Evaluating the Outcomes of Vertebral Biopsies Performed in Osteoporotic vertebral fractures: A Systematic Review and Meta-Analysis

Evaluating the Outcomes of Vertebral Biopsies Performed in Osteoporotic vertebral fractures: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Evaluating the Outcomes of Vertebral Biopsies Performed in Osteoporotic vertebral fractures: A Systematic Review and Meta-Analysis Halil Bulut, Chuck Lam, Veer Sheth, Iihan Ali, Morgan Jones, Rajesh Botchu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6906795/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Osteoporotic vertebral fractures (OVFs) are common among older adults and are generally treated conservatively. However, some patients initially diagnosed with benign OVFs may have underlying malignancies—such as metastatic solid tumors or hematologic cancers—that mimic osteoporotic fractures radiographically. This study aimed to determine the pooled prevalence of unsuspected malignancy in patients initially diagnosed with OVFs through a systematic review and meta-analysis. Methods A systematic literature search of the PubMed database was conducted through March 2025 in accordance with PRISMA guidelines. Studies were included if they involved adults with presumed osteoporotic vertebral fractures who underwent vertebral biopsy or histopathological evaluation. Pooled prevalence estimates of unsuspected malignancies were calculated using a random-effects model. The risk of bias in included studies was assessed using the Newcastle-Ottawa Scale. Results Twelve studies involving 3,229 patients met the inclusion criteria. The pooled prevalence of unsuspected malignancy among presumed OVF cases was 8.00% (95% CI: 5.43–10.6%). Subgroup analysis showed that 4.87% (95% CI: 2.30–7.44%) had metastatic solid tumors, while 2.62% (95% CI: 1.31–3.94%) had multiple myeloma. No biopsy-related complications were reported. Moderate to substantial heterogeneity was observed across studies. Conclusion Approximately one in twelve patients with an initial diagnosis of benign OVF may have an underlying malignancy. Vertebral biopsy is a safe and valuable diagnostic tool, particularly in cases with atypical clinical or radiologic features, to facilitate early cancer detection and appropriate oncologic intervention. Osteoporotic vertebral fractures Unsuspected malignancy Vertebral biopsy Metastatic spinal tumors Multiple myeloma Figures Figure 1 1. Introduction Osteoporotic vertebral fractures (OVFs) are among the most common fragility fractures encountered in the aging population, often resulting from low-energy trauma or occurring spontaneously due to reduced bone mineral density( 1 ). With an estimated lifetime risk of 15–25% in older adults, these fractures are frequently attributed to benign osteoporotic processes and are commonly managed conservatively based on clinical presentation and imaging findings( 1 ). However, a subset of patients initially presumed to have osteoporotic fractures may harbor underlying malignancy—either as primary vertebral tumors or metastatic disease—mimicking benign osteoporotic changes on imaging( 2 ). These "unsuspected malignancies" may go undiagnosed during initial evaluation, leading to delayed oncologic treatment and potentially worse outcomes( 2 , 3 ). Given the overlapping clinical and radiographic features between benign and malignant vertebral collapse, distinguishing the two remains a significant diagnostic challenge, particularly in the absence of systemic symptoms or known cancer history. Several studies have investigated the incidence of malignancy in patients presenting with presumed osteoporotic vertebral fractures, with reported rates varying widely across cohorts and healthcare settings( 2 , 4 – 15 ). These discrepancies may stem from differences in imaging protocols, biopsy rates, follow-up duration, and patient selection criteria. Despite growing clinical concern, there remains no consensus on the true prevalence of malignancy in this context or the optimal diagnostic pathway to identify such cases. This systematic review and meta-analysis aims to synthesize current evidence to determine the pooled prevalence of unsuspected malignancy among patients initially diagnosed with osteoporotic vertebral fractures. By quantifying this risk, we hope to inform clinical decision-making and guide future research on diagnostic strategies, including the potential role of advanced imaging and early biopsy in selected patients. 2. Methods This study was conducted as a systematic review and meta-analysis to evaluate the prevalence of unsuspected malignancy identified through vertebral biopsies in patients with presumed osteoporotic vertebral fractures (OVFs). The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to ensure methodological rigor and transparency ( 16 ). The protocol was registered prospectively in the International Prospective Register of Systematic Reviews (PROSPERO) under the ID CRD420251052182 ( 17 ). Eligibility Criteria Studies were considered eligible if they included adult patients (≥ 18 years) initially diagnosed with osteoporotic vertebral fractures and subsequently underwent vertebral biopsy or diagnostic workup capable of identifying malignancy. Eligible studies had to provide histopathologic confirmation of malignancy or follow-up radiological evidence excluding malignancy, and must be published in English in peer-reviewed journals. We included observational study designs—specifically retrospective or prospective cohort studies, cross-sectional studies, and registry/database-based studies. We excluded case reports, editorials, conference abstracts, and narrative reviews. Studies lacking a confirmed diagnostic outcome (i.e., no biopsy or radiological follow-up) or those exclusively involving vertebral fractures of traumatic, infectious, or pediatric origin were excluded. “Unsuspected malignancy” was defined as any newly discovered malignancy (e.g., solid tumor metastasis, multiple myeloma, lymphoma) identified during diagnostic workup in patients with an initial working diagnosis of benign osteoporotic compression fracture, in whom malignancy was not clinically suspected at the outset. Search Strategy and Data Sources A systematic literature search was conducted using PubMed from database inception to March 2025. Additional sources included OpenGrey for grey literature and hand-searching of reference lists from included full-text studies to identify further eligible articles. The search strategy included both Medical Subject Headings (MeSH) and free-text terms: (“osteoporotic vertebral fracture” OR “compression fracture” OR “vertebral insufficiency fracture”) AND (“malignancy” OR “cancer” OR “metastasis” OR “myeloma” OR “neoplasm”). Study Selection Process All retrieved records were first imported into EndNote for de-duplication. Subsequently, citations were uploaded into Covidence, an online systematic review platform, to facilitate title and abstract screening and full-text review. Two independent reviewers screened each article, and any disagreement was resolved by discussion or by a third reviewer when necessary. The process of selection was documented using a PRISMA 2020 flow diagram. Data Extraction A standardized data extraction form was developed and pilot-tested before full extraction. Two reviewers independently extracted relevant data from each study, including: ( 1 ) study characteristics (authors, year, country, study design), ( 2 ) patient demographics (age, sex, sample size), ( 3 ) biopsy protocols and imaging methods, ( 4 ) fracture location and diagnostic methods (biopsy vs radiologic follow-up), and ( 5 ) outcome measures such as prevalence of malignancy and type of malignancy (solid tumors, multiple myeloma). Discrepancies between reviewers were resolved by consensus. Risk of Bias Assessment The methodological quality and risk of bias of the included cohort studies were independently assessed using the Newcastle-Ottawa Scale (NOS), a validated tool for evaluating non-randomized studies in meta-analyses. The NOS assesses study quality across three domains: Selection (maximum 4 stars), Comparability (maximum 2 stars), and Outcome (maximum 3 stars), with a maximum total score of 9. Each study was evaluated based on criteria including the representativeness of the exposed cohort, selection of the non-exposed cohort, ascertainment of exposure, confirmation that the outcome was not present at baseline, comparability of cohorts based on design or analysis, adequacy of outcome assessment, length and completeness of follow-up. Two reviewers conducted the assessments independently, and any disagreements were resolved by consensus. Studies scoring 7–9 points were considered to have a low risk of bias, while those scoring less than 7 were considered to have a higher risk. Statistical Analysis Pooled prevalence estimates for solid malignancy metastasis, multiple myeloma, and overall malignant diagnoses were calculated using a random-effects model (DerSimonian-Laird method), given the expected variability across studies. Statistical heterogeneity was evaluated using the I² statistic, where values above 50% were considered to indicate moderate to substantial heterogeneity. Additional heterogeneity metrics included the H statistic, τ (tau), τ² (tau-squared), and the Diamond Ratio, each with 95% confidence intervals. Jamovi software program was used( 18 ). 