https://orcid.org/0000-0002-9750-8243
Abstract
The prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in prostate cancer patients and its relationship with prevalent vertebral fractures (PVF) has not yet been demonstrated. This study aimed to investigate the relationship of DISH, visceral fat accumulation, and other age-related diseases to PVF in elderly men with castration-naïve prostate cancer (CNPC). A total of 134 CNPC patients who were ≥65 years of age without bone metastases were registered in this study. DISH was found in 36.6% (49/134) of the patients in the study population. Patients with DISH were significantly older and had a lower total hip-bone mineral density (BMD) than those without DISH. On the other hand, there were no significant differences in fat distribution, prevalence of hypertension, dyslipidemia, diabetes, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c, prostate-specific antigen (PSA), or lumbar-BMD (L-BMD). A multivariate analysis of age, DISH, body mass index (BMI), visceral fat area (VFA), and total hip-BMD, which were significantly associated with PVF in a univariate analysis, showed that age (OR 1.11; p = .02) and DISH (OR 5.99; p = .0003) were independently associated with PVF. This study suggests that the presence of DISH may not be negligible when assessing the risk of vertebral fracture in prostate cancer patients before treatment.
Introduction
Prostate cancer is the second most prevalent cancer in the world in males and the fifth leading cause of cancer death [Citation1]. Although the incidence of prostate cancer in Asian countries, including Japan, is lower than in North America and Europe, it is expected that it will rapidly increase in the future as the population ages [Citation1–3]. Most prostate cancer treatments, mainly androgen deprivation therapy (ADT), lead to cancer treatment-induced bone loss (CTIBL) and increase the risk of fracture [Citation4–8], which is greatly related to the patient’s quality of life (QOL). Identifying the characteristics of patients at risk of fracture before the initiation of cancer treatment is becoming more important for maintaining QOL during and after cancer treatment in elderly patients.
Diffuse idiopathic skeletal hyperostosis (DISH) is a disease in which the longitudinal ligaments and tendon attachments of the spinal cord gradually become ossified, causing ankylosing disorders of the spine [Citation9]. Although ossification of the anterior longitudinal ligament is the main characteristic, it is sometimes accompanied by ossification of the posterior longitudinal ligament, the yellow ligament, and the extraspinal ligament. When multiple vertebral bodies are connected by ossification, the spine loses motility, causing falls due to imbalance and immobilization-associated osteoporosis [Citation10]. The risk of vertebral fracture in patients with DISH is known to be higher than that in patients without DISH [Citation10]. Although the cause of DISH is unknown, it is more common in males than in females, and it has been reported that aging, obesity, and type 2 diabetes are associated with the increase of its prevalence [Citation11–15]. It is reported that the prevalence of DISH in males is 13–22.7% [Citation12,Citation15,Citation16], while that in male patients over 70 years of age is 38–44% [Citation17]. Most patients with prostate cancer are elderly males. Moreover, visceral fat obesity is attracting attention as a risk factor because of the relationship between the progress of prostate cancer and visceral fat accumulation [Citation18,Citation19]. With these partially common epidemiological characteristics of prostate cancer and DISH, patients with prostate cancer are expected to have a high prevalence of DISH.
Although there have been reports on the relationship between DISH and prevalent vertebral fractures (PVF) [Citation10,Citation20], none have investigated the prevalence of DISH or its relationship with PVF in prostate cancer patients. In this study, in addition to DISH, age-related diseases such as visceral fat accumulation, hypertension, dyslipidemia, diabetes, and impaired glucose tolerance were used as evaluation factors. The purpose of this study was to investigate whether DISH, visceral fat accumulation, and other age-related diseases are associated with PVF in elderly patients with prostate cancer before the start of treatment.
