Preoperative occult vertebral fracture is a stronger predictor than osteopenia of the clinical outcomes after gastrectomy for gastric cancer
- Authors:
- Published online on: February 11, 2025 https://doi.org/10.3892/ol.2025.14925
- Article Number: 179
Abstract
Introduction
The mortality rate of cancer patients has been declining annually owing to advances in diagnostics, surgery, and medications. However, the estimated number of new cases of gastric cancer (GC) exceeds one million, ranking fifth among all newly diagnosed cancers, and many patients experience recurrence after gastrectomy for GC (1). Establishing an accurate prediction of its clinical outcomes is crucial for improving the quality of life of patients with GC and reducing mortality and medical burden.
Recent research has confirmed that sarcopenia or systemic inflammatory response markers such as the Glasgow Prognostic Score (GPS) or Prognostic Nutritional Index (PNI) can predict survival in patients with GC (2–4). Osteopenia, a condition of low bone mineral density (BMD), is associated with the progression of sarcopenia and is independently associated with poor prognosis in patients with various digestive tract cancers, including GC (5,6). Occult vertebral fracture (OVF) are the most common complications of osteopenia, and more than two-thirds of patients with this condition are incidentally diagnosed (7). Some reports have demonstrated the effectiveness of OVF in prognostic prediction in patients with colorectal liver metastasis and pancreatic cancer (8,9). However, no study has explored the correlation between OVF and the clinical outcomes of patients with GC. Therefore, the aim of this study was to investigate the prognostic impact of OVF in GC patients undergoing gastrectomy.
Materials and methods
Patients
This retrospective study included 242 patients who underwent primary gastrectomy for GC between October 2013 and February 2023 at the Fuji City General Hospital (Shizuoka, Japan). This study was approved by the Institutional Review Board of Fuji City General Hospital (approval no. 297: Approved February 15, 2023.). The requirement for acquisition of informed consent from patients was waived because of the retrospective design of this study and anonymized data. The inclusion criteria as follows: i) Patients underwent gastrectomy with Stage I, II, III GC, ii) not applicable for endoscopic submucosal dissection, and iii) computed tomography (CT) performed within 30 days before surgery. Patients who had stage IV disease (n=16), synchronous malignant neoplasms (n=3), and underwent emergency surgery (n=1) were excluded; the remaining 222 patients were enrolled in this study.
Treatment and follow-up
The Japanese Gastric Cancer Treatment Guidelines, including surgical indications, treatment, and selection of chemotherapy, were used in our treatment strategy for GC (10). Staging and pathological diagnoses were based on the Japanese Classification of Gastric Carcinoma (11). Neoadjuvant chemotherapy with S-1 plus cisplatin was administered to patients with bulky lymph nodes. Depending the location of the tumor, distal, total, or proximal gastrectomy was performed. Laparoscopic gastrectomy is primarily performed in patients with stage I clinical disease. In patients with clinical stage II or III disease, the attending surgeon selected between the laparoscopic and open surgical approaches. Postoperative complications were defined as grade III–V based on the Clavien-Dindo classification, occurring within 30 postoperative days (12). Patients with pathological stage II were treated with S-1 alone, and stage III were treated with S-1 alone or S-1 in combination with oxaliplatin with adjuvant chemotherapy, if the general condition was judged to be tolerated based on patients' performance status. Basic surveillance was conducted until death or 5 years post-operatively. Patients with stage I disease were followed-up every 6 months, and those with stage II or III were every 3 months to check for recurrence by performing blood tests, including those for the screening of tumor markers. Enhanced CT was performed every 6 months, and upper gastrointestinal endoscopy was performed every 1–2 years. For recurrence, systemic chemotherapy was administered based on the patient's performance status.