3. Results A comprehensive literature search yielded a total of 2,654 records. After screening and full-text review, 12 studies comprising 3,229 patients met the inclusion criteria. Of these, 12 studies were included in the meta-analysis. Pooled effect sizes were calculated using a random-effects model to account for between-study variability. Heterogeneity was assessed using the I², H, and Diamond Ratio statistics to ensure the robustness of the findings. Study Characteristics A total of 12 studies published between 2008 and 2024 were included, encompassing 3,229 patients with initially presumed osteoporotic vertebral fractures (OVFs). The number of patients per study ranged from 50 to 1,352. Across these studies, the prevalence of malignancy varied substantially, from as low as 2.04% (Venturi et al., 2011) to as high as 14.67% (Pneumaticos et al., 2010), with an overall trend suggesting a non-negligible proportion of unsuspected malignant diagnoses. The reported age of the patient cohorts was predominantly in the seventh to eighth decades of life, with mean or median ages ranging from 60 to 76 years. Prevalence for Solid Malignancy Metastasis Based on data from 9 studies, the pooled prevalence of vertebral biopsies for detecting solid tumor metastases in patients with osteoporotic vertebral fractures was 4.87% (95% CI: 2.30%–7.44%, p < 0.001). This indicates that nearly 1 in 20 biopsies revealed an unsuspected solid malignancy, highlighting the clinical relevance of histopathologic assessment in cases with atypical presentations or imaging findings. Prevalence for Multiple Myeloma The pooled prevalence for multiple myeloma was 2.62% (95% CI: 1.31%–3.94%, p < 0.001), derived from 8 studies. Although less frequent than solid metastasis, this underscores the utility of biopsy in revealing hematologic malignancies in patients initially presumed to have benign osteoporotic fractures. Combined Prevalence for All Malignant Diagnoses When considering all malignant etiologies—including both solid tumors and hematologic malignancies—the overall pooled prevalence across 12 studies was 8.00% (95% CI: 5.43%–10.6%, p < 0.001). This suggests that approximately 1 in 12 patients undergoing biopsy for vertebral compression fractures harbored a previously undetected malignancy, emphasizing the diagnostic value of biopsy, particularly in ambiguous or non-typical cases. Complications, Sequels, and Mortality Across all 12 included studies comprising a total of 3,229 patients, there were no reported biopsy-specific complications, sequelae, mortalities, or adverse events. Heterogeneity Assessment Heterogeneity metrics were evaluated for each diagnostic category to assess consistency across studies. For multiple myeloma, moderate heterogeneity was observed, with an I² of 53.8% (95% CI: 0.0% to 96.9%) and H = 2.17 (95% CI: 1.00 to 31.84). The Diamond Ratio was 2.22 (95% CI: 1.00 to 7.59), suggesting moderate dispersion in effect sizes. The between-study variance was low, as indicated by τ = 0.0119 and τ² = 0.000142. For solid malignancy metastasis, substantial heterogeneity was detected. The I² was 85.6% (95% CI: 70.1% to 97.1%), and H was 6.97 (95% CI: 3.35 to 34.83), reflecting considerable variability among studies. The Diamond Ratio was elevated at 4.37 (95% CI: 3.15 to 9.09), suggesting notable inconsistency in prevalence estimates. The between-study variance remained acceptable with τ = 0.0329 and τ² = 0.00108. For all malignant diagnoses combined, heterogeneity was moderate to high. The pooled I² was 82.9% (95% CI: 59.9% to 94.6%), H = 2.87 (95% CI: 1.19 to 8.50), and Diamond Ratio = 1.99 (95% CI: 1.19 to 3.28). Tau estimates (τ = low) indicated a modest level of between-study variance, suggesting moderate inconsistency across the included studies. Bias Assessment The risk of bias across the included cohort studies was evaluated using the Newcastle-Ottawa Scale (NOS), as shown in Table 3. Most studies demonstrated high methodological quality, with total scores ranging from 7 to 9 out of a maximum of 9. Eleven studies, including those by Wickstrøm et al. (2024), Schoenfeld et al. (2008), and Pagdal et al. (2016), achieved the maximum score of 9, indicating low risk of bias across all domains. These studies consistently demonstrated strong representativeness of the exposed cohort, appropriate selection of non-exposed groups, reliable ascertainment of exposure, and adequate follow-up procedures. A few studies, such as Jia et al. (2024), scored slightly lower (score: 7), mainly due to missing points in cohort representativeness and non-exposed selection. Overall, the quality of the evidence was robust, with the majority of studies exhibiting low risk of selection, comparability, and outcome bias. 4. Discussion This systematic review and meta-analysis found that about 8% of patients initially diagnosed with osteoporotic vertebral fractures (OVFs) actually had unsuspected malignancies. Among these cases, approximately 4.87% were solid tumor metastases, and around 2.62% were multiple myeloma. In other words, nearly one in every twelve patients thought to have benign OVFs were later diagnosed with an underlying cancer. These results highlight the need for careful evaluation, including biopsy, especially when clinical or imaging features are unusual, to avoid missing a malignant diagnosis. The identification of unsuspected malignancies has important implications for patient management(19-21). Early diagnosis of malignant vertebral involvement allows timely initiation of oncologic treatment, which can improve outcomes, reduce complications, and potentially improve quality of life(21,22). While most spinal malignancies tend to be metastatic and advanced at diagnosis, limiting the impact of early detection, there is clear benefit in detecting rare primary spinal tumors or oligometastatic disease early, where curative or more effective therapies may be possible(23). Vertebral biopsy remains a key diagnostic tool in differentiating benign osteoporotic fractures from malignant lesions. Our review confirms its safety, with no reported complications or mortality among thousands of patients. These qualities make biopsy a reliable method to guide treatment decisions, particularly when routine imaging findings are inconclusive or suspicious. Although advances in imaging modalities—such as MRI combined with bone scans or CT—have improved preoperative assessment and reduced the rate of unexpected malignancies, imaging alone may not always be definitive(24-27). Therefore, most authors advocate for routine biopsy during vertebroplasty or kyphoplasty, especially given the relatively low cost of biopsy needles and histopathological analysis (approximately 200 Euros)(28), which may be cost-effective compared to broader cancer screening programs(2, 4-15). The heterogeneity assessment revealed varying degrees of inconsistency across diagnostic categories, highlighting differences in study outcomes and potential clinical diversity. In the case of multiple myeloma, heterogeneity was moderate (I² = 53.8%), with a relatively low between-study variance (τ² = 0.000142), indicating that while some variability exists, the results across studies are generally comparable. The Diamond Ratio of 2.22 further supports moderate dispersion of effect sizes. In contrast, studies focusing on solid malignancy metastases demonstrated substantial heterogeneity (I² = 85.6%), suggesting a significant degree of variability, likely influenced by differences in study populations, imaging