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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Oncol.</journal-id>
<journal-title-group>
<journal-title>Frontiers in Oncology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Oncol.</abbrev-journal-title>
</journal-title-group>
<issn pub-type="epub">2234-943X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fonc.2026.1730986</article-id>
<article-version article-version-type="Version of Record" vocab="NISO-RP-8-2008"/>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Systematic Review</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Head-to-head comparative study of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in assessing bone metastasis of various cancers: a systematic review and meta-analysis</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>He</surname><given-names>MingLiu</given-names></name>
<uri xlink:href="https://loop.frontiersin.org/people/2392821/overview"/>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Writing &#x2013; original draft" vocab-term-identifier="https://credit.niso.org/contributor-roles/writing-original-draft/">Writing &#x2013; original draft</role>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Tan</surname><given-names>Jian</given-names></name>
<xref ref-type="corresp" rid="c001"><sup>*</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/3252968/overview"/>
<role vocab="credit" vocab-identifier="https://credit.niso.org/" vocab-term="Writing &#x2013; review &amp; editing" vocab-term-identifier="https://credit.niso.org/contributor-roles/writing-review-editing/">Writing &#x2013; review &amp; editing</role>
</contrib>
</contrib-group>
<aff id="aff1"><institution>Dazhou Dachuan District People&#x2019;s Hospital, (Dazhou Third People&#x2019;s Hospital)</institution>, <city>Dazhou</city>,&#xa0;<country country="cn">China</country></aff>
<author-notes>
<corresp id="c001"><label>*</label>Correspondence: Jian Tan, <email xlink:href="mailto:2378822574@qq.com">2378822574@qq.com</email></corresp>
</author-notes>
<pub-date publication-format="electronic" date-type="pub" iso-8601-date="2026-01-30">
<day>30</day>
<month>01</month>
<year>2026</year>
</pub-date>
<pub-date publication-format="electronic" date-type="collection">
<year>2026</year>
</pub-date>
<volume>16</volume>
<elocation-id>1730986</elocation-id>
<history>
<date date-type="received">
<day>23</day>
<month>10</month>
<year>2025</year>
</date>
<date date-type="accepted">
<day>08</day>
<month>01</month>
<year>2026</year>
</date>
<date date-type="rev-recd">
<day>05</day>
<month>01</month>
<year>2026</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2026 He and Tan.</copyright-statement>
<copyright-year>2026</copyright-year>
<copyright-holder>He and Tan</copyright-holder>
<license>
<ali:license_ref start_date="2026-01-30">https://creativecommons.org/licenses/by/4.0/</ali:license_ref>
<license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License (CC BY)</ext-link>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p>
</license>
</permissions>
<abstract>
<sec>
<title>Purpose</title>
<p>The objective of our systematic review and meta-analysis is to compare the performance of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in diagnosing bone metastasis of various cancer types. This analysis aims to provide an objective assessment of the diagnostic capabilities of these two imaging modalities.</p>
</sec>
<sec>
<title>Methods</title>
<p>We conducted a search on Embase, Web of Science, Pubmed for articles published between 2023 and 2025 that meet our criteria. This study focuses on exploring the diagnostic value of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in various cancer bone metastases. we used random-effects analysis to assess the diagnostic capabilities of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in patient-based analysis (PB) with bone metastasis and bone metastatic lesion-based analysis (LB).Heterogeneity of the data was assessed through sensitivity analysis. Furthermore, the included studies underwent quality assessment using the QUADAS-2 tool, which is a bias assessment tool utilized for diagnostic test accuracy studies.</p>
</sec>
<sec>
<title>Results</title>
<p>In the initial search, 235 articles were identified, and finally 10 clinical studies were included by excluding related articles. All included studies were retrospective, involved diverse cancer types, and did not contain overlapping patient cohorts from the same institution. In the patient-based analysis (PB), the detection rate of [<sup>68</sup>Ga]FAPI-04 PET/CT was determined to be 0.99 (95% CI: 0.90&#x2013;1.00, I&#xb2;=36.5%), whereas that of [<sup>18</sup>F]FDG PET/CT was 0.79 (95% CI: 0.54&#x2013;0.79, I&#xb2;=62.4%),Sensitivity analysis revealed potential sources of heterogeneity. In the lesion-based analysis (LB), the detection rate of [<sup>68</sup>Ga]FAPI-04 PET/CT was determined to be 1.00 (95% CI: 0.98&#x2013;1.00, I&#xb2;=91.5%), while [<sup>18</sup>F]FDG PET/CT showed a detection rate of 0.71 (95% CI: 0.61&#x2013;0.80, I&#xb2;=95.3%), with no significant sources of heterogeneity identified.</p>
</sec>
<sec>
<title>Conclusion</title>