Definition of sarcopenia, osteopenia, and OVF
Sarcopenia, osteopenia, and OVF were preoperatively evaluated using CT. Sarcopenia was defined as psoas muscle mass area (PMA) at the third lumbar vertebra below the sex-specific median size. The PMA was calculated as follows: Length of the major axes × the length of the minor axes × π (13). Osteopenia was defined as a decrease in the BMD below the standard value. The BMD was measured by bone mineral density in the midvertebral core of the 11th thoracic vertebra. The cut-off values of BMD were evaluated based on the previous reports as follow: Men=308.82–2.49 × age in years, women=311.84–2.41 × age in years (Fig. 1A and B) (14). OVF was evaluated using the anterior (A), central (C), and posterior (P) heights of the vertebrae from the 11th thoracic vertebra to the 5th lumbar vertebra. The criteria for OVF were C/A <0.8 or C/P <0.8 in the any of the vertebrae regardless of fracture history (pathological fractures and symptomatic fractures were excluded) (Fig. 1C and D) (15).
Measurement of preoperative GPS and PNI
The GPS was defined as a combination of C-reactive protein (CRP) and albumin levels. In cases where both levels were abnormal (CRP >1.0 mg/dl and albumin <3.5 g/dl), the score was 2; if one level was abnormal, the score was 1; and if neither level was abnormal, the score was 0 (16). The PNI was calculated as 10× serum albumin level (g/dl) +0.005× lymphocyte count (17).
Statistical analysis
All statistical analyses were conducted using a statistical software program (SPSS Statistics for Windows, version 22; IBM Corp., Armonk, N.Y., USA). Quantitative variables are expressed as median and interquartile range, and differences were analyzed using the Mann-Whitney U test. Qualitative variables were compared using the Fisher's exact test. The Kaplan-Meier method was used to analyze the survival rates, and the log-rank test was used to compare the differences between the survival rates of the groups. A Cox proportional hazards regression model was used to identify the independent prognostic factors associated with disease-free survival (DFS) and overall survival (OS) rates. Variables identified as significant in univariate analysis were included in multivariate analysis. The continuous variables were classified into two groups. The cutoff value for CEA was set at the upper normal limit, and the cutoff values for age, PNI, operative time, and intraoperative blood loss were determined via a receiver operating characteristic curve using the survival status at the 3-year follow-up. P<0.05 was considered to indicate a statistically significant difference.
Results
Patients' characteristics
The patient characteristics and associations between clinical variables and OVF are summarized in Table I. The median patient age was 74 years (range: 68–80 years). This study included 170 (77%) men. Osteopenia, sarcopenia, and OVF were observed in 68 (31%), 110 (50%), and 64 (28%) patients, respectively. The pathological diagnosis of GC showed that 91 (41%), 55 (25%), and 76 (34%) patients had stage I, II, and III cancers, respectively.
In the univariate analysis, patients with OVF were significantly associated with older age (P<0.01), operative approach (open gastrectomy, P=0.01), T factor (P<0.01), lymph node metastases (P<0.01), advanced stage (P<0.01), and adjuvant chemotherapy (P<0.01). In terms of body composition, patients with OVF had higher GPS (P=0.04) and lower BMD (P<0.01), PMA (P=0.02), and PNI (P=0.01) than those without OVF. In addition, postoperative recurrence occurred in 28 (44%) patients in the OVF group and 25 (16%) patients in the non-OVF group. Of these, 11 (17%) patients in the OVF group and 12 (8%) patients in the non-OVF group were administered with postoperative chemotherapy for recurrence.
Univariate and multivariate DFS analyses of patients with GC
Table II shows the prognostic factors for the DFS rates according to Cox proportional hazard analysis. The univariate analysis of the DFS rates indicated that osteopenia (P<0.01), sarcopenia (P<0.01), OVF (P<0.01), GPS score of 1 or 2 (P=0.02), PNI <45 (P=0.04), intraoperative blood loss ≥227 ml (P=0.01), stage ≥II (P<0.01), and R1 or R2 (P<0.01) were significant prognostic factors. The multivariate analysis revealed that OVF [hazard ratio (HR): 2.35, 95% confidence interval (CI): 1.30–4.27; P<0.01], stage ≥II (HR, 6.15; 95% CI, 2.36–16.01; P<0.01), and R1 or R2 (HR, 2.35; 95% CI, 1.30–4.27; P<0.01) were independent and significant predictors of DFS.
