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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 7  |  Page : 140-143

Serum bone-specific alkaline phosphatase as a biomarker for osseous metastases in patients with malignant carcinomas: A systematic review and meta-analysis


1 Department of Orthopedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China
2 Department of Endocrinology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, China
3 Institution of Hematology Research, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China

Date of Web Publication29-Nov-2014

Correspondence Address:
Pei-Jian Tong
Department of Orthopedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.145842

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 > Abstract 

Objective: Bone metastasis was common in patients with malignant tumors. The purpose of this study was to investigate the serum bone-specific alkaline phosphatase (B-ALP) as a biomarker in the diagnosis of osseous metastases in patients with cancers.
Methods: We searched the databases of Pubmed, Cochrane Library, Medline, CNKI and Wanfang to screen the relevant articles about the serum B-ALP detection in the diagnosis of osseous metastases in patients with malignant carcinomas. The pooled sensitivity, specificity, summary receiver operating characteristic (SROC) curve were calculated by STATA12.0 software.
Results: Nineteen trials with 3 268 subjects were finally included in this study. The mean level of serum B-ALP was 41.50 ± 26.61 μg/L (216.90 ± 139.00U/L) in patients with osseous metastases and 14.49 ± 5.52 μg/L (103.30 ± 39.44 U/L) in patients without osseous metastases. The serum level of B-ALP was significant higher in the osseous metastases group than that in the control group (P < 0.05); The pooled sensitivity and specificity for diagnosis of osseous metastases were 0.74 with its 95% confidence interval (95% CI) of 0.62-0.83 and 0.80 (95% CI: 0.67-0.89), respectively. The area under the SRCO was 0.86 (95% CI: 0.83-0.89).
Conclusion: Serum B-ALP can be a promising biomarker for detection of osseous metastases in patients with cancers.

Keywords: Biomarker, bone-specific alkaline phosphatase, meta-analysis, osseous metastases


How to cite this article:
Du WX, Duan SF, Chen JJ, Huang JF, Yin LM, Tong PJ. Serum bone-specific alkaline phosphatase as a biomarker for osseous metastases in patients with malignant carcinomas: A systematic review and meta-analysis. J Can Res Ther 2014;10, Suppl S3:140-3

How to cite this URL:
Du WX, Duan SF, Chen JJ, Huang JF, Yin LM, Tong PJ. Serum bone-specific alkaline phosphatase as a biomarker for osseous metastases in patients with malignant carcinomas: A systematic review and meta-analysis. J Can Res Ther [serial online] 2014 [cited 2019 Aug 22];10:140-3. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/140/145842

Wen-Xi Du and Shu-Fang Duan contribute equally to this work



 > Introduction Top


This project was supported by the grants from National Natural Science Foundation of China (to Wen-Xi Du, No. 81202709), The Natural Science Foundation of Zhejiang Province (to Wen-Xi Du, No. Y2111092) and Program for Zhejiang Leading Team of S and T Innovation (to Wen-Xi Du, No. 2011R50022-07).

In recent years, increasing attention has been focused on the biochemical markers of metastatic bone cancer such as C-telopeptide-cross-linked type I collagen, osteocalcin, bone-specific alkaline phosphatase (B-ALP). Several articles have indicated that B-ALP was over-expressed in patients with bone metastases disease. And it could be a biomarker for diagnosis of osseous metastases in patients with cancers. However with a small number cases and controls in each of the individual studies, the statistical power was limited. Moreover, the conclusion was not conclusive. Thus, we performed this systematic review and meta-analysis in order to further evaluation the clinical value of serum B-ALP in detection of bone metastases diseases.


 > Methods Top


Search strategy

We searched the databases of Pubmed, Cochrane Library, Medline, CNKI and Wanfang to screen the relevant articles about the serum B-ALP detection in the diagnosis of osseous metastases in patients with malignant carcinomas. The searching words were showed as follows: B-ALP, bone metastases/bone metastasis, osseous metastases/osseous metastasis, diagnosis. Furthermore, for obtaining additional relevant articles, we reviewed the conference summaries and reference lists of retrieved studies, and even contacted authors to obtain further information, if necessary.

Data extraction

Data of each individual included article was extracted by two reviewers (Wen-Xi Du and Shu-Fang Duan) independently. Any disagreement was consulted to another two investigators (Li-Ming Yin and Pei-Jian Tong) for consensus. The general characteristics of first and corresponding author, year of publication, cancer types were extracted and recorded in the excel software. And the detailed information for pooling the sensitivity, specificity and ROC were extracted carefully and checked by Dr. Jun-Jie Chen and Jie-Feng Huang.

Statistical analysis

All the data were analyzed using STATA12.0 (StataCorp LP, http://www.stata.com) and MetaAnalyst3.13 (http://tuftscaes.org/meta_analyst) software. Statistical heterogeneity among the included studies was assessed by Chi-square test, [1] and the inconsistency was calculated by I 2 . [2] If heterogeneity was found (P < 0.05 or I 2 > 50%), the random effect method (Dersimonian-Laird method) was used to pool the data and subgroups analysis was done for further evaluation. Inversely, without significant heterogeneity, fixed-effect method was used. The diagnosis index of sensitivity, specificity and area under the ROC were pooled by the statistical software. Two-tailed P ≤ 0.05 was considered as statistical significance.