<p>By comparing the available data, [<sup>68</sup>Ga]FAPI-04 PET/CT appears to show a higher detection rate for bone metastases in various malignancies compared with [<sup>18</sup>F]FDG PET/CT. However, this finding should be interpreted with caution, as pooled sensitivity, specificity, PPV, NPV, DOR, or HSROC analyses could not be performed due to insufficient available data,</p>
</sec>
</abstract>
<kwd-group>
<kwd>bone metastasis</kwd>
<kwd>FAPI</kwd>
<kwd>FDG</kwd>
<kwd>meta-analysis</kwd>
<kwd>PET/CT</kwd>
</kwd-group>
<funding-group>
<funding-statement>The author(s) declared that financial support was not received for this work and/or its publication.</funding-statement>
</funding-group>
<counts>
<fig-count count="7"/>
<table-count count="2"/>
<equation-count count="0"/>
<ref-count count="33"/>
<page-count count="10"/>
<word-count count="3491"/>
</counts>
<custom-meta-group>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Cancer Imaging and Image-directed Interventions</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<title>Introduction</title>
<p>Bone metastasis is a common complication of advanced cancer (<xref ref-type="bibr" rid="B1">1</xref>), especially tumors originating from breast and prostate. About 70% of breast cancer and prostate patients have bone metastasis. Unfortunately, once the tumor has bone metastasis, it is extremely prone to fracture (<xref ref-type="bibr" rid="B2">2</xref>, <xref ref-type="bibr" rid="B3">3</xref>), bone pain and other complications, the patients&#x2019; quality of life is significantly affected (<xref ref-type="bibr" rid="B4">4</xref>, <xref ref-type="bibr" rid="B5">5</xref>). Therefore, the accurate diagnosis of malignant tumor bone metastasis plays a crucial role in guiding subsequent treatment and assessing the prognosis of patients. Currently, the use of whole-body scanning with [99mTc]Tc-MDP is considered the standard of practice for detecting bone metastases in malignant tumors. The tracer is absorbed, and the absorption intensity is associated with local blood flow and osteoblast activity. [99mTc]Tc-MDP identifies affected bone cells rather than the tumor itself. This technique relies on the osteoblastic response, thus being highly sensitive for advanced-stage malignant tumor bone metastasis. However, its accuracy in early diagnosis and treatment is not high, and its sensitivity and specificity are not ideal (<xref ref-type="bibr" rid="B6">6</xref>).</p>
<p>The [<sup>18</sup>F]FDG PET/CT technology is a PET/CT that combines positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and computed tomography (CT) (<xref ref-type="bibr" rid="B7">7</xref>). By imaging the metabolism of glucose in tissue, it provides a non-invasive method for bone metastasis of cancer and provides relevant data for the staging and typing of bone metastatic tumors (<xref ref-type="bibr" rid="B8">8</xref>). The European Organization for Cancer Research and treatment (EORTC) imaging team assessed the ability of current mainstream imaging examinations to assess bone metastasis, and [<sup>18</sup>F]FDG PET/CT showed great advantages in terms of whole body coverage, reproducibility, and ease of use in multicenter trials (<xref ref-type="bibr" rid="B9">9</xref>). At present, [<sup>18</sup>F]FDG PET/CT is mainly used to distinguish between benign and malignant tumors in multiple organ systems, but its role in the evaluation of bone tumors is not clear (<xref ref-type="bibr" rid="B10">10</xref>). Fibroblast activating protein (FAP) is a characteristic expression of cancer-related cells. [<sup>68</sup>Ga]FAPI-04 PET/CT demonstrates favorable performance in studying various solid tumors by labeling fibroblast activation protein inhibitors (FAPI) (<xref ref-type="bibr" rid="B11">11</xref>). Moreover, [<sup>68</sup>Ga]FAPI-04 PET/CT accumulates at a high level in tumors, showing excellent pharmacokinetic and biochemical characteristics (<xref ref-type="bibr" rid="B9">9</xref>). Compared with other imaging diagnosis methods, [<sup>68</sup>Ga]FAPI-04 PET/CT also demonstrated improved background signal levels (<xref ref-type="bibr" rid="B12">12</xref>). However, the expression of fibroblast activating protein (FAPI) is not significant in normal tissues, but it is highly expressed in abnormal conditions such as wound healing and arthritis, which affects the accuracy of [<sup>68</sup>Ga]FAPI-04 PET/CT to some extent (<xref ref-type="bibr" rid="B13">13</xref>&#x2013;<xref ref-type="bibr" rid="B15">15</xref>).</p>
<p>In this paper, our objective is to conduct a meta-analysis by gathering available literature and its corresponding data, with the purpose of comparing the diagnostic performance of FAPI and FDG in the detection of bone metastases in malignant tumors. This analysis aims to provide an authoritative and comprehensive assessment of the two methods, while maintaining a cautious approach to drawing conclusions from the results.</p>
</sec>
<sec id="s2" sec-type="materials|methods">
<title>Materials and methods</title>
<sec id="s2_1">
<title>Search strategy</title>
<p>We endeavored to conduct a comprehensive search on the Pubmed, Embase, and Web of Science databases for relevant literature published between 2023 and 2025, utilizing the following term combinations: (1) positron emission tomography or PET, (2) FAPI-04 or <sup>68</sup>Ga-FAPI or FAPI or fibroblast activation protein, and (3) bone metastasis or bone metastases.</p>
