Research ArticleClinical Studies
Open Access

Preoperative Osteopenia as Risk Factor for Death from Other Diseases After Gastrectomy in Elderly Patients

SHOTA SHIMIZU, TOMOYUKI MATSUNAGA, YU SAKANO, MASAHIRO MAKINOYA, YUJI SHISHIDO, KOZO MIYATANI, YUSUKE KONO, YUKI MURAKAMI, TAKEHIKO HANAKI, KYOICHI KIHARA, MANABU YAMAMOTO, NARUO TOKUYASU, SHUICHI TAKANO, TERUHISA SAKAMOTO, TOSHIMICHI HASEGAWA and YOSHIYUKI FUJIWARA
In Vivo November 2023, 37 (6) 2662-2668; DOI: https://doi.org/10.21873/invivo.13375

Abstract

Background/Aim: Preoperative osteopenia, defined as low bone mineral density, is a prognostic factor in patients with digestive tract cancers, including gastric cancer (GC). However, the correlation between preoperative osteopenia and GC in elderly patients is unclear. Patients and Methods: We enrolled 251 patients who had undergone curative surgery for histopathologically diagnosed gastric adenocarcinoma from January 2008 to December 2012. Patients were classified into the non-elderly group (n=169) and the elderly group (n=82). Bone mineral density was calculated as the average pixel density (Hounsfield units) within a circle of the mid-vertebral core at the bottom of the 11th thoracic vertebra on preoperative computed tomography. Results: Although overall survival was significantly shorter in the elderly compared to the non-elderly group (p=0.0062), there was no significant difference in disease-specific survival between the two groups (p=0.71) because of the higher rate of death from other diseases. In addition, the elderly group had a significantly higher incidence of osteopenia (p<0.001) and a significantly lower prognostic nutritional index (p<0.001). Multivariate analysis revealed that preoperative osteopenia and a low preoperative prognostic nutritional index were significant risk factors for death from other diseases after gastrectomy in elderly patients. Conclusion: In elderly patients with GC, preoperative osteopenia is an important factor to consider in terms of both curability and death from other diseases.

Key Words:

Gastric cancer (GC) is one of the leading causes of death. Although the prognosis for patients with GC has improved, GC still accounts for the fifth-highest number of cancer deaths worldwide (1). Additionally, because of the aging of society, the number of elderly persons who have GC is increasing. Postoperative long-term outcomes are poor in elderly patients because their poor physical or nutritional status increases the risk of morbidity and death (2-5). Therefore, it is important to determine the optimal treatment strategies for elderly patients because of their risk of dying of causes other than their primary disease.

In recent years, many noninvasive prognostic predictors of GC that reflect inflammation, immunity, and nutrition have been established (6-10). These predictors include the neutrophil/lymphocyte ratio (NLR) and the prognostic nutritional index (PNI), and they are undoubtedly important in elderly patients with GC (11, 12). The PNI has been shown to be a risk factor for death from other diseases in elderly patients with GC (4).

Preoperative osteopenia has recently received attention, and it was shown to be a significant prognostic factor in patients with digestive tract cancers (13-16). The researchers in these previous studies measured bone mineral density (BMD) by calculating the average pixel density within a circle of the 11th thoracic vertebra (Th11) using preoperative computed tomography (CT). However, none of them mentioned the correlation between preoperative osteopenia and GC in elderly patients. The current study was therefore performed to evaluate the possibility of osteopenia as a risk factor for death from other diseases in elderly patients with GC.

Patients and Methods

This retrospective analysis involved 251 patients who underwent curative gastrectomy (R0 resection) for gastric adenocarcinoma at our institution from January 2008 to December 2012. Patients were classified into the elderly group and non-elderly group using 75 years as the age boundary. The patients’ clinicopathologic findings were examined according to the Japanese Classification of Gastric Carcinoma (17). Distal partial, proximal partial, or total gastrectomy with regional lymph node dissection was performed depending on the tumor location and progression. Causes of death were determined by reviewing clinical records or by direct inquiry of family members. In some cases, a postmortem was performed to determine the cause of death. Postoperative complications were evaluated according to the Clavien-Dindo classification, and we considered grade ≥II complications to be postoperative complications.