modalities, or diagnostic criteria. This was further supported by a high Diamond Ratio of 4.37, indicating pronounced inconsistency in prevalences. Nonetheless, the between-study variance remained within an acceptable range (τ² = 0.00108), implying that while heterogeneity is present, it is not extreme. When all malignant diagnoses were combined, the heterogeneity was moderate to high (I² = 82.9%), with a Diamond Ratio of 1.99 and a modest τ², reflecting a reasonable level of consistency across the broader spectrum of malignancies. These findings underscore the importance of considering diagnostic category-specific factors when interpreting pooled results and suggest that while some variability exists, the aggregated data still offer meaningful insights for clinical application. Implications for Practice The diagnosis of OVFs is common in elderly patients presenting with back pain and spinal deformity. However, emerging evidence highlights a significant risk of misdiagnosis due to underlying malignancies mimicking benign fractures. Studies demonstrate that approximately 8% of patients initially diagnosed with benign OVFs harbor unsuspected malignancies, including solid tumor metastases and multiple myeloma. This striking figure underscores the critical need for routine consideration of vertebral biopsy in cases with ambiguous clinical or radiologic findings. Incorporating vertebral biopsy into the diagnostic workflow has important practical implications. First, it enables early and accurate differentiation between benign osteoporotic fractures and malignant involvement. Imaging techniques such as MRI and CT scans, though valuable, cannot always conclusively distinguish these entities, especially in cases with atypical fracture morphology or when patients have risk factors inconsistent with osteoporosis. By confirming histopathology, biopsy prevents delays in cancer diagnosis and facilitates timely referral for oncologic management, which may improve patient survival and quality of life. Furthermore, vertebral biopsy is a minimally invasive, safe procedure with an excellent safety profile. Large-scale analyses report no significant complications, sequelae, or mortality associated with this diagnostic approach, making it a low-risk option for patients. The procedure is also cost-effective, with expenses far below those of extensive systemic cancer screening, which supports its use in clinical practice. In light of these findings, clinicians should maintain a high index of suspicion for malignancy in patients with vertebral fractures that do not fit the typical osteoporotic pattern, those with poor response to conservative treatment, or those with systemic symptoms. Establishing clear criteria for biopsy referral can enhance diagnostic accuracy, reduce misdiagnosis, and ensure that patients receive appropriate and timely care. Future research should focus on developing and validating reliable clinical and radiologic prediction models to identify patients with a higher likelihood of malignancy among those presenting with presumed osteoporotic vertebral fractures. The incorporation of advanced imaging techniques, such as PET-CT and diffusion-weighted MRI, alongside novel biomarkers, holds promise for improving early detection and differentiation between benign and malignant fractures. Prospective, multicenter studies employing standardized biopsy protocols and diagnostic pathways are essential to reduce heterogeneity and enhance the accuracy of diagnosis. Additionally, long-term follow-up studies are needed to evaluate outcomes related to survival, functional recovery, and quality of life after diagnosis, thereby clarifying the clinical benefits of timely identification and management of occult malignancies in this patient group. Limitations This analysis has several important limitations. First, the observational nature of the included studies introduces a risk of selection bias, which may affect the validity of pooled estimates. Second, there was considerable variability in biopsy indications and procedural methodologies across studies, potentially contributing to the observed heterogeneity and limiting the comparability of outcomes. Finally, the absence of uniform imaging protocols and clinical diagnostic criteria reduces the generalizability of the findings, as the prevalence may vary significantly depending on institutional practices and patient selection criteria. Strengths Despite these limitations, this study offers several notable strengths. It provides a comprehensive synthesis of prevalence across a broad range of malignancies, with detailed heterogeneity metrics that allow for transparent interpretation of variability among studies. Additionally, the use of robust statistical indicators such as the I² statistic, Diamond Ratio, and tau estimates strengthens the reliability of the heterogeneity assessment and improves the interpretability of the meta-analytic results. 5. Conclusions In conclusion, this systematic review and meta-analysis demonstrate that approximately 8% of patients initially diagnosed with benign osteoporotic vertebral fractures actually harbor unsuspected malignancies, including both solid tumor metastases and hematologic cancers such as multiple myeloma. Given the significant prevalence and the diagnostic challenges posed by overlapping clinical and imaging features, vertebral biopsy emerges as a safe, effective, and indispensable tool in the evaluation of atypical or ambiguous cases. Early identification of malignancy through biopsy allows for timely oncologic intervention, which may improve patient outcomes and quality of life. Therefore, clinicians should maintain a high index of suspicion and consider biopsy when clinical or radiographic findings do not fully align with typical osteoporotic fractures to avoid delayed cancer diagnosis and optimize management strategies. Declarations Author Contribution H.B. conceived the study and performed the data analysis. C.L., V.S., and I.A. contributed to data curation. H.B. and C.L. wrote the main manuscript text. M.J., R.B., C.E., A.H., and K.O. critically reviewed the manuscript. R.B. provided editorial input and refinement. All authors reviewed and approved the final version of the manuscript. References Hernlund, E., Svedbom, A., Ivergård, M. et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. Arch Osteoporos 8, 136 (2013). https://doi.org/10.1007/s11657-013-0136-1 Osterhoff, G., Scheyerer, M.J., Spiegl, U.J.A. et al. The role of routine transpedicular biopsies during kyphoplasty or vertebroplasty for vertebral compression fractures in the detection of malignant diseases: a systematic review. Arch Orthop Trauma Surg 143, 1887–1893 (2023). https://doi.org/10.1007/s00402-022-04392-7 Kafchinski LA. 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Study Characteristics Author Year Patient Count Malignant Cases Malignancy (%) Age (Mean/Median) Multiple Myeloma (n) Primary Bone Tumors (n) Metastatic Tumors (n) Wickstrøm et al 2024 459 27 5.88 75 NSM NSM NSM Schoenfeld et al 2008 50 4 8.00 76 1 0 3 Hershkovich et al 2020 113 13 11.50 71 9 0 4 Chou et al 2013 450 61 13.56 — 9 0 52 Joseph et al 2012 56 8 14.29 60 NSM NSM NSM Nowak et al 2018 97 10 10.31 68 — 0 10 Pagdal et al 2016 84 10 11.90 63 8 0 2 Venturi et al 2011 98 2 2.04 73 0 1 (Chondrosarcoma) 1 Jia et al 2024 1,352 44 3.25 70 24 0 20 Muijs et al 2009 71 3 4.23 73 1 0 0 Sozzi et al 2021 324 20 6.17 73 12 0 8 Pneumaticos et al 2010 75 11 14.67 69 3 0 8 NSM: not specifically mentioned Table 2. Prevalence of Malignancy in Vertebral Biopsies Among Patients with Osteoporotic Fractures Diagnosis Category Pooled Prevalence (%) 95% CI (Lower–Upper) p -Value Number of Studies ( k ) Solid Malignancy Metastasis 4.87 2.30 – 7.44 <0.001 9 Multiple Myeloma 2.62 1.31 – 3.94 <0.001 8 All Malignant Diagnoses 8.00 5.43 – 10.60 <0.001 12 Table 3. Newcastle-Ottawa Scale (NOS) Bias Assessment for Included Cohort Studies Study Representativeness of Exposed Cohort Selection of Non-Exposed Ascertainment of Exposure Outcome Not Present at Start Comparability Assessment of Outcome Adequate Follow-Up Length Adequacy of Follow-Up Total Score (Max 9) Wickstrøm et al (2024) ★ ★ ★ ★ ★★ ★ ★ ★ 9 Schoenfeld et al (2008) ★ ★ ★ ★ ★★ ★ ★ ★ 9 Hershkovich et al (2020) ★ ★ ★ ★ ★★ ★ ★ ★ 9 Chou et al (2013) ★ ★ ★ ★★ ★ ★ ★ 8 Joseph et al (2012) ★ ★ ★ ★★ ★ ★ ★ 8 Nowak et al (2018) ★ ★ ★ ★★ ★ ★ ★ 8 Venturi et al (2011) ★ ★ ★ ★ ★★ ★ ★ ★ 9 Jia et al (2024) ★ ★ ★★ ★ ★ ★ 7 Muijs et al (2009) ★ ★ ★ ★ ★★ ★ ★ ★ 9 Sozzi et al (2021) ★ ★ ★ ★★ ★ ★ ★ 8 Pneumaticos et al (2010) ★ ★ ★ ★ ★★ ★ ★ ★ 9 Pagdal et al (2016) ★ ★ ★ ★ ★★ ★ ★ ★ 9 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6906795","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":472068351,"identity":"0a6e716c-8aa0-416b-b238-4f341f0d4a7e","order_by":0,"name":"Halil Bulut","email":"data:image/png;base64,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","orcid":"","institution":"Istanbul University Cerrahpaşa","correspondingAuthor":true,"prefix":"","firstName":"Halil","middleName":"","lastName":"Bulut","suffix":""},{"id":472068352,"identity":"dc1c2beb-9e06-4288-962f-d70890b95ccb","order_by":1,"name":"Chuck Lam","email":"","orcid":"","institution":"University of Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Chuck","middleName":"","lastName":"Lam","suffix":""},{"id":472068353,"identity":"2d167e7f-71ad-4c04-afbc-ba36e9726564","order_by":2,"name":"Veer Sheth","email":"","orcid":"","institution":"University of Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Veer","middleName":"","lastName":"Sheth","suffix":""},{"id":472068354,"identity":"3ad6f7b2-07b2-4660-ac70-af6ca9c63198","order_by":3,"name":"Iihan Ali","email":"","orcid":"","institution":"Imperial College London","correspondingAuthor":false,"prefix":"","firstName":"Iihan","middleName":"","lastName":"Ali","suffix":""},{"id":472068355,"identity":"13c70d1a-8c39-44fd-8799-c36d2c8ba81c","order_by":4,"name":"Morgan Jones","email":"","orcid":"","institution":"Royal National Orthopaedic Hospital NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Morgan","middleName":"","lastName":"Jones","suffix":""},{"id":472068356,"identity":"c99efc54-35ea-45ae-8c7a-52decff074e6","order_by":5,"name":"Rajesh Botchu","email":"","orcid":"","institution":"Royal National Orthopaedic Hospital NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Rajesh","middleName":"","lastName":"Botchu","suffix":""},{"id":472068357,"identity":"98e6b706-71e4-478a-a10b-513e91ff50ce","order_by":6,"name":"Constantino Errani","email":"","orcid":"","institution":"Istituto Ortopedico Rizzoli","correspondingAuthor":false,"prefix":"","firstName":"Constantino","middleName":"","lastName":"Errani","suffix":""},{"id":472068360,"identity":"e44be0e7-af6f-4467-a6a2-76b0104af83a","order_by":7,"name":"Azmi Hamzaoglu","email":"","orcid":"","institution":"Istanbul Bilim University","correspondingAuthor":false,"prefix":"","firstName":"Azmi","middleName":"","lastName":"Hamzaoglu","suffix":""},{"id":472068362,"identity":"3d256bb2-437b-483f-86e6-59f454b4c5b9","order_by":8,"name":"Korhan Ozkan","email":"","orcid":"","institution":"Acıbadem Maslak Hospital","correspondingAuthor":false,"prefix":"","firstName":"Korhan","middleName":"","lastName":"Ozkan","suffix":""}],"badges":[],"createdAt":"2025-06-16 15:08:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6906795/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6906795/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85070460,"identity":"5bdfdcce-1ff9-4570-b4f1-8bfc89822483","added_by":"auto","created_at":"2025-06-20 15:36:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":134012,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Flow chart.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6906795/v1/3309148476df6a47f03e8724.png"},{"id":87412325,"identity":"469c2da4-fa40-46f3-90c4-7e22420514d2","added_by":"auto","created_at":"2025-07-23 14:02:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1242146,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6906795/v1/8c9e4c41-0150-46fe-bd9d-c723f4a52882.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluating the Outcomes of Vertebral Biopsies Performed in Osteoporotic vertebral fractures: A Systematic Review and Meta-Analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOsteoporotic vertebral fractures (OVFs) are among the most common fragility fractures encountered in the aging population, often resulting from low-energy trauma or occurring spontaneously due to reduced bone mineral density(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). With an estimated lifetime risk of 15–25% in older adults, these fractures are frequently attributed to benign osteoporotic processes and are commonly managed conservatively based on clinical presentation and imaging findings(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, a subset of patients initially presumed to have osteoporotic fractures may harbor underlying malignancy—either as primary vertebral tumors or metastatic disease—mimicking benign osteoporotic changes on imaging(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). These \"unsuspected malignancies\" may go undiagnosed during initial evaluation, leading to delayed oncologic treatment and potentially worse outcomes(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Given the overlapping clinical and radiographic features between benign and malignant vertebral collapse, distinguishing the two remains a significant diagnostic challenge, particularly in the absence of systemic symptoms or known cancer history.\u003c/p\u003e \u003cp\u003eSeveral studies have investigated the incidence of malignancy in patients presenting with presumed osteoporotic vertebral fractures, with reported rates varying widely across cohorts and healthcare settings(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). These discrepancies may stem from differences in imaging protocols, biopsy rates, follow-up duration, and patient selection criteria. Despite growing clinical concern, there remains no consensus on the true prevalence of malignancy in this context or the optimal diagnostic pathway to identify such cases.\u003c/p\u003e \u003cp\u003eThis systematic review and meta-analysis aims to synthesize current evidence to determine the pooled prevalence of unsuspected malignancy among patients initially diagnosed with osteoporotic vertebral fractures. By quantifying this risk, we hope to inform clinical decision-making and guide future research on diagnostic strategies, including the potential role of advanced imaging and early biopsy in selected patients.\u003c/p\u003e "},{"header":"2. Methods","content":"\u003cp\u003eThis study was conducted as a systematic review and meta-analysis to evaluate the prevalence of unsuspected malignancy identified through vertebral biopsies in patients with presumed osteoporotic vertebral fractures (OVFs). The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to ensure methodological rigor and transparency (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The protocol was registered prospectively in the International Prospective Register of Systematic Reviews (PROSPERO) under the ID CRD420251052182 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\u003cp\u003eStudies were considered eligible if they included adult patients (≥ 18 years) initially diagnosed with osteoporotic vertebral fractures and subsequently underwent vertebral biopsy or diagnostic workup capable of identifying malignancy. Eligible studies had to provide histopathologic confirmation of malignancy or follow-up radiological evidence excluding malignancy, and must be published in English in peer-reviewed journals. We included observational study designs—specifically retrospective or prospective cohort studies, cross-sectional studies, and registry/database-based studies.\u003c/p\u003e\u003cp\u003eWe excluded case reports, editorials, conference abstracts, and narrative reviews. Studies lacking a confirmed diagnostic outcome (i.e., no biopsy or radiological follow-up) or those exclusively involving vertebral fractures of traumatic, infectious, or pediatric origin were excluded. “Unsuspected malignancy” was defined as any newly discovered malignancy (e.g., solid tumor metastasis, multiple myeloma, lymphoma) identified during diagnostic workup in patients with an initial working diagnosis of benign osteoporotic compression fracture, in whom malignancy was not clinically suspected at the outset.\u003c/p\u003e\u003ch2\u003eSearch Strategy and Data Sources\u003c/h2\u003e\u003cp\u003eA systematic literature search was conducted using PubMed from database inception to March 2025. Additional sources included OpenGrey for grey literature and hand-searching of reference lists from included full-text studies to identify further eligible articles. The search strategy included both Medical Subject Headings (MeSH) and free-text terms: (“osteoporotic vertebral fracture” OR “compression fracture” OR “vertebral insufficiency fracture”) AND (“malignancy” OR “cancer” OR “metastasis” OR “myeloma” OR “neoplasm”).