</sec>
<sec id="s2_2">
<title>Inclusion and exclusion criteria</title>
<p>Inclusion criteria for relevant literature: 1. Studies involving patients with tumor bone metastasis. 2. Comparative studies directly comparing FDG and FAPI, which may be prospective or retrospective experimental studies. 3. Studies with a total sample size exceeding 10 individuals. 4. Sources of information with high credibility and comprehensive relevant data. Exclusion criteria: 1. Studies conducted on animals rather than humans. 2. Literature types such as abstracts, discussions, literature reviews, etc. 3. Studies lacking extractable relevant detection rates. Based on the aforementioned criteria, the titles and abstracts of articles were evaluated to determine their suitability for inclusion. Further assessment was conducted on the full texts of the retained articles to ensure compliance with the inclusion criteria.</p>
</sec>
<sec id="s2_3">
<title>Quality assessment and data extraction</title>
<p>We utilized the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool to independently assess the quality of the included studies. The risk of bias and applicability of each study were carefully evaluated by two researchers. The evaluation of each study was rated as high, low, or unclear in terms of risk of bias and applicability. To ensure the resolution of any potential disagreements, a third reviewer was engaged. The analysis was conducted using RevMan (version 5.3).</p>
<p>Data extraction from all included papers was independently performed by two researchers. The extracted data encompassed the following aspects: (1) Author and Publication Year;(2) Study Characteristics, including the author&#x2019;s country, as well as relevant research design, analysis, and reference standard;(3) Patient Characteristics, encompassing clinical indications, the number of patients, whether chemotherapy was administered before PET, and the mean/median age;(4) Technical Characteristics, comprising imaging scanner modality, types of imaging tests, ligand dose, time interval between injection and acquisition, image analysis, and detection rate. When the information was not explicitly stated in the text, we attempted manual retrieval of data from the literature, tables, and figures. In instances where the paper lacked sufficient information, we reached out to the corresponding authors via email, requesting additional data or clarification. Any disagreements between the two researchers were resolved through mutual consensus.</p>
</sec>
</sec>
<sec id="s3" sec-type="results">
<title>Results</title>
<sec id="s3_1">
<title>Study selection</title>
<p>Initially, a total of 235 articles were identified in the search. After excluding 58 articles, 177 studies were determined as relevant. Among them, 78 case reports, abstracts, reviews, meta-analyses, and 67 articles with entirely unrelated titles and abstracts to this study were excluded, leaving 32 studies for further evaluation. Subsequently, 8 articles lacking relevant data, 7 articles irrelevant to the research, and 7 non-English articles were excluded, resulting in a total of 10 articles are related to the detection performance of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in malignant tumor bone metastasis (<xref ref-type="bibr" rid="B16">16</xref>&#x2013;<xref ref-type="bibr" rid="B25">25</xref> (p68)). The ProcessOn flow diagram of the study selection process is shown in <xref ref-type="fig" rid="f1"><bold>Figure&#xa0;1</bold></xref>.</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>Flow diagram of study selection.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-16-1730986-g001.tif">
<alt-text content-type="machine-generated">Flowchart showing the process of selecting studies for a systematic review. Initially, 235 records are identified from PubMed, Embase, and Web of Science. After removing duplicates, 177 records remain. 145 articles are excluded due to being case reports or irrelevant. 32 full-text articles are assessed, and 22 are excluded for lacking relevant data, being irrelevant, or not in English. Ultimately, 10 studies are included in the review and meta-analysis.</alt-text>
</graphic></fig>
</sec>
<sec id="s3_2">
<title>Study description and quality assessment</title>
<p><xref ref-type="table" rid="T1"><bold>Table&#xa0;1</bold></xref> provides an overview of the extracted research and patient characteristics from 10 different studies, which collectively involved 472 patients. Technical details are outlined in <xref ref-type="table" rid="T2"><bold>Table&#xa0;2</bold></xref>. Furthermore, an evaluation of the quality of the relevant studies was conducted using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The quality assessment plot indicates that the primary concentration of high-risk bias issues lies in the flow and timing domain((<xref ref-type="fig" rid="f2"><bold>Figure&#xa0;2</bold></xref>), the possible reason for this could be the exclusion of some patients from the analysis in most studies. Overall, the bias risk in these articles was deemed satisfactory.</p>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Study and patient characteristics of the included studies.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" rowspan="2" align="center">Author</th>
