According to 2020 cancer statistics report, pancreatic cancer (PC) is the seventh leading cause of cancer death in both sexes, accounting for numerous deaths due to its poor prognosis. The incidence rate of PC is higher in countries with a higher human development index, and its incidence has remained stable over time (1). According to a study, PC is predicted to overtake breast cancer as the third leading cause of cancer death in 28 European countries by 2025 (2). This indicates that PC exhibits a high incidence and mortality in digestive system tumors. Despite significant advances in detecting and treating PC, only 4% of patients survive five years after diagnosis (3).

Cancer metastasis involves a multi-step invasion and metastasis cascade process. Under complex gene regulation mechanisms, primary tumor cells migrate away from the primary site to other sites and gradually grow into secondary tumors (4, 5). We are concerned about cancer metastasis because it is responsible for 90% of cancer deaths, not the primary tumor (6). Bone is the third most common site of metastasis for solid tumors (7). In addition, complications such as pain, pathological fracture, nerve root or spinal cord compression, hypercalcemia, and severe bone marrow infiltration caused by bone metastasis significantly affect patients’ quality of life (8). Therefore, the survival rate of pancreatic cancer with bone metastasis (PCBM) patients has remained low.

The different incidence of PCBM reported in literature (from 5% to 20%) should depend on either the possible overlapping between bone localization and symptoms associated with the primary tumor or the longer survival obtained in the past few years due to new and more effective chemotherapy regimens in both adjuvant and advanced settings (9–12). There seems to be some suggestion that patients who have a primary that is in the tail of the pancreas are more likely to develop bone metastasis (13). Bone surveys using standard roentgenograms, CT scans, MRIs, and positron emission topographic (PET) scans have been used to detect skeletal metastases in pancreatic cancer (14–17). It seems that no imaging modality appears to have a superior detection rate. However, when used in conjunction, the rates of detection may be much higher. In terms of treatment, the literature shows that a first-line chemotherapy regimen was administered with gemcitabine plus nab-paclitaxel in combination with zoledronic acid (18). The previous clinical reports on PCBM primarily focused on case reports and single-institutional cohort studies (19–21). Due to the small sample size and low credibility of these studies, there is an apparent deficiency in their guiding value for clinical practice. In addition, due to the relatively low incidence of PCBM, most current treatment schemes for multi-directional control of PC from clinical experience. Therefore, we are in urgent need of practical tools and concise guidelines for clinical treatment.

Nomograms are widely used in cancer prognosis and recurrence mainly because they can simplify statistical prediction models to a single numerical estimate of the probability of events (such as death or recurrence) depending on the situation of individual patients (22–24). A user-friendly graphical interface can generate insights in the clinical process, thus promoting nomogram use for clinical decision-making (25). For many cancers, nomograms are superior to traditional TNM staging systems (26) and have become a new standard (27, 28). As far as we know, no model has been developed to predict the overall survival (OS) of PC patients with BM. As a result, we want to construct and validate nomogram, and use it to predict 1-, 2-, 3-year OS in PCBM.

Skeletal metastases represent an underappreciated site of metastasis in patients with pancreatic cancer. Previous reports have estimated the prevalence to range from 5% to 20% (11, 12). Recently, there are many studies focused on treatment of PCBM, the researchers look forward to develop more individualized drug screening to replace traditional radiotherapy and chemotherapy (33, 34). PCBM is a relatively uncommon type of tumor bone metastasis. Due to its rarity, most studies on PCBM are case reports or single-institutional cohort studies (19–21). Therefore, it is critical to identify risk and prognostic factors of PCBM. To the best of our knowledge, our research is the first multicenter and comprehensive retrospective study to establish nomogram models to predict the risk and prognosis of BM in PC patients. Moreover, the ROC curve, calibration plot, and DCA revealed that the nomogram possesses considerable predictive power. This tool will make it easier to implement in clinical practice and enable doctors to determine the most appropriate treatment strategy for their patients.

As previously stated, there were few reports regarding the risk factors of PCBM. In a study of other digestive system tumors, the risk of developing BM was significantly associated with adenocarcinoma, gender, tumor size, poor grade, CEA positive, T1 stage, N1/N2 stage, brain metastasis, liver metastasis, and lung metastasis (29, 35, 36). In our study, risk factors for BM in PC patients included age, neuroendocrine carcinoma, primary site, N1 stage, radiotherapy, brain metastasis, liver metastasis and lung metastasis. As a result, clinicians should keep a keen sense and close attention to these risk factors for their PC patients. For these patients with potential risks, doctors should advise them to have PET-CT/ECT scans in a timely manner. According to our multivariate Cox analysis results, age, race, histological subtype, grade, surgery, chemotherapy, and lung metastasis were noteworthy predictors of BM in PC patients. Normal may appear to be a factor affecting prognosis, but in actual analysis, it is not. Based on the prognostic factors obtained in this study, doctors can more effectively evaluate the prognosis and provide clinical guidance for PC patients with BM.

