Osteosarcoma is the most common primary bone tumor in childhood and adolescence. It is the second highest cause of cancer-related death in these age groups due to development of often fatal metastasis, usually in the lungs [
Alkaline phosphatases (ALPs) are a family of metalloenzymes that catalyze the hydrolysis of organic phosphate esters at an alkaline environment with low substrate specificity [
We searched PubMed, Embase, and Web of Science databases on May 1, 2015, for relevant articles. The search terms were used as follows: (1) osteosarcoma or bone sarcoma or osteogenic sarcoma and (2) alkaline phosphatase or ALP or SALP or SAP or AP or AKP or ALKP. Studies were considered eligible if they met the following criteria: (1) prospective or retrospective cohort study; (2) tumors being histologically confirmed as osteosarcoma; (3) studies examining the relation between SALP level and prognosis (OS, EFS, or metastasis); (4) publications written in English; (5) studies providing sufficient information to estimate HR or RR with corresponding 95% CIs. The exclusion criteria included (1) articles published in non-English; (2) case reports, editorials, letters, reviews, and conference abstracts; (3) only the most recent or complete study, when multiple publications from a particular research group reported data from overlapping samples.
Two reviewers extracted data from eligible studies independently. Discontents between reviewers were resolved by discussion and through consultation. The following items were collected from each study: first author’s name, year of publication, country, sample size, age, cut-off values, tumor stage (Enneking stage), follow-up time, HRs of the elevated SALP for OS or EFS, RRs of the elevated SALP and presence of metastasis at diagnosis or metastasis development of localized osteosarcoma patients, and their 95% CIs and
For each individual study with assessment of OS or EFS, the HRs and their 95% CIs were extracted if the author had reported the data. Otherwise, these data were calculated according to the methods described by Parmar et al. [
2186 relevant citations were identified for initial review using search strategies as described previously. Of these, 2123 were initially excluded after reading the titles and abstracts and 42 were excluded after assessing the full texts (28 studies without sufficient information for extraction, 7 studies on bone-specific ALP, and 7 studies by same authors on possibly the same patient populations) (Figure
Main characteristics and results of the eligible studies for evaluation of overall survival.
Study |
Country | Number of patients | Age (y) |
ALP cut-off (IU/L) | Enneking stage | HR (95% CI) | Follow-up (m) |
---|---|---|---|---|---|---|---|
Aparicio et al., 1999 [ |
Spain | 33 | 17 (12–42) | 115 | II | 1.26 (0.42–3.74) | 96 (60–156) |
Foukas et al., 2002 [ |
UK | 45 | 18 (6–48) | NA | IIB | 3.44 (1.52–7.79) | 68 (28–88) |
Ford et al., 2004 [ |
UK | 350 | NS (<40) | NA | II | 1.66 (1.09–2.51) | NA |
Bramer et al., 2005 [ |
UK | 89 | NA | NA | II | 1.49 (0.72–3.06) | NA |
Mialou et al., 2005 [ |
France | 60 | 13.5 (2–19) | 500 | IIIB | 2.2 (1.2–4.1) | NA |
Yalçın et al., 2008 [ |
Turkey | 55 | 13 (7–17) | NA | II-III | 1.1 (0.5–2.41) | NA |
Chou et al., 2009 [ |
USA | 91 | NA | NA | III | 3.16 (1.77–5.36) | 89 (1–141) |
Kim et al., 2009 [ |
Korea | 67 | 15.7 (3.8–644) | NA | II | 1.37 (0.54–3.45) | 59.9 |
Wu et al., 2009 [ |
Taiwan ROC | 91 | 20.2 (5–84) | A† | II-III | 2.52 (1.32–4.75) | 58.2 (2–233) |
Yao et al., 2009 [ |
China | 57 | 16 (6–70) | 136 | II-III | 3.45 (1.4–8.46) | 32.5 (10–52) |
Hagleitner et al., 2011 [ |
Netherlands | 94 | 17.8 (4.5–39.5) | NA | II-III | 1.66 (0.88–3.11) | 67.2 (28.8–360) |
Ferrari et al., 2012 [ |
Italy | 209 | 14 (4–39) | A |
II | 1.69 (0.98–2.9) | 76 (31–115) |
Han et al., 2012 [ |
China | 177 | 23.2 (5–57) | A |
II | 1.80 (1.28–2.51) | 87 (8–144) |
Durnali et al., 2013 [ |
Turkey | 211 | 20 (13–74) | A |
II-III | 1.75 (1.23–2.5) | 30.5 (0.5–213) |
Min et al., 2013 [ |
China | 333 | 19 (5–78) | NA | II-III | 1.73 (1.28–2.33) | NA (1–100) |
Hung et al., 2015 [ |
Taiwan ROC | 69 | 13.5 (3.8–17.7) | 150 | II-III | 3.08 (1.05–9.08) | 51.6 (18–111.6) |
Berner et al., 2015 [ |
Norway | 301 | NA | A |
II-III | 1.64 (1.22–2.19) | NA |
NA: not available, A: available (see the footnotes for details), HR: hazard ratio, CI: confidence interval, y: year(s), and m: month(s).