 | Table II.Univariate and multivariate analyses of clinicopathological variables in relation to disease-free survival after gastrectomy for gastric cancer. |
Univariate and multivariate OS rate analyses of patients with GC
Table III shows the prognostic factors for the OS rates according to Cox proportional hazard analysis. Univariate analysis of the OS rates indicated that osteopenia (P=0.01), sarcopenia (P<0.01), OVF (P<0.01), GPS score of 1 or 2 (P<0.01), PNI <45 (P<0.01), intraoperative blood loss ≥227 ml (P<0.01), stage ≥II (P<0.01), and R1 or R2 (P<0.01) were significant prognostic factors. The multivariate analysis revealed that OVF (HR, 2.16; 95% CI, 1.15–4.03; P=0.02), stage ≥II (HR, 5.31; 95% CI, 2.02–13.93; P<0.01), and R1 or R2 (HR, 5.95; 95% CI, 2.47–14.35; P<0.01) were independent and significant predictors of OS.
| Table III.Univariate and multivariate analyses of clinicopathological variables in relation to overall survival after gastrectomy for gastric cancer. |
Impact of OVF on DFS and OS after gastrectomy for GC
Patients with OVF had significantly lower DFS and OS rates than those without OVF. (DFS: 5-year survival rate, 46.0 vs. 79.8%, respectively, P<0.01; OS: 5-year survival rate, 46.7 vs. 84.4%, respectively, P<0.01) (Fig. 2). In terms of bone status, 121 (55%) patients had healthy bones, 37 (17%) had osteopenia without OVF, 33 (15%) had non-osteopenic OVF, and 31 (14%) had osteopenia with OVFs. Patients with OVF had significantly lower DFS and OS rates than those without OVF, regardless of osteopenia (P<0.01, P<0.01, respectively) (Fig. 3). The 5-year mortality rates after gastrectomy were as follows: healthy bone (14.1%); osteopenia without OVF (10.8%); non-osteopenic OVF (36.4%); and osteopenia with OVF (51.6%) (Fig. 4).
Discussion
Our results showed that preoperative OVF was significantly associated with poor prognosis and recurrence in patients undergoing gastrectomy for GC. To the best of our knowledge, this is the first report to demonstrate the impact of OVF on mortality in patients with GC.
OVF is common and result in acute and chronic pain, reduced quality of life, and diminished lifespan (7). OVF is a public health problem, with approximately 750,000 cases occurring annually. The prevalence of OVF increased from 3% in women aged <60 years to 20% in those aged >70 years and from 7.5 to 20% in men in the same age group, increasing in prevalence with age (18). In the present study, the OVF rate was 26% in women and 29% in men, with a median age of 74. OVF is the hallmark of osteopenia, which is characterized by a low BMD and occurs at a higher incidence earlier in life than any other type of osteoporotic fractures (19). We have previously shown that osteopenia could be a prognostic factor in patients with GC (5). However, in the present study, we found that OVF, a complication of osteopenia, was a stronger predictor than osteopenia. In addition, the combination of OVF and osteopenia is associated with worse prognosis. Thus, this study identified a strong prognostic factor and is a valuable finding.
The presence of one or more OVF was estimated to increase the risk of fractures by approximately 5–10 fold. Furthermore, mortality is reported to increase by approximately 10%, 5 years after OVF (20,21). If the presence of OVF alone increases mortality, even in the absence of cancer, it can be inferred that the prognosis of patients with GC with preoperative OVF is even worse. In the current study, patients with OVF had significantly worse OS and DFS rates than those without OVF.