\u003c/p\u003e\u003ch3\u003eStudy Selection Process\u003c/h3\u003e\u003cp\u003eAll retrieved records were first imported into EndNote for de-duplication. Subsequently, citations were uploaded into Covidence, an online systematic review platform, to facilitate title and abstract screening and full-text review. Two independent reviewers screened each article, and any disagreement was resolved by discussion or by a third reviewer when necessary. The process of selection was documented using a PRISMA 2020 flow diagram.\u003c/p\u003e\u003ch3\u003eData Extraction\u003c/h3\u003e\u003cp\u003eA standardized data extraction form was developed and pilot-tested before full extraction. Two reviewers independently extracted relevant data from each study, including: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) study characteristics (authors, year, country, study design), (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) patient demographics (age, sex, sample size), (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) biopsy protocols and imaging methods, (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) fracture location and diagnostic methods (biopsy vs radiologic follow-up), and (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) outcome measures such as prevalence of malignancy and type of malignancy (solid tumors, multiple myeloma). Discrepancies between reviewers were resolved by consensus.\u003c/p\u003e\u003ch3\u003eRisk of Bias Assessment\u003c/h3\u003e\u003cp\u003eThe methodological quality and risk of bias of the included cohort studies were independently assessed using the Newcastle-Ottawa Scale (NOS), a validated tool for evaluating non-randomized studies in meta-analyses. The NOS assesses study quality across three domains: Selection (maximum 4 stars), Comparability (maximum 2 stars), and Outcome (maximum 3 stars), with a maximum total score of 9. Each study was evaluated based on criteria including the representativeness of the exposed cohort, selection of the non-exposed cohort, ascertainment of exposure, confirmation that the outcome was not present at baseline, comparability of cohorts based on design or analysis, adequacy of outcome assessment, length and completeness of follow-up.\u003c/p\u003e\u003cp\u003eTwo reviewers conducted the assessments independently, and any disagreements were resolved by consensus. Studies scoring 7–9 points were considered to have a low risk of bias, while those scoring less than 7 were considered to have a higher risk.\u003c/p\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003ePooled prevalence estimates for solid malignancy metastasis, multiple myeloma, and overall malignant diagnoses were calculated using a random-effects model (DerSimonian-Laird method), given the expected variability across studies. Statistical heterogeneity was evaluated using the I² statistic, where values above 50% were considered to indicate moderate to substantial heterogeneity. Additional heterogeneity metrics included the H statistic, τ (tau), τ² (tau-squared), and the Diamond Ratio, each with 95% confidence intervals. Jamovi software program was used(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eA comprehensive literature search yielded a total of 2,654 records. After screening and full-text review, 12 studies comprising 3,229 patients met the inclusion criteria. Of these, 12 studies were included in the meta-analysis. Pooled effect sizes were calculated using a random-effects model to account for between-study variability. Heterogeneity was assessed using the I², H, and Diamond Ratio statistics to ensure the robustness of the findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 12 studies published between 2008 and 2024 were included, encompassing 3,229 patients with initially presumed osteoporotic vertebral fractures (OVFs). The number of patients per study ranged from 50 to 1,352. Across these studies, the prevalence of malignancy varied substantially, from as low as 2.04% (Venturi et al., 2011) to as high as 14.67% (Pneumaticos et al., 2010), with an overall trend suggesting a non-negligible proportion of unsuspected malignant diagnoses. The reported age of the patient cohorts was predominantly in the seventh to eighth decades of life, with mean or median ages ranging from 60 to 76 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrevalence for Solid Malignancy Metastasis\u003c/strong\u003e\u003cbr\u003eBased on data from 9 studies, the pooled prevalence of vertebral biopsies for detecting solid tumor metastases in patients with osteoporotic vertebral fractures was 4.87% (95% CI: 2.30%–7.44%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). This indicates that nearly 1 in 20 biopsies revealed an unsuspected solid malignancy, highlighting the clinical relevance of histopathologic assessment in cases with atypical presentations or imaging findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrevalence for Multiple Myeloma\u003c/strong\u003e\u003cbr\u003eThe pooled prevalence for multiple myeloma was 2.62% (95% CI: 1.31%–3.94%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), derived from 8 studies. Although less frequent than solid metastasis, this underscores the utility of biopsy in revealing hematologic malignancies in patients initially presumed to have benign osteoporotic fractures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCombined Prevalence for All Malignant Diagnoses\u003c/strong\u003e\u003cbr\u003eWhen considering all malignant etiologies—including both solid tumors and hematologic malignancies—the overall pooled prevalence across 12 studies was 8.00% (95% CI: 5.43%–10.6%, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). This suggests that approximately 1 in 12 patients undergoing biopsy for vertebral compression fractures harbored a previously undetected malignancy, emphasizing the diagnostic value of biopsy, particularly in ambiguous or non-typical cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComplications, Sequels, and Mortality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcross all 12 included studies comprising a total of 3,229 patients, there were no reported biopsy-specific complications, sequelae, mortalities, or adverse events.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHeterogeneity Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHeterogeneity metrics were evaluated for each diagnostic category to assess consistency across studies. For multiple myeloma, moderate heterogeneity was observed, with an I² of 53.8% (95% CI: 0.0% to 96.9%) and H = 2.17 (95% CI: 1.00 to 31.84). The Diamond Ratio was 2.22 (95% CI: 1.00 to 7.59), suggesting moderate dispersion in effect sizes. The between-study variance was low, as indicated by τ = 0.0119 and τ² = 0.000142. For solid malignancy metastasis, substantial heterogeneity was detected. The I² was 85.6% (95% CI: 70.1% to 97.1%), and H was 6.97 (95% CI: 3.35 to 34.83), reflecting considerable variability among studies. The Diamond Ratio was elevated at 4.37 (95% CI: 3.15 to 9.09), suggesting notable inconsistency in prevalence estimates. The between-study variance remained acceptable with τ = 0.0329 and τ² = 0.00108. For all malignant diagnoses combined, heterogeneity was moderate to high. The pooled I² was 82.9% (95% CI: 59.9% to 94.6%), H = 2.87 (95% CI: 1.19 to 8.50), and Diamond Ratio = 1.99 (95% CI: 1.19 to 3.28). Tau estimates (τ = low) indicated a modest level of between-study variance, suggesting moderate inconsistency across the included studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBias Assessment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias across the included cohort studies was evaluated using the Newcastle-Ottawa Scale (NOS), as shown in Table 3. Most studies demonstrated high methodological quality, with total scores ranging from 7 to 9 out of a maximum of 9. Eleven studies, including those by Wickstrøm et al. (2024), Schoenfeld et al. (2008), and Pagdal et al. (2016), achieved the maximum score of 9, indicating low risk of bias across all domains. These studies consistently demonstrated strong representativeness of the exposed cohort, appropriate selection of non-exposed groups, reliable ascertainment of exposure, and adequate follow-up procedures. A few studies, such as Jia et al. (2024), scored slightly lower (score: 7), mainly due to missing points in cohort representativeness and non-exposed selection. Overall, the quality of the evidence was robust, with the majority of studies exhibiting low risk of selection, comparability, and outcome bias.