The blood test data collected from the patients’ records included the serum albumin level (g/dl) and the total peripheral blood lymphocyte and neutrophil counts (cells/mm3). The NLR was calculated as follows: NLR=peripheral neutrophil count/peripheral lymphocyte count. The PNI was calculated as follows: PNI=10×serum albumin level+0.005×total peripheral lymphocyte count (18). We also collected data on BMD and the skeletal muscle index (SMI) using preoperative plain CT. BMD was measured in the trabecular bone by calculating the average pixel density within a circle of the mid-vertebral core at the bottom of the 11th thoracic vertebra (Th11) (Figure 1). We used 160 Hounsfield unit (HUs) as the cut-off as described in previous studies (19-21). The SMI was calculated as follows: SMI=skeletal muscle area measured at the level of the third lumbar vertebra/patient’s height (cm2/m2) (22). This study was approved by the institutional review board of our institution.

Figure 1.
Figure 1.

Measurement of trabecular bone mineral density (BMD) within a circle of the mid-vertebral core at the bottom of the 11th thoracic vertebra (Th11) in the (A) osteopenia group and (B) non-osteopenia group.

Statistical analysis. Differences in clinicopathological characteristics between the two groups were evaluated using the chi-squared test for categorical variables and the Mann-Whitney U-test for continuous variables. We calculated the Youden index using receiver operating characteristic analysis to determine optimal cutoffs for the NLR, PNI, and SMI in the survival analysis. Survival curves were calculated according to the Kaplan-Meier method. For the analysis of disease-specific survival (DSS), patients who died of their primary disease during follow-up were examined. Differences between the curves were identified using the log-rank test. Multivariate analyses were performed using a Cox proportional hazards model. A p-value of <0.05 was considered statistically significant. GraphPad Prism (GraphPad Software, Inc., La Jolla, CA, USA) and SPSS for Windows version 24 (IBM Corp., Armonk, NY, USA) were used for the statistical analyses.

Results

Impact of osteopenia in elderly patients. Of the 251 patients, 169 (67.3%) and 82 (32.7%) were assigned to the non-elderly and elderly group, respectively. The clinicopathological characteristics of both groups are shown in Table I. Significantly more patients had osteopenia in the elderly than non-elderly group (p<0.001). In addition, the elderly group had a significantly lower SMI in men (p=0.043), lower PNI (p<0.001), and higher incidence of venous invasion (p=0.008) than the non-elderly group.

View this table:
Table I.

Comparison of patient characteristics in non-elderly and elderly groups.

Short-term and long-term outcomes. Table II shows the postoperative short-term outcomes. There was no significant difference between the two groups. We evaluated the 5-year overall survival (OS) rate and DSS rate. There were no significant differences in DSS between the two groups regardless of the pStage (all patients: p=0.454, pStage I: p=0.278, pStage ≥II: p=0.249) (Figure 2). However, OS was significantly shorter in the elderly than the non-elderly group regardless of the pStage (all patients: p<0.0001, pStage I: p<0.0001, pStage ≥II: p=0.0035) (Figure 3). Although the percentage of patients who died of their primary disease was not different between the two groups, the percentage of patients who died of other diseases was significantly higher in the elderly group than that in the non-elderly group (Table I). The causes of death from other diseases in the elderly group were cervical stroke (20%), other malignancies (10%), cardiovascular disease (10%), pneumonia (10%), renal failure (7%), and others/unknown (43%).

View this table:
Table II.

Postoperative complications in non-elderly and elderly groups.

Figure 2.
Figure 2.

Disease-specific survival (DSS) curves in the elderly and non-elderly groups in (A) all patients, (B) patients with pStage I disease, and (C) patients with pStage ≥II disease.

Figure 3.
Figure 3.

Overall survival (OS) curves in the elderly and non-elderly groups in (A) all patients, (B) patients with pStage I disease, and (C) patients with pStage ≥II disease.

Osteopenia as risk factor for death from other diseases in elderly patients. Of the 82 elderly patients, 47 (57.3%) and 35 (42.7%) were assigned to the osteopenia and non-osteopenia group, respectively. The clinicopathological characteristics of both groups are shown in Table III. There were no significant differences in any characteristics between the two groups, including the postoperative short-term outcomes.

View this table:
Table III.

Comparison of characteristics of elderly patients with and without preoperative osteopenia.

We performed univariate and multivariate analyses to evaluate the risk factors for death from other diseases in elderly patients after gastrectomy. Univariate analysis revealed that the significant factors were preoperative osteopenia (p=0.005), a high preoperative NLR (p<0.001), and a low preoperative PNI (p<0.001). In the multivariate analysis, the independent risk factors were preoperative osteopenia (p=0.014) and a low preoperative PNI (p=0.007) (Table IV).

View this table:
Table IV.

Univariate and multivariate analyses of death from other diseases after gastrectomy in elderly patients with gastric cancer.