<th valign="middle" rowspan="2" align="center">Year</th>
<th valign="middle" colspan="3" align="center">Study characteristics</th>
<th valign="middle" colspan="4" align="center">Patient characteristics</th>
</tr>
<tr>
<th valign="middle" align="center">Country</th>
<th valign="middle" align="center">Study design</th>
<th valign="middle" align="center">Analysis</th>
<th valign="middle" align="center">No. of patients</th>
<th valign="middle" align="center">Clinical indication</th>
<th valign="middle" align="center">Mean/Median age</th>
<th valign="middle" align="center">Primary cancer</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="middle" align="center">Sahin et&#xa0;al. (<xref ref-type="bibr" rid="B17">17</xref>)</td>
<td valign="middle" align="center">2025</td>
<td valign="middle" align="center">China</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB AND PB</td>
<td valign="middle" align="center">23</td>
<td valign="middle" align="center">Initial staging</td>
<td valign="middle" align="center">Median =51 years</td>
<td valign="middle" align="center">Lung Cancer</td>
</tr>
<tr>
<td valign="middle" align="center">Wang et&#xa0;al. (<xref ref-type="bibr" rid="B18">18</xref>)</td>
<td valign="middle" align="center">2024</td>
<td valign="middle" align="center">China</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB AND PB</td>
<td valign="middle" align="center">10</td>
<td valign="middle" align="center">Initial staging<break/>Post-treatment</td>
<td valign="middle" align="center">Median = 59 years</td>
<td valign="middle" align="center">Gastric Carcinomas</td>
</tr>
<tr>
<td valign="middle" align="center">Arak et&#xa0;al. (<xref ref-type="bibr" rid="B19">19</xref>)</td>
<td valign="middle" align="center">2024</td>
<td valign="middle" align="center">Turkey</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB</td>
<td valign="middle" align="center">75</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">Median = 55 years</td>
<td valign="middle" align="center">NA</td>
</tr>
<tr>
<td valign="middle" align="center">Guo et&#xa0;al. (<xref ref-type="bibr" rid="B20">20</xref>)</td>
<td valign="middle" align="center">2025</td>
<td valign="middle" align="center">China</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB AND PB</td>
<td valign="middle" align="center">48</td>
<td valign="middle" align="center">Initial staging<break/>Post-treatment</td>
<td valign="middle" align="center">Median = 57 &#xb1; 13 years</td>
<td valign="middle" align="center">NA</td>
</tr>
<tr>
<td valign="middle" align="center">Civan et&#xa0;al. (<xref ref-type="bibr" rid="B21">21</xref>)</td>
<td valign="middle" align="center">2024</td>
<td valign="middle" align="center">Turkey</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB</td>
<td valign="middle" align="center">20</td>
<td valign="middle" align="center">Initial staging<break/>Post-treatment</td>
<td valign="middle" align="center">Median = 62 years</td>
<td valign="middle" align="center">Renal Carcinoma</td>
</tr>
<tr>
<td valign="middle" align="center">Lanzafame et&#xa0;al. (<xref ref-type="bibr" rid="B16">16</xref>)</td>
<td valign="middle" align="center">2024</td>
<td valign="middle" align="center">German</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB</td>
<td valign="middle" align="center">200</td>
<td valign="middle" align="center">Initial staging<break/>Post-treatment</td>
<td valign="middle" align="center">Median = 55 years</td>
<td valign="middle" align="center">NA</td>
</tr>
<tr>
<td valign="middle" align="center">Chen et&#xa0;al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">China</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB AND PB</td>
<td valign="middle" align="center">34</td>
<td valign="middle" align="center">Initial staging</td>
<td valign="middle" align="center">Median = 51 years</td>
<td valign="middle" align="center">Gastric Carcinomas</td>
</tr>
<tr>
<td valign="middle" align="center">Ballal et&#xa0;al. (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">India</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">PB</td>
<td valign="middle" align="center">5</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">Median = 53.2 &#xb1; 11.7 years</td>
<td valign="middle" align="center">Thyroid cancer</td>
</tr>
<tr>
<td valign="middle" align="center">Kepenek et&#xa0;al. (<xref ref-type="bibr" rid="B22">22</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">Turkey</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB</td>
<td valign="middle" align="center">44</td>
<td valign="middle" align="center">Initial staging</td>
<td valign="middle" align="center">Median = 56.82 &#xb1; 15.58 years</td>
<td valign="middle" align="center">NA</td>
</tr>
<tr>
<td valign="middle" align="center">Li et&#xa0;al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">China</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB</td>
<td valign="middle" align="center">8</td>
<td valign="middle" align="center">Initial staging<break/>Post-treatment</td>
<td valign="middle" align="center">Median = 59.09 &#xb1; 10.98 years</td>
<td valign="middle" align="center">Biliary tract carcinoma</td>
</tr>
<tr>