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis found that about 8% of patients initially diagnosed with osteoporotic vertebral fractures (OVFs) actually had unsuspected malignancies. Among these cases, approximately 4.87% were solid tumor metastases, and around 2.62% were multiple myeloma. In other words, nearly one in every twelve patients thought to have benign OVFs were later diagnosed with an underlying cancer. These results highlight the need for careful evaluation, including biopsy, especially when clinical or imaging features are unusual, to avoid missing a malignant diagnosis.\u003c/p\u003e\n\u003cp\u003eThe identification of unsuspected malignancies has important implications for patient management(19-21). Early diagnosis of malignant vertebral involvement allows timely initiation of oncologic treatment, which can improve outcomes, reduce complications, and potentially improve quality of life(21,22). While most spinal malignancies tend to be metastatic and advanced at diagnosis, limiting the impact of early detection, there is clear benefit in detecting rare primary spinal tumors or oligometastatic disease early, where curative or more effective therapies may be possible(23).\u003c/p\u003e\n\u003cp\u003eVertebral biopsy remains a key diagnostic tool in differentiating benign osteoporotic fractures from malignant lesions. Our review confirms its safety, with no reported complications or mortality among thousands of patients. These qualities make biopsy a reliable method to guide treatment decisions, particularly when routine imaging findings are inconclusive or suspicious.\u003c/p\u003e\n\u003cp\u003eAlthough advances in imaging modalities—such as MRI combined with bone scans or CT—have improved preoperative assessment and reduced the rate of unexpected malignancies, imaging alone may not always be definitive(24-27). Therefore, most authors advocate for routine biopsy during vertebroplasty or kyphoplasty, especially given the relatively low cost of biopsy needles and histopathological analysis (approximately 200 Euros)(28), which may be cost-effective compared to broader cancer screening programs(2, 4-15).\u003c/p\u003e\n\u003cp\u003eThe heterogeneity assessment revealed varying degrees of inconsistency across diagnostic categories, highlighting differences in study outcomes and potential clinical diversity. In the case of multiple myeloma, heterogeneity was moderate (I² = 53.8%), with a relatively low between-study variance (τ² = 0.000142), indicating that while some variability exists, the results across studies are generally comparable. The Diamond Ratio of 2.22 further supports moderate dispersion of effect sizes. In contrast, studies focusing on solid malignancy metastases demonstrated substantial heterogeneity (I² = 85.6%), suggesting a significant degree of variability, likely influenced by differences in study populations, imaging modalities, or diagnostic criteria. This was further supported by a high Diamond Ratio of 4.37, indicating pronounced inconsistency in prevalences. Nonetheless, the between-study variance remained within an acceptable range (τ² = 0.00108), implying that while heterogeneity is present, it is not extreme. When all malignant diagnoses were combined, the heterogeneity was moderate \u0026nbsp;to high (I² = 82.9%), with a Diamond Ratio of 1.99 and a modest τ², reflecting a reasonable level of consistency across the broader spectrum of malignancies. These findings underscore the importance of considering diagnostic category-specific factors when interpreting pooled results and suggest that while some variability exists, the aggregated data still offer meaningful insights for clinical application.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplications for Practice\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe diagnosis of OVFs is common in elderly patients presenting with back pain and spinal deformity. However, emerging evidence highlights a significant risk of misdiagnosis due to underlying malignancies mimicking benign fractures. Studies demonstrate that approximately 8% of patients initially diagnosed with benign OVFs harbor unsuspected malignancies, including solid tumor metastases and multiple myeloma. This striking figure underscores the critical need for routine consideration of vertebral biopsy in cases with ambiguous clinical or radiologic findings.\u003c/p\u003e\n\u003cp\u003eIncorporating vertebral biopsy into the diagnostic workflow has important practical implications. First, it enables early and accurate differentiation between benign osteoporotic fractures and malignant involvement. Imaging techniques such as MRI and CT scans, though valuable, cannot always conclusively distinguish these entities, especially in cases with atypical fracture morphology or when patients have risk factors inconsistent with osteoporosis. By confirming histopathology, biopsy prevents delays in cancer diagnosis and facilitates timely referral for oncologic management, which may improve patient survival and quality of life.\u003c/p\u003e\n\u003cp\u003eFurthermore, vertebral biopsy is a minimally invasive, safe procedure with an excellent safety profile. Large-scale analyses report no significant complications, sequelae, or mortality associated with this diagnostic approach, making it a low-risk option for patients. The procedure is also cost-effective, with expenses far below those of extensive systemic cancer screening, which supports its use in clinical practice.\u003c/p\u003e\n\u003cp\u003eIn light of these findings, clinicians should maintain a high index of suspicion for malignancy in patients with vertebral fractures that do not fit the typical osteoporotic pattern, those with poor response to conservative treatment, or those with systemic symptoms. Establishing clear criteria for biopsy referral can enhance diagnostic accuracy, reduce misdiagnosis, and ensure that patients receive appropriate and timely care.\u003c/p\u003e\n\u003cp\u003eFuture research should focus on developing and validating reliable clinical and radiologic prediction models to identify patients with a higher likelihood of malignancy among those presenting with presumed osteoporotic vertebral fractures. The incorporation of advanced imaging techniques, such as PET-CT and diffusion-weighted MRI, alongside novel biomarkers, holds promise for improving early detection and differentiation between benign and malignant fractures. Prospective, multicenter studies employing standardized biopsy protocols and diagnostic pathways are essential to reduce heterogeneity and enhance the accuracy of diagnosis. Additionally, long-term follow-up studies are needed to evaluate outcomes related to survival, functional recovery, and quality of life after diagnosis, thereby clarifying the clinical benefits of timely identification and management of occult malignancies in this patient group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This analysis has several important limitations. First, the observational nature of the included studies introduces a risk of selection bias, which may affect the validity of pooled estimates. Second, there was considerable variability in biopsy indications and procedural methodologies across studies, potentially contributing to the observed heterogeneity and limiting the comparability of outcomes. Finally, the absence of uniform imaging protocols and clinical diagnostic criteria reduces the generalizability of the findings, as the prevalence may vary significantly depending on institutional practices and patient selection criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Despite these limitations, this study offers several notable strengths. It provides a comprehensive synthesis of prevalence across a broad range of malignancies, with detailed heterogeneity metrics that allow for transparent interpretation of variability among studies. Additionally, the use of robust statistical indicators such as the I² statistic, Diamond Ratio, and tau estimates strengthens the reliability of the heterogeneity assessment and improves the interpretability of the meta-analytic results.