§: ALP cut-off: >18 y 150 IU/L; <18 y 110 IU/L.
Δ: ALP cut-off: 0–17 y 400 IU/L; >17 y 105 IU/L.
Main characteristics and results of the eligible studies for evaluation of event-free survival.
Study |
Country | Number of patients | Age (y) | ALP cut-off (IU/L) | Enneking stage | HR (95% CI) | Follow-up (m) |
---|---|---|---|---|---|---|---|
Mialou et al., 2005 [ |
France | 48 | 13.5 (2–19) | 500 | IIIB | 2.7 (1.5–4.8) | NA |
Lee et al., 2007 [ |
Korea | 45 | <15 | A† | II | 4.55 (1.22–16.99) | 54 (6–153) |
Yalçın et al., 2008 [ |
Turkey | 55 | 13 (7–17) | NA | II-III | 1.11 (0.54–2.31) | NA |
Kim et al., 2009 [ |
Korea | 67 | 15.7 (3.8–64.4) | NA | II | 1.84 (0.84–4.07) | 59.9 |
Chou et al., 2009 [ |
USA | 91 | NA | NA | III | 2.83 (1.68–4.79) | 89 (1–141) |
Ferrari et al., 2012 [ |
Italy | 209 | 14 (4–39) | A |
II | 1.71 (1.09–2.67) | 76 (31–115) |
Berner et al., 2015 [ |
Norway | 237 | NA | AΔ | II-III | 1.78 (1.26–2.52) | NA |
NA: not available, A: available (see the footnotes for details), HR: hazard ratio, CI: confidence interval, y: year(s), and m: month(s).
Δ: ALP cut-off: 0–17 y 400 IU/L; >17 y 105 IU/L.
Main characteristics and results of the eligible studies for evaluation of presence of metastasis at diagnosis.
Study |
Country | Number of patients | Age (y) | ALP cut-off (IU/L) | Enneking stage | RR (95% CI) |
---|---|---|---|---|---|---|
Bacci et al., 1993 [ |
Italy | 549 | NA | A |
II-III | 5.53 (2.85–10.74) |
Wu et al., 2009 [ |
Taiwan ROC | 91 | 20.2 (5–84) | A |
II-III | 16.5 (1.05–260.27) |
Hung et al., 2015 [ |
Taiwan ROC | 76 | 13.5 (3.8–17.7) | 150 | II-III | 18.6 (1.17–294.97) |
NA: not available, A: available (see the footnotes for details), RR: relative risk, and CI: confidence interval.
Main characteristics and results of the eligible studies for evaluation of metastasis development for nonmetastatic patients.
Study |
Country | Number of patients | Age (y) | ALP cut-off (IU/L) |
Enneking stage | RR (95% CI) | Follow-up (m) |
---|---|---|---|---|---|---|---|
Smeland et al., 2003 [ |
Norway | 104 | NA | A† | II | 1.66 (0.68–4.07) | 83 (42–124) |
Han et al., 2012 [ |
China | 177 | 23.2 (5–57) | A |
II | 2.17 (0.97–4.84) | 87 (8–144) |
Kim et al., 2014 [ |
Korea | 91 | NA | A |
IIB | 2.03 (1.04–3.97) | NA |
NA: not available, A: available (see the footnotes for details), RR: relative risk, y: year(s), and m: month(s).
Flow diagram of the study selection process.
HRs of OS could be extracted from 17 studies (Table
17 studies with a total of 2272 osteosarcoma patients dealing with SALP level and OS were meta-analyzed [
Forest plot showing the association between SALP and overall survival (OS) of osteosarcoma.
Forest plot showing the association between SALP and event-free survival (EFS) of osteosarcoma.
Three studies with 816 patients investigated the relationship between SALP level and presence of metastasis at diagnosis [
Forest plot showing the association between SALP and presence of metastasis of osteosarcoma at diagnosis.
Forest plot showing the association between SALP and occurrence of metastasis for nonmetastatic osteosarcoma patients.
Because of the limited articles about metastasis, stratifying analysis was only conducted on the correlation between SALP and OS or EFS. Main results of subgroup analysis for OS and EFS were listed in Tables
A summary of HRs for the overall and subgroup analyses of SALP and OS of osteosarcoma patients.