<td valign="middle" align="center">Chen et&#xa0;al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">China</td>
<td valign="middle" align="center">Pro</td>
<td valign="middle" align="center">LB AND PB</td>
<td valign="middle" align="center">5</td>
<td valign="middle" align="center">Initial staging</td>
<td valign="middle" align="center">Median = 51 years</td>
<td valign="middle" align="center">Gastric Carcinomas</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>PB, patient-based; LB, lesion-based; Pro, prospective; Retro, retrospective; NA, not available.</p></fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T2" position="float">
<label>Table&#xa0;2</label>
<caption>
<p>Technical aspects of included studies.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="center">Author</th>
<th valign="middle" align="center">Year</th>
<th valign="middle" align="center">Scanner modality</th>
<th valign="middle" align="center">Ligand dose ([68 Ga]Ga-DOTA-FAPI-04)</th>
<th valign="middle" align="center">Time from injection to acquisition ([68 Ga]Ga-DOTA-FAPI-04)</th>
<th valign="middle" align="center">Ligand dose ([18F]FDG)</th>
<th valign="middle" align="center">Time from injection to acquisition ([18F]FDG)</th>
<th valign="middle" align="center">Image analysis</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="middle" align="center">Sahin et&#xa0;al. (<xref ref-type="bibr" rid="B17">17</xref>)</td>
<td valign="middle" align="center">2025</td>
<td valign="middle" align="center">GE Healthcare</td>
<td valign="middle" align="center">2&#x2013;3 MBq/kg</td>
<td valign="middle" align="center">45min</td>
<td valign="middle" align="center">5 MBq/kg</td>
<td valign="middle" align="center">60min</td>
<td valign="middle" align="center">Visual and quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Wang et&#xa0;al. (<xref ref-type="bibr" rid="B18">18</xref>)</td>
<td valign="middle" align="center">2024</td>
<td valign="middle" align="center">Hebei Andike Positron Technology Co., Ltd</td>
<td valign="middle" align="center">1.5&#x2013;1.8MBq/kg</td>
<td valign="middle" align="center">60 &#xb1; 5min</td>
<td valign="middle" align="center">3.7 MBq/kg</td>
<td valign="middle" align="center">60 &#xb1; 5min</td>
<td valign="middle" align="center">Quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Arak et&#xa0;al. (<xref ref-type="bibr" rid="B19">19</xref>)</td>
<td valign="middle" align="center">2024</td>
<td valign="middle" align="center">General Electric Company, Milwaukee, Wisconsin, USA and General Electric Company, Milwaukee, Wisconsin, USA</td>
<td valign="middle" align="center">5 MBq/Kg</td>
<td valign="middle" align="center">60min</td>
<td valign="middle" align="center">2&#x2013;3 MBq/kg</td>
<td valign="middle" align="center">45min</td>
<td valign="middle" align="center">Visual and quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Guo et&#xa0;al. (<xref ref-type="bibr" rid="B20">20</xref>)</td>
<td valign="middle" align="center">2025</td>
<td valign="middle" align="center">Philips Medical Systems, The Netherlands and Philips Medical Systems, The<break/>Netherlands</td>
<td valign="middle" align="center">3.7 MBq/kg</td>
<td valign="middle" align="center">60 &#xb1; 10 min</td>
<td valign="middle" align="center">1.9 to 3.7 MBq/kg</td>
<td valign="middle" align="center">60 &#xb1; 10 min</td>
<td valign="middle" align="center">Visual and quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Civan et&#xa0;al. (<xref ref-type="bibr" rid="B21">21</xref>)</td>
<td valign="middle" align="center">2024</td>
<td valign="middle" align="center">GE Healthcare IQ Discovery PET/CT</td>
<td valign="middle" align="center">125 MBq</td>
<td valign="middle" align="center">15min</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">Quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Lanzafame et&#xa0;al. (<xref ref-type="bibr" rid="B16">16</xref>)</td>
<td valign="middle" align="center">2024</td>
<td valign="middle" align="center">Siemens Healthineers</td>
<td valign="middle" align="center">120 &#xb1; 38.3 MBq</td>
<td valign="middle" align="center">23.5 &#xb1; 19.0 min</td>
<td valign="middle" align="center">248.6 &#xb1; 89.2 MBq</td>
<td valign="middle" align="center">69.5 &#xb1; 15.5 min</td>
<td valign="middle" align="center">Visual and quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Chen et&#xa0;al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">Discovery MI,G.E. Healthcare;BiograpmCT,Siemens Healthineers;</td>
<td valign="middle" align="center">133.2&#x2013;281.2MBq</td>
<td valign="middle" align="center">60min</td>
<td valign="middle" align="center">203.5&#x2013;358.9MBq</td>
<td valign="middle" align="center">60min</td>
<td valign="middle" align="center">Visual and quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Ballal et&#xa0;al. (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">185&#x2013;370 MBq</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">185 - 370<break/>MBq</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">Quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Kepenek et&#xa0;al. (<xref ref-type="bibr" rid="B22">22</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">GE Healthcare, Milwaukee, WI, USA</td>