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn conclusion, this systematic review and meta-analysis demonstrate that approximately 8% of patients initially diagnosed with benign osteoporotic vertebral fractures actually harbor unsuspected malignancies, including both solid tumor metastases and hematologic cancers such as multiple myeloma. Given the significant prevalence and the diagnostic challenges posed by overlapping clinical and imaging features, vertebral biopsy emerges as a safe, effective, and indispensable tool in the evaluation of atypical or ambiguous cases. Early identification of malignancy through biopsy allows for timely oncologic intervention, which may improve patient outcomes and quality of life. Therefore, clinicians should maintain a high index of suspicion and consider biopsy when clinical or radiographic findings do not fully align with typical osteoporotic fractures to avoid delayed cancer diagnosis and optimize management strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eH.B. conceived the study and performed the data analysis. C.L., V.S., and I.A. contributed to data curation. H.B. and C.L. wrote the main manuscript text. M.J., R.B., C.E., A.H., and K.O. critically reviewed the manuscript. R.B. provided editorial input and refinement. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References ","content":"\u003col\u003e\n\u003cli\u003eHernlund, E., Svedbom, A., Iverg\u0026aring;rd, M. et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. Arch Osteoporos 8, 136 (2013). https://doi.org/10.1007/s11657-013-0136-1\u003c/li\u003e\n\u003cli\u003eOsterhoff, G., Scheyerer, M.J., Spiegl, U.J.A. et al. The role of routine transpedicular biopsies during kyphoplasty or vertebroplasty for vertebral compression fractures in the detection of malignant diseases: a systematic review. Arch Orthop Trauma Surg 143, 1887\u0026ndash;1893 (2023). https://doi.org/10.1007/s00402-022-04392-7\u003c/li\u003e\n\u003cli\u003eKafchinski LA. Metastasectomy for oligometastatic bone disease of the appendicular skeleton: A concise review. J Surg Oncol. 2023 Sep;128(3):438-444. doi: 10.1002/jso.27403. PMID: 37537980.\u003c/li\u003e\n\u003cli\u003eWickstr\u0026oslash;m LA, Rafaelsen SR, Andersen M\u0026Oslash;, Andreasen ADK, Elmose SF, Carreon L. Rate of unexpected malignancy in patients undergoing percutaneous vertebroplasty after implementing a new scanning protocol. Spine (Phila Pa 1976). 2024;49(18):E300\u0026ndash;E305.\u003c/li\u003e\n\u003cli\u003eSchoenfeld AJ, DiNicola NJ, Ehrler DM, Koerber A, Paxos M, Shorten SD, et al. Retrospective review of biopsy results following percutaneous fixation of vertebral compression fractures. Injury. 2008;39(3):327\u0026ndash;333.\u003c/li\u003e\n\u003cli\u003eHershkovich O, Bayley E, Rudik O, Alexandrovsky V, Friedlander A, Daglen E, et al. Cost-benefit analysis of routine bone biopsy during augmentation of osteoporotic vertebral compression fractures. Spine (Phila Pa 1976). 2020;45(23):1634\u0026ndash;1638.\u003c/li\u003e\n\u003cli\u003eChou KN, Lin BJ, Chien LY, Tsai WC, Ma HI, Hueng DY. Simple transpedicular vertebral biopsy for diagnosis of malignancy in vertebral compression fracture. Neurol India. 2013;61(6):587\u0026ndash;592.\u003c/li\u003e\n\u003cli\u003eJoseph RN, Swift AJ, Maliakal PJ. Single-centre prospective study of the efficacy of percutaneous cement augmentation in the treatment of vertebral compression fractures. Br J Neurosurg. 2013;27(4):459\u0026ndash;464.\u003c/li\u003e\n\u003cli\u003eNowak S, M\u0026uuml;ller J, Schroeder HWS, M\u0026uuml;ller JU. Incidence of unexpected positive histology in kyphoplasty. Eur Spine J. 2018;27(4):847\u0026ndash;850.\u003c/li\u003e\n\u003cli\u003ePagdal SS, Nadkarni S, Hardikar SM, Hardikar MS. Role of transpedicular percutaneous vertebral biopsy for diagnosis of pathology in vertebral compression fractures. Asian Spine J. 2016;10(5):925\u0026ndash;929.\u003c/li\u003e\n\u003cli\u003eVenturi C, Barbero S, Tappero C, Ciccone V, Mastrogiacomo F, Molinaro L, et al. Coaxial biopsy during percutaneous vertebroplasty in patients with presumed osteoporotic vertebral compression fractures: retrospective review of biopsy results. Radiol Med. 2011;116(2):302\u0026ndash;309.\u003c/li\u003e\n\u003cli\u003eMuijs SPJ, Akkermans PA, van Erkel AR, Dijkstra SD. The value of routinely performing a bone biopsy during percutaneous vertebroplasty in treatment of osteoporotic vertebral compression fractures. Spine (Phila Pa 1976). 2009;34(22):2395\u0026ndash;2399.\u003c/li\u003e\n\u003cli\u003eSozzi C, Trentadue M, Nicol\u0026igrave; L, Tavani F, Piovan E. Utility of vertebral biopsy before vertebroplasty in patients with diagnosis of vertebral compression fracture. Radiol Med. 2021;126(7):956\u0026ndash;962.\u003c/li\u003e\n\u003cli\u003ePneumaticos SG, Chatziioannou SN, Savvidou C, Pilichou A, Rontogianni D, Korres DS. Routine needle biopsy during vertebral augmentation procedures. Is it necessary? Eur Spine J. 2010;19(11):1894\u0026ndash;1898.\u003c/li\u003e\n\u003cli\u003eJia J, Li J. Age was a protective factor for unexpected malignant diagnoses in patients with vertebral compression fracture. Clin Neurol Neurosurg. 2024;243:108377.\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hr\u0026oacute;bjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71. doi: 10.1136/bmj.n71. PMID: 33782057; PMCID: PMC8005924.\u003c/li\u003e\n\u003cli\u003eChuck Lam, Halil Bulut, Korhan Ozkan. Malignancy Rates in Osteoporotic Vertebral Fractures: A Systematic Review and Meta-Analysis. PROSPERO 2025 CRD420251052182. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD420251052182.\u003c/li\u003e\n\u003cli\u003eThe jamovi project (2025). jamovi (Version 2.6) [Computer Software]. Retrieved from https://www.jamovi.org\u003c/li\u003e\n\u003cli\u003ePatel SS, Tao D, McMurry HS, Shatzel JJ. Screening for occult cancer after unprovoked venous thromboembolism: Assessing the current literature and future directions. Eur J Haematol. 2023 Jan;110(1):24-31. doi: 10.1111/ejh.13874. Epub 2022 Oct 17.\u003c/li\u003e\n\u003cli\u003ePiccioli A, Lensing AW, Prins MH, Falanga A, Scannapieco GL, Ieran M, Cigolini M, Ambrosio GB, Monreal M, Girolami A, Prandoni P; SOMIT Investigators Group. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost. 2004 Jun;2(6):884-9. doi: 10.1111/j.1538-7836.2004.00720.x. PMID: 15140122.\u003c/li\u003e\n\u003cli\u003eNottebaert M, Exner GU, von Hochstetter AR, Schreiber A. Metastatic bone disease from occult carcinoma: a profile. Int Orthop. 1989;13(2):119-23. doi: 10.1007/BF00266372. PMID: 2744913.\u003c/li\u003e\n\u003cli\u003eSutcliffe P, Connock M, Shyangdan D, Court R, Kandala NB, Clarke A. A systematic review of evidence on malignant spinal metastases: natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression. Health Technol Assess. 2013 Sep;17(42):1-274. doi: 10.3310/hta17420.\u003c/li\u003e\n\u003cli\u003eBarzilai O, Versteeg AL, Sahgal A, Rhines LD, Bilsky MH, Sciubba DM, Schuster JM, Weber MH, Pal Varga P, Boriani S, Bettegowda C, Fehlings MG, Yamada Y, Clarke MJ, Arnold PM, Gokaslan ZL, Fisher CG, Laufer I, The Ao Spine Knowledge Forum Tumor. Survival, local control, and health-related quality of life in patients with oligometastatic and polymetastatic spinal tumors: A multicenter, international study. Cancer. 2019 Mar 1;125(5):770-778. doi: 10.1002/cncr.31870. Epub 2018 Nov 29.\u003c/li\u003e\n\u003cli\u003eMotohashi M, Funauchi Y, Adachi T, Fujioka T, Otaka N, Kamiko Y, Okada T, Tateishi U, Okawa A, Yoshii T, Sato S. A New Deep Learning Algorithm for Detecting Spinal Metastases on Computed Tomography Images. Spine (Phila Pa 1976). 2024 Mar 15;49(6):390-397. doi: 10.1097/BRS.0000000000004889. Epub 2023 Dec 12.\u003c/li\u003e\n\u003cli\u003eHoshiai S, Hanaoka S, Masumoto T, Nomura Y, Mori K, Okamoto Y, Saida T, Ishiguro T, Sakai M, Nakajima T. Effectiveness of temporal subtraction computed tomography images using deep learning in detecting vertebral bone metastases. Eur J Radiol. 2022 Sep;154:110445. doi: 10.1016/j.ejrad.2022.110445. Epub 2022 Jul 20.\u003c/li\u003e\n\u003cli\u003eOng W, Zhu L, Zhang W, Kuah T, Lim DSW, Low XZ, Thian YL, Teo EC, Tan JH, Kumar N, Vellayappan BA, Ooi BC, Quek ST, Makmur A, Hallinan JTPD. Application of Artificial Intelligence Methods for Imaging of Spinal Metastasis. Cancers (Basel). 2022 Aug 20;14(16):4025. doi: 10.3390/cancers14164025.