Discussion

There was no difference in the incidence of postoperative complications between the elderly and non-elderly groups, which indicates that gastrectomy itself does not increase surgical risk in elderly patients. Additionally, there was no difference in DSS between the two groups regardless of the pStage. However, although both groups received similar treatments, elderly patients had a higher risk of dying of other diseases than did non-elderly patients, consistent with a previous report (4). The PNI in the elderly group was lower than that in the non-elderly group, and elderly patients tended to have a higher incidence of preoperative osteopenia. Elderly patients usually have a worse nutritional status and frailty of bone with aging, and our data revealed that a low preoperative PNI and preoperative osteopenia were associated with death from other diseases in elderly patients. Hashimoto et al. (4) reported that a low preoperative PNI and multiple comorbidities were important risk factors for death from other diseases in elderly patients with GC, consistent with the results of our study. However, the importance of preoperative osteopenia in elderly patients with GC has not been discussed in previous reports.

Osteopenia is a recently reported prognostic factor in several digestive tract cancers, including GC (13-16). Osteopenia is reportedly associated with a poor prognosis because of tumor-derived cytokines (e.g., parathyroid hormone-related protein, interleukin-1, and interleukin-6), which stimulate osteoblasts and activate the NF-kB pathway (23). Moreover, high expression of bone morphogenetic protein, which is correlated with bone homeostasis, is correlated with a poor prognosis or cancer cell growth in several digestive tract cancers (24-26). Although tumor factors may become the cause of osteopenia in some patients, our data indicate that patient-related factors such as advanced age and a low nutritional status are more important than tumor factors. To some extent, the progression of osteopenia with aging is a national phenomenon; thus, complete prevention of osteopenia is difficult to achieve. In the current study, however, the PNI was also a prognostic factor for death from other disease. Considering that a balanced diet and exercise are important for bone health and function (27, 28), interventions by preoperative nutritional support and rehabilitation may be effective for prevention of osteopenia. Moreover, some reports have mentioned the usefulness of vitamin D for GC cell growth inhibition (29, 30). Because vitamin D is related to bone homeostasis (31), intake of vitamin D may also be effective for patients who have GC with preoperative osteopenia.

As our data showed, malnutrition and osteopenia are important risk factors for death from other diseases, such as cerebral stroke or other malignancies, because they cause frailty in elderly patients. Kuwada et al. (5) reported that sarcopenia increases the risk of death from other causes after gastrectomy, but our data did not show the importance of sarcopenia. In addition, invasive surgery such as total gastrectomy was reported to cause postoperative poor oral ingestion and postoperative osteopenia (32, 33). Yoshikawa et al. (34) reported that limited lymph node dissection did not cause low DSS in elderly patients with GC. Therefore, it may be best to avoid invasive surgery in elderly patients with osteopenia because such treatment may lead to further frailty in exchange for curability.

Our study had several limitations. First, this was a retrospective study and was thus subject to bias. Second, the cutoff value for defining osteopenia is not well established; therefore, we used a cutoff based on previous reports. Third, although we used 75 years as the age cutoff for elderly patients, there is no standard definition of “elderly”. Fourth, the number of patients we examined was small and the results must therefore be confirmed in a large-scale, prospective, randomized controlled trial.

Conclusion

Our study indicates the potential of preoperative osteopenia to predict the prognosis in elderly patients with GC. We should pay more attention to surgical patients with GC who have preoperative osteopenia, and invasive treatments may need to be avoided in these patients considering the possibility of death from other diseases.

Acknowledgements

The Authors thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Footnotes

  • Authors’ Contributions

    Study conception and design: SS; Acquisition of data: SS; Analysis and interpretation of data: SS and TM; Drafting of manuscript: SS and TM; Critical revision: YF; Final approval of the article: all Authors.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received July 5, 2023.
  • Revision received August 6, 2023.
  • Accepted August 7, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Preoperative Osteopenia as Risk Factor for Death from Other Diseases After Gastrectomy in Elderly Patients
SHOTA SHIMIZU, TOMOYUKI MATSUNAGA, YU SAKANO, MASAHIRO MAKINOYA, YUJI SHISHIDO, KOZO MIYATANI, YUSUKE KONO, YUKI MURAKAMI, TAKEHIKO HANAKI, KYOICHI KIHARA, MANABU YAMAMOTO, NARUO TOKUYASU, SHUICHI TAKANO, TERUHISA SAKAMOTO, TOSHIMICHI HASEGAWA, YOSHIYUKI FUJIWARA
In Vivo Nov 2023, 37 (6) 2662-2668; DOI: 10.21873/invivo.13375
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