<td valign="middle" align="center">2 MBq/kg</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">3.5&#x2013;5.5 MBq/kg</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">Visual and quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Li et&#xa0;al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">Isotope Technologies Munich GmBH, Munich, Germany</td>
<td valign="middle" align="center">1.85&#x2013;3.7 MBq/kg</td>
<td valign="middle" align="center">2.5min</td>
<td valign="middle" align="center">1.85&#x2013;3.7 MBq/kg</td>
<td valign="middle" align="center">2min</td>
<td valign="middle" align="center">Visual and quantitative</td>
</tr>
<tr>
<td valign="middle" align="center">Chen et&#xa0;al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="middle" align="center">2023</td>
<td valign="middle" align="center">NA</td>
<td valign="middle" align="center">281.2 MBq (range, 203.5&#x2013;358.9)</td>
<td valign="middle" align="center">60min</td>
<td valign="middle" align="center">194.3 MBq (range 133.2&#x2013;281.2)</td>
<td valign="middle" align="center">60min</td>
<td valign="middle" align="center">Visual and quantitative</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>PB, patient-based; LB, lesion-based; Pro, prospective; Retro, retrospective; NA, not available.</p></fn>
</table-wrap-foot>
</table-wrap>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>Summary of risk of bias and applicability concerns of the included studies.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-16-1730986-g002.tif">
<alt-text content-type="machine-generated">Chart comparing risk of bias and applicability concerns for studies from Arak et al. 2024 to Wang et al. 2024. Risk of bias categories include patient selection, index test, reference standard, and flow and timing, with indicators for high (red), unclear (yellow), and low (green) risk. Applicability concerns assessed for patient selection, index test, and reference standard, primarily showing low risk.</alt-text>
</graphic></fig>
</sec>
<sec id="s3_3">
<title>Diagnostic performance of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT for bone metastasis</title>
<p>In the patient-based related studies, a random-effects model was utilized, and the results, as shown in <xref ref-type="fig" rid="f3"><bold>Figure&#xa0;3</bold></xref>, indicate that the detection rate of [<sup>68</sup>Ga]FAPI-04 PET/CT was 0.99 (95% CI: 0.90&#x2013;1.00, I&#xb2;=36.5%), while that of [<sup>18</sup>F]FDG PET/CT was 0.79 (95% CI: 0.54&#x2013;0.79, I&#xb2;=62.4%). A statistically significant difference was observed between the two modalities (P = 0.0003).</p>
<fig id="f3" position="float">
<label>Figure&#xa0;3</label>
<caption>
<p>The forest plot shows the pooled detection rate of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in patient-based studies of bone metastases from malignant tumors. The symbol (&#x25c6;) represents the estimated detection rate.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-16-1730986-g003.tif">
<alt-text content-type="machine-generated">Forest plot comparing two radiotracers: [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG. Each row lists study names with corresponding event counts, proportions, confidence intervals, and weights. Heterogeneity statistics are provided for each radiotracer. Summary estimates are represented by diamonds, with random effects models indicating a higher proportion for [68Ga]Ga-DOTA-FAPI-04.</alt-text>
</graphic></fig>
<p>In the lesion-based related studies, a random-effects model was also employed, and the results, presented in <xref ref-type="fig" rid="f4"><bold>Figure&#xa0;4</bold></xref>, demonstrate that the detection rate of [<sup>68</sup>Ga]FAPI-04 PET/CT was 1.00 (95% CI: 0.98&#x2013;1.00, I&#xb2;=91.5%), whereas [<sup>18</sup>F]FDG PET/CT showed a detection rate of 0.71 (95% CI: 0.61&#x2013;0.80, I&#xb2;=95.3%). The difference in detection rates between the two imaging methods was statistically significant (P&lt;0.0001).</p>
<fig id="f4" position="float">
<label>Figure&#xa0;4</label>
<caption>
<p>The forest plot shows the pooled detection rate of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in lesion-based studies of bone metastases from malignant tumors. The symbol (&#x25c6;) represents the estimated detection rate.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-16-1730986-g004.tif">
<alt-text content-type="machine-generated">Forest plot comparing the effectiveness of two radiotracers: [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG, both lesion-based. Each study is listed with event counts, total population, and corresponding proportions with 95% confidence intervals. Diamonds at the bottom represent the summary effect sizes for each radiotracer and overall, with significant heterogeneity indicated.</alt-text>
</graphic></fig>
</sec>
<sec id="s3_4">
<title>Heterogeneity analysis</title>
<p>In the patient-based studies, the detection rate of [<sup>68</sup>Ga]FAPI-04 PET/CT was 0.99 (95% CI: 0.90&#x2013;1.00, I&#xb2;=36.5%), indicating no significant heterogeneity among the included studies (I&#xb2; &lt; 50%). In contrast, the detection rate of [<sup>18</sup>F]FDG PET/CT was 0.79 (95% CI: 0.54&#x2013;0.79, I&#xb2;=62.4%). Sensitivity analysis suggested that the study by Chen et&#xa0;al. might be the primary source of heterogeneity; after its exclusion, the heterogeneity decreased to I&#xb2;=0(<xref ref-type="fig" rid="f5"><bold>Figure&#xa0;5</bold></xref>).</p>