However, biological mechanisms underlying bone metabolism and malignancy remain unclear. Recently, it was suggested that the RANK/RANKL system may be associated with bone metabolism and cancer development. RANKL is a member of the tumor necrosis factor family that binds to its receptor RANK to control osteoclast differentiation, activation, and survival. Proinflammatory and pro-osteolytic cytokines derived from cancer cells such as tumor necrosis factor-alpha, parathyroid hormone-related protein, interleukin (IL)-1, IL-6, and IL-8 activates RANK/RANKL signaling mechanism, causing bone loss (22). Furthermore, the RANK/RANKL pathway promotes epithelial-mesenchymal transition and metastasis (23). In the current study, the OVF group had more advanced disease stage (T-factor; P<0.01; lymph node metastases; P<0.01; stage, P<0.01).
Various systemic diseases, including metabolic, genetic, immune, inflammatory, and endocrine diseases, are associated with an increased risk of OVF; besides, deficiencies of vitamin D and estrogen are also one of the causes (20). Vitamin D and estrogen have been reported to be involved in the development of GC. Du et al have shown that vitamin D and its metabolites inhibit the viability, growth, and metastasis of GC cells. In addition, vitamin D metabolites may inhibit Helicobacter pylori infection and H. pylori-associated GC (24). According to recent reports, vitamin D may be involved in the anti-cancer mechanism of GC by affecting the expression of microRNAs, promoting the effects of cisplatin, and regulating intracellular signal transduction (25). Ge et al reported that estrogen receptors might be related to the progression and deterioration of GC (26). Thus, vitamin D and estrogen may be associated with the occurrence of GC and OVF; however, further research is needed to assess the relationship between GC and OVF.
The risk of bone loss after gastrectomy in patients with GC increases owing to malabsorption and malnutrition. The absorption of calcium and vitamin D is impaired because most of the stomach has been removed (27). Postoperative BMD in patients with GC after gastrectomy is decreased, and a knowledge of the presence of OVF preoperatively in patients with GC is more important than in other cancers because the conditions of patients with lower preoperative BMD are expected to be worse after gastrectomy (28). Calcium, vitamin D, and weight-bearing exercises are important for patients with osteopenia, and bisphosphonates, raloxifene, and nasal calcitonin have been shown to reduce the incidence of new OVF by 30–50% (29). OVF is often asymptomatic or underdiagnosed and under-treated (7). However, the diagnosis of OVF during routine medical care and appropriate intervention may improve the prognosis of patients with GC and OVF.
This study has several limitations. First, it was retrospective and conducted at a single institution with a small number of patients. Second, the effect of chemotherapy on recurrent cases is not reflected in the OS, which may lead to bias. Third, the definitions of sarcopenia, osteopenia, and OVF are controversial, and the cut-off values vary among studies. Fourth, we did not consider the diets rich in calcium, patients' medical histories and medications, such as vitamin D supplements and bisphosphonates. People with symptomatic fractures are excluded in the current study, however, those people have interventions such as vitamin D or bisphosphonate, and may have a good prognosis. Similarly, people with osteopenia or racial differences who have bisphosphonates or a high calcium diet may have a better prognosis. Therefore, we believe that further analysis by these factors will help to elucidate the mechanism of OVF and GC. Taken together, our findings need to be validated in large-scale prospective studies. Furthermore, evaluation in different racial groups is also needed in the future.
In conclusion, we demonstrated that preoperative OVF was significantly associated with worse DFS and OS rates in patients who underwent gastrectomy for GC. In addition, we showed that the combination of osteopenia and OVF could be a stronger prognostic indicator than osteopenia and OVF alone.
Acknowledgements
Not applicable.
Funding
This research was supported by JPSP KAKENHI (grant no. 23K16454).
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
NF, KF, TI, FY and KE conceptualized the study. NF, KF and FY analysed the data. NF wrote the original draft, and FY, KE and TI revised and edited the draft. TM and KF performed statistical analyses. KaT, KeT, MY and MT collected the data and analyzed the results. NF and KaT confirm the authenticity of all the raw data. All authors read and approved the final version of the manuscript.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Fuji City General Hospital (297). The requirement for acquisition of informed consent from patients was waived because of the retrospective design of this study and the use of anonymized data.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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