In our study, younger PC patients had a higher risk of developing BM, but older ones with BM had a worse prognosis. Why might reducing age promote the development of metastasis? At the biological level some scientists would suggest two possible reasons, one related to the immune system and the other the mechanical properties of tissues (37). Recent study has shown that harnessing the immune system, such as CD4+T cells play an important role in metastatic process. The hypothesis suggests that age-related deterioration of the system may actually play a protective role by depriving the metastasis process of key immune-cellular components (38). Extra-cellular matrix (ECM) composition and remodeling are now considered necessary for tumorigenesis and progression of metastasis, including pre-metastatic niche construction. However, aging can also alter ECM through nonenzymatic glycosylation to reduce the activity of matrix modifying proteases, which are an essential factor in the selection of cancer cells during metastasis (39). Thus, age-dependent changes to ECM might also be protective. Several previous studies have also demonstrated that older age affects the prognosis of cancer patients with BM. In those studies, older patients indicated a low survival rate (40–42). We suspect that this phenomenon may be associated with low immunity and body degradation in elderly patients, but we cannot collect any further relevant information in the database.

In addition, compared with other people of color, black people with PCBM had the worst prognosis. Although the disparity in PC incidence and mortality between black and white patients in the United State (US) is narrowing, blacks continue to have a higher PC incidence and mortality rate than whites (43). In the multiracial environment of the US, cancer survival rates varied greatly among different races, and this difference was even more pronounced between whites and blacks (44, 45).

Adenocarcinoma was generally considered to be the most prevalent histological subtype of PC. To our knowledge, we reported for the first time the relationship between histological subtype and prognosis in PCBM patients. Adenocarcinoma alone was previously reported to exhibit the lowest median overall survival and poor prognosis in PC patients, which was extremely similar to our results (46). Concurrently, nomogram model suggested that grade was an independent prognostic risk factor for PCBM patients. At present, the first-line treatment of metastasis PC includes surgical resection and chemotherapy (47). Our study found that surgery and chemotherapy improved the survival prognosis of BM patients and further validated the reliability of this scheme in terms of clinical data.

Unlike BM, PC had a characteristic trend of preferential metastasis to the liver and lung, but brain metastasis of PC was almost as rare as BM (48–50). Interestingly, although brain and liver metastasis were risk factors for PCBM, they had no significant impact on the survival of PCBM patients. It was suggested that oncologists should take timely and effective measures to prevent metastasis in PC patients and pay attention to whether PC patients develop lung metastasis following BM.

In this study, we established a relatively complete evaluation system to accurately estimate the risk and prognosis of PCBM. We visualize these data using nomograms, which is more conducive to clinicians’ judgment and targeted treatment. To improve our model’s applicability, we used multicenter data from SEER database and validated the nomogram through internal and external validation. Due to the heterogeneity of data, we could not evaluate the nomogram only through internal validation; therefore, we utilized external validation to address this issue more effectively. External validation data were obtained from two large clinical hospitals in China to avoid selective bias. Surprisingly, nomogram showed satisfactory predictive value not only in training and internal validation cohort but also in external validation cohort.

Indeed, there are some limitations in our research. First of all, our external validation data comes from Asians, while the SEER database includes blacks, whites, and other people of color. Second, nomogram is based on retrospective studies, requiring further validation in prospective cohort and clinical trials. Third, we omitted certain potentially critical data, such as patient’s specific surgical procedure and chemotherapy regimen. Despite these limitations in this retrospective study, the nomogram model has practical utility in white, black and yellow population. The nomogram has been proved to be a efficient and instructive model, which can effectively assist clinicians in providing personalized treatment.

To sum up, we first identified the risk factors of PCBM based on univariate and multivariate logistic regression analyses, and then determined prognostic factors using univariate and multivariate Cox regression analyses, resulting in the establishment of two nomograms. These nomograms can help clinicians effectively identify high-risk patients and treat them with different outcomes.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

The studies involving human participants were reviewed and approved by the ethics committee of the Zhejiang Provincial People’s Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

QB conceived the idea, reviewed, and edited the manuscript. WZ wrote the manuscript. LJ, SZ, FF, and YZ contributed to literature retrieval. XW, JL, YT, and YK carried out research selection, data extraction, and statistical analysis. WZ and LJ prepared tables and figures. All authors contributed to this article and approved the submitted version.

This research was supported in part by The Key Research and Development Program of Zhejiang Province under grant number 2021C03078, and the Natural Science Foundation of Zhejiang Province under grant number LQ19H160014, and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission under grant number 2019KY320.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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