<fig id="f5" position="float">
<label>Figure&#xa0;5</label>
<caption>
<p>Sensitivity analysis of patient-based detection using [&#xb9;&#x2078;F]FDG PET/CT.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-16-1730986-g005.tif">
<alt-text content-type="machine-generated">Forest plot showing the impact of omitting studies on a random effects model. Each line represents a study, displaying proportion values with confidence intervals and p-values. The summarized proportion is 0.79 with a confidence interval of 0.54 to 0.97. Heterogeneity statistics include Tau-squared, Tau, and I-squared, indicating variability among studies.</alt-text>
</graphic></fig>
<p>The lesion-based studies, [<sup>68</sup>Ga]FAPI-04 PET/CT was 1.00 (95% CI: 0.98&#x2013;1.00, I&#xb2;=91.5%), whereas that of [18F]FDG PET/CT was 0.71 (95% CI: 0.61&#x2013;0.80, I&#xb2;=95.3%). Sensitivity analysis did not identify any apparent sources of heterogeneity (<xref ref-type="fig" rid="f6"><bold>Figures&#xa0;6</bold></xref>, <xref ref-type="fig" rid="f7"><bold>7</bold></xref>).</p>
<fig id="f6" position="float">
<label>Figure&#xa0;6</label>
<caption>
<p>Sensitivity analysis of lesion-based detection using [&#x2076;&#x2078;Ga]FAPI-04 PET/CT.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-16-1730986-g006.tif">
<alt-text content-type="machine-generated">Forest plot showing a meta-analysis of studies from 2023 to 2025. Studies omitted include those by Chen, Li, Kepenek, Lanzafame, Civan, Arak, Wang, Guo, and Sahin. Proportions are mostly 1.00 with confidence intervals ranging from 0.97 to 1.00. P-values are marked. Random effects model summary: proportion 1.00, confidence interval 0.98 to 1.00. Heterogeneity indicators Tau2, Tau, and I2 are also provided.</alt-text>
</graphic></fig>
<fig id="f7" position="float">
<label>Figure&#xa0;7</label>
<caption>
<p>Sensitivity analysis of lesion-based detection using [&#xb9;&#x2078;F]FDG PET/CT.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fonc-16-1730986-g007.tif">
<alt-text content-type="machine-generated">Forest plot showing the effect size for multiple studies from 2023 to 2025. Each line represents a study with its proportion and confidence interval; points and whiskers indicate effect estimates and confidence limits. The pooled estimate from a random effects model is 0.71 with a confidence interval of 0.61 to 0.80. Heterogeneity statistics are included, such as Tau squared, Tau, and I squared percentages, indicating variability among studies.</alt-text>
</graphic></fig>
</sec>
</sec>
<sec id="s4" sec-type="discussion">
<title>Discussion</title>
<p>The diagnostic performance of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in detecting bone metastases from malignant tumors remains a subject of ongoing investigation, as current findings show notable inconsistencies across studies. For example, Yue et&#xa0;al. reported that [<sup>68</sup>Ga]FAPI-04 PET/CT demonstrated superior sensitivity compared with [<sup>18</sup>F]FDG PET/CT in detecting tumor recurrence and peritoneal lymph node metastases, suggesting potential advantages in certain metastatic patterns. However, [<sup>18</sup>F]FDG PET/CT exhibited higher sensitivity in identifying bone metastases (<xref ref-type="bibr" rid="B26">26</xref>).Similarly, Dna et&#xa0;al. found that in the assessment of bone metastases from malignant tumors, [<sup>68</sup>Ga]FAPI-04 PET/CT showed slightly lower pooled sensitivity than [<sup>18</sup>F]FDG PET/CT in patient-based analyses, whereas [<sup>18</sup>F]FDG PET/CT demonstrated higher sensitivity in lesion-based analyses (<xref ref-type="bibr" rid="B27">27</xref>). This difference may arise from the distinct biological mechanisms reflected by the two tracers: FDG indicates tumor glucose metabolism, while FAPI reflects the activation of cancer-associated fibroblasts, representing tumor cells and the tumor microenvironment, respectively.</p>
<p>Meanwhile, FAPI also shows increased uptake in several benign skeletal conditions&#x2014;such as osteoarthritis, fracture healing, fibrosis or post-radiotherapy changes, osteomyelitis, and postoperative or mechanical stress reactions&#x2014;which may interfere with lesion-based evaluation and lead to overestimation of its diagnostic performance (<xref ref-type="bibr" rid="B15">15</xref>, <xref ref-type="bibr" rid="B28">28</xref>). Additionally, differences in uptake timing between the tracers, particularly the rapid clearance and early imaging characteristics of FAPI, may influence image quality and quantitative assessment. Considering the variability in metabolic activity and stromal activation across different tumor types and clinical contexts, the comparative diagnostic value of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT remains insufficiently defined. Thus, larger and methodologically robust prospective studies are needed to clarify their roles in detecting bone metastases.</p>
