JAM, Abudu AA, Grimer RJ, Carter SR, Tillman RM. Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer. 2007;43:1944-1951. [DOI] [PubMed] [Google Scholar]
- 5.Chandrasekar CR, Grimer RJ, Carter SR, et al. Pathological fracture of the proximal femur in osteosarcoma: need for early radical surgery? ISRN Oncol. 2012;2012:512389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Cho WH, Song WS, Jeon DG, et al. Differential presentations, clinical courses, and survivals of osteosarcomas of the proximal humerus over other extremity locations. Ann Surg Oncol. 2010;17:702-708. [DOI] [PubMed] [Google Scholar]
- 7.Chung LH, Wu PK, Chen CF, Weng HK, Chen TH, Chen WM. Pathological fractures in predicting clinical outcomes for patients with osteosarcoma. BMC Musculoskelet Disord. 2016;17:1-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Deng ZP, Ding Y, Puri A, et al. The surgical treatment and outcome of nonmetastatic extremity osteosarcoma with pathological fractures. Chin Med J (Engl). 2015;128:2605-2608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ferguson PC, Mclaughlin CE, Griffin AM, Bell RS, Deheshi BM, Wunder JS. Clinical and functional outcomes of patients with a pathologic fracture in high-grade osteosarcoma. J Surg Oncol. 2010;102:120-124. [DOI] [PubMed] [Google Scholar]
- 10.Finn HA, Simon MA. Limb-salvage surgery in the treatment of osteosarcoma in skeletally immature individuals. Clin Orthop Relat Res. 1991;262:108-118. [PubMed] [Google Scholar]
- 11.Grimer RJ, Taminiau AM, Cannon SR. Surgical outcomes in osteosarcoma. J Bone Joint Surg Br. 2002;84:395-400. [DOI] [PubMed] [Google Scholar]
- 12.Jeon D-G, Lee S-Y, Kim J-W. Bone primary sarcomas undergone unplanned intralesional procedures - the possibility of limb salvage and their oncologic results. J Surg Oncol. 2006;94:592-598. [DOI] [PubMed] [Google Scholar]
- 13.Kelley LM, Schlegel M, Hecker-Nolting S, et al. Pathological fracture and prognosis of high-grade osteosarcoma of the extremities: an analysis of 2,847 consecutive Cooperative Osteosarcoma Study Group (COSS) patients. J Clin Oncol. 2020;38:823-833. [DOI] [PubMed] [Google Scholar]
- 14.Kim MS, Lee SY, Lee TR, et al. Prognostic effect of pathologic fracture in localized osteosarcoma: a cohort/case controlled study at a single institute. J Surg Oncol. 2009;100:233-239. [DOI] [PubMed] [Google Scholar]
- 15.Lee RKL, Chu WCW, Leung JHY, Cheng FWT, Li CK. Pathological fracture as the presenting feature in pediatric osteosarcoma. Pediatr Blood Cancer. 2013;60:1118-1121. [DOI] [PubMed] [Google Scholar]
- 16.Liu Y, Xu Y, Lin N, Jiang S, Wang Y, Ye Z. High-dose methotrexate (HD-MTX) used as an adjunct with other chemotherapeutics for the treatment of osteosarcoma. Cell Biochem Biophys. 2015;71:1097-1104. [DOI] [PubMed] [Google Scholar]
- 17.Longhi A, Errani C, De Paolis M, Mercuri M, Bacci G. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev. 2006;32:423-436. [DOI] [PubMed] [Google Scholar]
- 18.Lozano Calderón SA, Garbutt C, Kim J, et al. Clinical and molecular analysis of pathologic fracture-associated osteosarcoma: microRNA profile is different and correlates with prognosis. Clin Orthop Relat Res. 2019;477:2114-2126. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Malagelada F, Tarrago LT, Tibrewal S, Ibanez AP, Jeyaseelan L, Alegria IG. Pathological fracture in osteosarcoma: is it always an indication for amputation? Ortop Traumatol Rehabil. 2014;16:67-74. [DOI] [PubMed] [Google Scholar]
- 20.McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): an R package and Shiny Web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12:55-61. [DOI] [PubMed] [Google Scholar]
- 21.Moradi B, Zahlten-Hinguranage A, Lehner B, Zeifang F. The impact of pathological fractures on therapy outcome in patients with primary malignant bone tumours. Int Orthop. 2010;34:1017-1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Puri A, Byregowda S, Gulia A, Crasto S, Chinaswamy G. A study of 853 high grade osteosarcomas from a single institution—are outcomes in Indian patients different? J Surg Oncol. 2018;117:299-306. [DOI] [PubMed] [Google Scholar]
- 23.Salunke AA, Chen Y, Tan JH, Chen X, Khin LW, Puhaindran ME. Does a pathological fracture affect the prognosis in patients with osteosarcoma of the extremities? Bone Joint J. 2014;96:1396-1403. [DOI] [PubMed] [Google Scholar]
- 24.Schlegel M, Zeumer M, Prodinger PM, et al. Impact of pathological fractures on the prognosis of primary malignant bone sarcoma in children and adults: a single-center retrospective study of 205 patients. Oncol. 2018;94:354-362. [DOI] [PubMed] [Google Scholar]
- 25.Scully SP, Ghert MA, Zurakowski D, Thompson RC, Gebhardt MC. Pathologic fracture in osteosarcoma: prognostic importance and treatment implications. J Bone Joint Surg Am. 2002;84:49-57. [PubMed] [Google Scholar]
- 26.Scully SP, Temple HT, O’Keefe RJ, Mankin HJ, Gebhardt M. The surgical treatment of patients with osteosarcoma who sustain a pathologic fracture. Clin Orthop Relat Res. 1996;324:227-232. [DOI] [PubMed] [Google Scholar]
- 27.Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Sun L, Li Y, Zhang J, Li H, Li B, Ye Z. Prognostic value of pathologic fracture in patients with high grade localized osteosarcoma: a systemic review and meta-analysis of cohort studies. J Orthop Res. 2015;33:131-139. [DOI] [PubMed] [Google Scholar]
- 29.Vermesan D, Vermesan H, Dragulescu SI, et al. Secondary pathologic fractures in osteosarcoma: prognosis and evolution. Eur Rev Med Pharmacol Sci. 2009;13:71-76. [PubMed] [Google Scholar]
- 30.Weiss A, Khoury JD, Hoffer FA, et al. Telangiectatic osteosarcoma: the St. Jude Children’s Research Hospital’s experience. Cancer. 2007;109:1627-1637. [DOI] [PubMed] [Google Scholar]
- 31.Xie L, Guo W, Li Y, Ji T, Sun X. Pathologic fracture does not influence local recurrence and survival in high-grade extremity osteosarcoma with adequate surgical margins. J Surg Oncol. 2012;106:820-825. [DOI] [PubMed] [Google Scholar]
- 32.Yin J-Q, Fu Y-W, Xie X-B, et al. Telangiectatic osteosarcoma: outcome analyses and a diagnostic model for differentiation from aneurysmal bone cyst. J Bone Oncol. 2018;11:10-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Zhou Y, Lu Q, Xu J, et al. The effect of pathological fractures on the prognosis of patients with osteosarcoma: a meta-analysis of 14 studies. Oncotarget. 2017;8:73037-73049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Zuo D, Zheng L, Sun W, Hua Y, Cai Z. Pathologic fracture does not influence prognosis in stage IIB osteosarcoma: a case-control study. World J Surg Oncol. 2013;11:148. [DOI] [PMC free article] [PubMed] [Google Scholar]