\u003c/li\u003e\n\u003cli\u003eShah, A.A.; Schwab, J.H. Predictive Modeling for Spinal Metastatic Disease. Diagnostics 2024, 14, 962. https://doi.org/10.3390/diagnostics14090962\u003c/li\u003e\n\u003cli\u003eLi Q, Hua S, Wang C, Cai S, Zhang J (2014) The value of routine biopsy during percutaneous kyphoplasty for vertebral compression fractures. PLoS ONE 9(12):e115417. https://doi.org/10.1371/journal.pone.0115417\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Study Characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"680\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient Count\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMalignant Cases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMalignancy (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (Mean/Median)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultiple Myeloma (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary Bone Tumors (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic Tumors (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWickstr\u0026oslash;m et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e459\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNSM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSchoenfeld et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e8.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHershkovich et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e11.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChou et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e13.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJoseph et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e14.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eNSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eNSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNSM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNowak et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e10.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePagdal et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e11.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVenturi et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (Chondrosarcoma)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJia et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1,352\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMuijs et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e4.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSozzi et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e324\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePneumaticos et al\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e14.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNSM: not specifically mentioned\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Prevalence of Malignancy in Vertebral Biopsies Among Patients with Osteoporotic Fractures\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"661\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eDiagnosis Category\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003ePooled Prevalence (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e95% CI (Lower\u0026ndash;Upper)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/em\u003e-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNumber of Studies (\u003cem\u003e\u003cstrong\u003ek\u003c/strong\u003e\u003c/em\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSolid Malignancy Metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.30 \u0026ndash; 7.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultiple Myeloma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.31 \u0026ndash; 3.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Malignant Diagnoses\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e8.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e5.43 \u0026ndash; 10.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3.\u003cstrong\u003eNewcastle-Ottawa Scale (NOS) Bias Assessment for Included Cohort Studies\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"643\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRepresentativeness of Exposed Cohort\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSelection of Non-Exposed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAscertainment of Exposure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome Not Present at Start\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparability\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAssessment of Outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdequate Follow-Up Length\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdequacy of Follow-Up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal Score (Max 9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWickstr\u0026oslash;m et al (2024)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSchoenfeld et al (2008)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHershkovich et al (2020)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChou et al (2013)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJoseph et al (2012)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNowak et al (2018)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVenturi et al (2011)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJia et al (2024)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMuijs et al (2009)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSozzi et al (2021)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePneumaticos et al (2010)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePagdal et al (2016)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e★\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Osteoporotic vertebral fractures, Unsuspected malignancy, Vertebral biopsy, Metastatic spinal tumors, Multiple myeloma","lastPublishedDoi":"10.21203/rs.3.rs-6906795/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6906795/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eOsteoporotic vertebral fractures (OVFs) are common among older adults and are generally treated conservatively. However, some patients initially diagnosed with benign OVFs may have underlying malignancies\u0026mdash;such as metastatic solid tumors or hematologic cancers\u0026mdash;that mimic osteoporotic fractures radiographically. This study aimed to determine the pooled prevalence of unsuspected malignancy in patients initially diagnosed with OVFs through a systematic review and meta-analysis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA systematic literature search of the PubMed database was conducted through March 2025 in accordance with PRISMA guidelines. Studies were included if they involved adults with presumed osteoporotic vertebral fractures who underwent vertebral biopsy or histopathological evaluation. Pooled prevalence estimates of unsuspected malignancies were calculated using a random-effects model. The risk of bias in included studies was assessed using the Newcastle-Ottawa Scale.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTwelve studies involving 3,229 patients met the inclusion criteria. The pooled prevalence of unsuspected malignancy among presumed OVF cases was 8.00% (95% CI: 5.43\u0026ndash;10.6%). Subgroup analysis showed that 4.87% (95% CI: 2.30\u0026ndash;7.44%) had metastatic solid tumors, while 2.62% (95% CI: 1.31\u0026ndash;3.94%) had multiple myeloma. No biopsy-related complications were reported. Moderate to substantial heterogeneity was observed across studies.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eApproximately one in twelve patients with an initial diagnosis of benign OVF may have an underlying malignancy. Vertebral biopsy is a safe and valuable diagnostic tool, particularly in cases with atypical clinical or radiologic features, to facilitate early cancer detection and appropriate oncologic intervention.\u003c/p\u003e","manuscriptTitle":"Evaluating the Outcomes of Vertebral Biopsies Performed in Osteoporotic vertebral fractures: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-20 15:36:54","doi":"10.21203/rs.3.rs-6906795/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"23d36c53-2cc4-480b-9bdf-13e79cdd9fce","owner":[],"postedDate":"June 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-23T13:53:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-20 15:36:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6906795","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6906795","identity":"rs-6906795","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}