<p>Regarding the detection rates in patients with malignant tumor bone metastasis, [<sup>68</sup>Ga]FAPI-04 PET/CT demonstrates a detection rate of 0.99 (95% CI: 0.90&#x2013;1.00, I&#xb2;=36.5%), while [<sup>18</sup>F]FDG PET/CT was 0.79 (95% CI: 0.54&#x2013;0.79, I&#xb2;=62.4%).Regarding the detection rates of bone metastatic lesions, [<sup>68</sup>Ga]FAPI-04 PET/CT exhibits a detection rate of 1.00 (95% CI: 0.98&#x2013;1.00, I&#xb2;=91.5%), whereas [<sup>18</sup>F]FDG PET/CT demonstrates a detection rate of 0.71 (95% CI: 0.61&#x2013;0.80, I&#xb2;=95.3%). These results suggest that [<sup>68</sup>Ga]FAPI-04 PET/CT appears to have superior diagnostic capabilities compared to [<sup>18</sup>F]FDG PET/CT, whether in detecting bone metastasis in patients or detecting bone metastatic lesions. This result is consistent with the findings reported by Li et&#xa0;al. and Wu et&#xa0;al. (<xref ref-type="bibr" rid="B29">29</xref>, <xref ref-type="bibr" rid="B30">30</xref>).The possible explanation for this observation is that [<sup>68</sup>Ga]FAPI and [<sup>18</sup>F]FDG reflect two different aspects of tumor behavior. [<sup>18</sup>F]FDG directly targets the metabolic activity of tumor cells, whereas [<sup>68</sup>Ga]FAPI targets fibroblast activation protein expressed on cancer-associated fibroblasts within the tumor stroma (<xref ref-type="bibr" rid="B31">31</xref>, <xref ref-type="bibr" rid="B32">32</xref>). FAP is a marker of desmoplastic reaction and has been reported to play a key role in influencing tumor immunity and multidrug resistance, which may be related to reduced transtumoral transport of cells and therapeutic agents (<xref ref-type="bibr" rid="B33">33</xref>).</p>
<p>In the patient-based studies, the I&#xb2; value for [<sup>68</sup>Ga]FAPI-04 PET/CT was less than 50%, indicating no significant heterogeneity among the included studies. In contrast, for [<sup>18</sup>F]FDG PET/CT, the heterogeneity markedly decreased to I&#xb2; = 0 after excluding the study by Chen et&#xa0;al., suggesting that this study may have been the primary source of heterogeneity. In the lesion-based studies, sensitivity analysis did not reveal any apparent sources of heterogeneity. We believe that large-scale, multicenter prospective studies are still needed, with standardized study designs and imaging protocols, to minimize heterogeneity as much as possible. In addition, subgroup analyses based on tumor type, metastatic burden, and imaging equipment could help to further identify the potential sources of heterogeneity, thereby improving the robustness and reliability of the pooled results. Such efforts would also help to further validate and clarify the differences and advantages between [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT in the diagnosis of bone metastases.</p>
<p>Our meta-analysis also has certain limitations. First, this study mainly focused on comparing the detection rates of [<sup>68</sup>Ga]FAPI-04 PET/CT and [<sup>18</sup>F]FDG PET/CT, without extracting data on false positives, false negatives, or other diagnostic parameters. Given that FAPI may show increased uptake in inflammatory or other non-malignant conditions (<xref ref-type="bibr" rid="B13">13</xref>, <xref ref-type="bibr" rid="B14">14</xref>), this could influence the results. Second, the sample size was relatively small, and larger datasets are required to strengthen the conclusions. Moreover, although substantial heterogeneity was observed in both lesion-based and patient-based analyses, no subgroup or stratified analyses were actually performed to explore potential sources of heterogeneity related to [<sup>18</sup>F]FDG PET/CT. Therefore, these limitations should be considered when interpreting the findings.</p>
</sec>
<sec id="s5" sec-type="conclusions">
<title>Conclusion</title>
<p>In the context of malignant bone metastases, both patient-based and lesion-based analyses suggest that [<sup>68</sup>Ga]FAPI-04 PET/CT may exhibit higher detection rates than [<sup>18</sup>F]FDG PET/CT. However, increased FAPI uptake can also occur in inflammatory or other benign conditions, which may influence these findings. Moreover, the available PET/CT evidence is derived from studies with relatively small sample sizes. Importantly, detection rate alone cannot distinguish true-positive from false-positive findings. Therefore, larger and methodologically rigorous prospective studies are required to more clearly define the comparative diagnostic performance of these tracers.</p>
</sec>
</body>
<back>
<sec id="s6" sec-type="data-availability">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.</p></sec>
<sec id="s7" sec-type="author-contributions">
<title>Author contributions</title>
<p>MH: Writing &#x2013; original draft. JT: Writing &#x2013; review &amp; editing.</p></sec>
<sec id="s9" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></sec>
<sec id="s10" sec-type="ai-statement">
<title>Generative AI statement</title>
<p>The author(s) declared that generative AI was not used in the creation of this manuscript.</p>
<p>Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.</p></sec>
<sec id="s11" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p></sec>
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<p><ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/3266671">Qiubai Li</ext-link>, University Hospitals Cleveland Medical Center, United States</p></fn>
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