 > Results Top


Characteristic of individual studies

According to the inclusion criteria, nineteen studies including 1384 case and 1884 controls were finally included in this systematic review and meta-analysis. Of the included 19 trials, 6 studies provided the true positive (tp) false positive (fp) false negative (fn) and true negative (tn) rate in each individual study. 15 studies provided the serum B-ALP level in case and control groups. And 14 trials provided the diagnosis sensitivity and specificity [Table 1].
Table 1: The detail information of each individual study


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The serum level of bone-specific alkaline phosphatase

Fifteen studies provided the serum B-ALP level in case and control groups. The serum level of B-ALP range from 24.1 ± 18.9-83.2 ± 65.6 μg/L (103.3 ± 60.0-483.0 U/L) in the bone metastases group to 10.0 ± 5.5-21.48 ± 6.07 μg/L (69-175.9 ± 38.8 U/L). The summary level of serum B-ALP were 41.50 ± 26.61 μg/L (216.90 ± 139.00U/L) in patients with osseous metastases and 14.49 ± 5.52 (103.30 ± 39.44 U/L) in patients without osseous metastases respectively [Table 2]. And the serum level of B-ALP in the osseous metastases group was significant higher than that in the control group (P < 0.05) [Figure 1].
Figure 1: The distribution of serum bone-specific alkaline phosphatase of the included studies

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Table 2: The serum level of B-ALP in the included trials


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The pooled diagnosis value

Fourteen trials provided the diagnosis sensitivity and specificity. The sensitivity and specificity range from 0.27 (0.14-0.45) to 0.93 (0.63-0.99) and 0.64 (0.44-0.80) to 1.00 (0.89-1.00). The pooled sensitivity [Figure 2], and specificity [Figure 3] were 0.74 (95% CI: 0.62-0.83) and 0.80 (95% CI: 0.67-0.89) respectively in the case and control groups.
Figure 2: The forest plot of sensitivity for bone-specific alkaline phosphatase in the diagnosis of osseous metastases

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Figure 3: The forest plot of specificity for bone-specific alkaline phosphatase in the diagnosis of osseous metastases

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The summary receiver operating characteristic

Six studies provided the true positive (tp) false positive (fp) false negative (fn) and true negative (tn) rate in each individual study. The summary ROC was synthesized by the STATA12.0 software. The AUC of the SROC 0.86 (95% CI: 0.83-0.89) [Figure 4].
Figure 4: The area under the curve of the summary receiver operating characteristic curve for diagnosis of osseous metastases by serum bone-specific alkaline phosphatase

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 > Discussion Top


Cancer is a major public health problem in the world wide. It was reported that one in 4 deaths in the United States is due to cancer. [22] And bone metastases are one of the most common metastasis place for most of the cancers. It was estimated that about 80% of patients with advanced stage of cancer was finally developed with bone metastases. [23] The main tools for diagnosis of bone metastases lesion were X-ray, computed tomography, magnetic resonance imaging and emission computed tomography. All the above were based on the imagined system. Patients who underwent the above examination will received X-ray exposure. Thus, the imagine system for diagnosis of metastasis disease has its own disadvantages

Recently, several studies indicated that serum level of B-ALP changed rapidly with the development of cancer. [4],[7] And some of them demonstrated that the serum B-ALP could be a biomarker for early diagnosis of bone metastasis diseases. [3] Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. And B-ALP was one of the alkaline phosphatase which was specifically elevated in patients with bone metabolic disease.

In this systematic review and meta-analysis, we further included 19 trials. Of the included studies, some articles provided the serum B-ALP level in bone metastases patients and controls, some papers provided the diagnosis sensitivity and specificity and some trials provided the diagnosis true positive, false positive, false negative and true negative. Hence, we pooled the serum B-ALP, sensitivity, specificity and SROC by using the individual data. The aggregated data showed that the serum level of B-ALP was significant higher in the osseous metastases group than that in the control group (P < 0.05); The pooled sensitivity and specificity for diagnosis of osseous metastases were 0.74 with its 95% confidence interval (95% CI) of 0.62-0.83 and 0.80 (95% CI: 0.67-0.89), respectively. The area under the summary receiver operating characteristic curve was 0.86 (95% CI: 0.83-0.89). The results indicating that serum B-ALP can be a promising biomarker for detection of osseous metastases in patients with cancers with relative high diagnosis sensitivity and specificity.

However, the number of case and control in the each individual study were relative small. The included articles in this meta-analysis are most from China and published in Chinese with low quality. Thus, the conclusion of this meta-analysis should be further assessed by multiple center prospective randomized diagnosis trials.

 
 > References Top

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