Number of studies | Patients number | HR (95% CI) | Heterogeneity | |||
---|---|---|---|---|---|---|
Chi-squared |
|
|
||||
Overall | 17 | 2272 | 1.82 (1.61–2.06) | 13.68 | 0% | 0.622 |
Age | ||||||
Preadult and adult | 14 | 2088 | 1.82 (1.60–2.06) | 10.83 | 0% | 0.625 |
Preadult only | 3 | 184 | 1.87 (1.20–2.91) | 2.84 | 2.96% | 0.242 |
Enneking stage | ||||||
II | 7 | 910 | 1.75 (1.42–2.15) | 3.53 | 0% | 0.740 |
II-III | 8 | 1211 | 1.77 (1.61–2.06) | 6.02 | 0% | 0.538 |
III | 2 | 151 | 2.67 (1.75–4.06) | 0.71 | 0% | 0.400 |
Sample size | ||||||
<100 | 11 | 751 | 2.13 (1.70–2.66) | 10.94 | 8.6% | 0.362 |
>100 | 6 | 1521 | 1.71 (1.48–1.98) | 0.20 | 0% | 0.999 |
Geographic region | ||||||
Asia | 6 | 734 | 1.89 (1.55–2.31) | 4.16 | 0% | 0.527 |
Non-Asia | 11 | 1538 | 1.78 (1.53–2.07) | 9.29 | 0% | 0.505 |
HR: hazard ratio, OS: overall survival, and CI: confidence interval.
A summary of HRs for the overall and subgroup analyses of SALP and EFS of osteosarcoma patients.
Number of studies | Patients number | HR (95% CI) | Heterogeneity | |||
---|---|---|---|---|---|---|
Chi-squared |
|
|
||||
Overall | 7 | 752 | 1.97 (1.61–2.42) | 7.65 | 21.6% | 0.265 |
Age | ||||||
Preadult and adult | 4 | 385 | 1.90 (1.45–2.48) | 5.33 | 43.7% | 0.149 |
Preadult only | 3 | 367 | 2.07 (1.51–2.83) | 2.15 | 7.1% | 0.341 |
Enneking stage | ||||||
II | 3 | 321 | 1.88 (1.29–2.73) | 1.91 | 0% | 0.386 |
II-III | 2 | 292 | 1.63 (1.19–2.23) | 1.32 | 24.3% | 0.250 |
III | 2 | 139 | 2.77 (1.88–4.09) | 0.01 | 0% | 0.906 |
Sample size | ||||||
<100 | 5 | 306 | 2.28 (1.68–3.09) | 6.09 | 34.3% | 0.193 |
>100 | 2 | 446 | 1.75 (1.33–2.31) | 0.02 | 0% | 0.89 |
Geographic region | ||||||
Asia | 2 | 112 | 2.34 (1.19–4.60) | 1.34 | 25.2% | 0.248 |
Non-Asia | 5 | 640 | 1.94 (1.56–2.40) | 6.05 | 33.8% | 0.196 |
HR: Hazard ratio, EFS: event-free survival, and CI: confidence interval.
Publication bias of the included studies was assessed by funnel plots and Begg’s test. As shown in Figure
Funnel plots assessing possible publication bias for prognosis ((a) OS; (b) EFS; (c) presence of metastasis at diagnosis; (d) metastasis development for nonmetastatic patients).
Sensitivity analysis for prognosis of survival rates ((a) OS; (b) EFS).
In the early studies, elevated SALP levels had been reported in 40% to 80% of patients with osteosarcoma [
The present meta-analysis suggested that osteosarcoma patients with high SALP levels have significantly poorer OS or EFS when compared with those with normal levels. The results also showed that patients with high SALP significantly correlated with greater ratio of presence of metastasis at diagnosis, indicating that osteosarcoma metastases obviously relate to higher SALP levels. However, it failed to obtain significant correlation between SALP level and metastasis development through nonmetastatic osteosarcoma patients, with the combined RR being 1.95 (95% CI: 0.98–2.91). Among the included three studies, it is worthwhile to notice that Kim et al. [
Assessment of SALP levels in children and adolescents is difficult because those levels are usually greater than in adults, they show a tetrabasic pattern with the highest levels in infancy and puberty and troughs at mid-childhood and at the end of puberty [
In previous studies, cultured human osteosarcoma cell lines [
Meanwhile, some limitations in this meta-analysis should be noticed. First, publication bias might be present if studies unpublished or in other languages that meet the inclusion criteria were missed. The tendency to publish positive findings over negative results may also introduce some bias. Second, some studies included both children and adults in one group, and the effect of age on the levels of SALP was not taken into account for their analyses. Moreover, normal value of SALP is complicated in preadult osteosarcoma patients; most of the studies including young patients did not apply corresponding cut-off point detailed enough by age, which would make the results less accurate. Third, HRs were calculated from data or extrapolated from survival curves in the eligible studies; the HR information obtained by statistical software unavoidably developed a decrease of reliability. Fourth, all the included articles were retrospective studies; ideally, prospective studies would be required to generate more robust conclusions. In addition, since there are multiple sources of human SALP, the prognostic value of total SALP for osteosarcoma is limited by its lack of specificity [
SALP is a routine diagnostic test in clinical laboratories; measurement of SALP is simple, rapid, and cost-effective and provides valuable information for patients with osteosarcoma. In spite of the limitations mentioned above, our meta-analysis permits the conclusion that high SALP is obviously associated with poor OS or EFS and presence of metastasis when diagnosed. SALP level is a convenient and effective biomarker of prognosis for osteosarcoma.
The authors declare that they have no conflict of interests.
This work was supported by the National Natural Science Foundation of the People’s Republic of China (Grant nos. 81172547 and 30973444).