Methods
Patient demographics
Between October 2016 and December 2019, 256 cases of prostate cancer diagnosed based on a prostate biopsy at our institution were extracted from the electronic medical record system database. Exclusion criteria were <65 years of age (n = 52), bone metastasis (n = 21), cases in which bone densitometry was not performed (n = 42), and cases in which blood tests were missed (n = 7); hence, a total of 134 patients were included for this study. All patients were under pre-treatment conditions (castration-naïve prostate cancer; CNPC). Blood samples were taken 1–3 weeks prior to the date of prostate biopsy. Age, body mass index (BMI), history of hypertension, dyslipidemia, and diabetes, prostate-specific antigen (PSA), hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) were retrospectively investigated. There were no patients in this cohort with a history of osteoporosis treatment or a history of serious trauma. All protocols of this retrospective study were approved by the review board and ethics committee of Koto Hospital, Tokyo, Japan (No. 2019124).
The diagnosis of PVF and DISH
Computed tomography (CT) from the chest to the pelvis was performed on all patients before the start of treatment for the staging of prostate cancer. Using the sagittal CT images, the anterior, central, and posterior heights of each vertebral body from Th1 to L5 were measured. PVF was diagnosed when at least one of these three measurements was reduced by ≥20% in comparison to the height of the nearest uncompressed vertebral body [Citation21]. According to the criteria recommended by Resnick and Niwayama [Citation22], DISH was defined if the following three conditions were satisfied: (1) the presence of four or more consecutive vertebral fusions with adjacent ligamentous ossification, (2) a preserved intervertebral disc space in the diseased area, (3) the absence of inflammatory changes in apophyseal joints and sacroiliac joints. DISH and PVF were diagnosed by a board-certified spine surgeon (approved by the Board of the Japanese Society for Spine Surgery and Related Research) (H. T).
Bone densitometry and the analysis of fat distribution
In all cases, the bone mineral density (BMD) in lumbar vertebrae (L1–4) and the total femur was evaluated by dual-energy X-ray absorptiometry using a Lunar Prodigy (GE Lunar Corp., Madison, WI). The visceral fat area (VFA) and subcutaneous fat area (SFA) in the axial CT image at the umbilicus level were measured using an imaging software program (SYNAPSE VINCENT; Fujifilm Medical, Tokyo, Japan).
Statistical analyses
The Student’s t-test was used for the comparison of continuous variables and the chi-squared test was used for the comparison of categorical data between two groups. The clinical factors affecting PVF were examined by univariate and multivariate logistic regression analyses. p Values of <.05 were considered to indicate statistical significance. All statistical analyses were performed using JMP® 14 (SAS Institute Inc., Cary, NC).
Results
Patient characteristics
demonstrates the characteristics of patients with and without DISH. The mean age of the total of 134 CNPC patients was 75.2 years (range, 65–89 years), and 49 patients out of 134 (36.6%) were diagnosed with DISH. Patients with DISH were significantly older (with vs. without: 76.6 vs. 74.4 years, p = .0272) and had a significantly lower total hip-BMD (TH-BMD) (0.82 vs. 0.89 g/cm2, p = .0102) than those without DISH. On the other hand, there were no significant differences in BMI, SFA, VFA, prevalence of hypertension, dyslipidemia and diabetes, FPG, HbA1c, PSA, and lumbar-BMD (L-BMD).
Table 1. The clinical characteristics of prostate cancer patients with and without DISH.
Clinical factors related to PVF
A comparison of clinical parameters between patients with and without PVF is shown in . The presence of DISH, advanced age, lower BMI, lower VFA, and lower TH-BMD were associated with PVF (p < 0.0001, p = .0021, p = .0266, p = .022, p = .0195, respectively). SFA, hypertension, dyslipidemia, diabetes, FPG, HbA1c, PSA, and L-BMD were not associated with PVF ().
Table 2. Comparison of clinical parameters between prostate cancer patients with and without prevalent vertebral fractures.
Univariate and multivariate regression analyses
Univariate analyses of all clinical parameters revealed that the following the factors were significantly associated with PVF: age (OR 1.13; p = .0023), DISH (OR 5.82; p = .0001), BMI (OR 0.86; p = .023), VFA (OR 0.98; p = .016), TH-BMD (OR 0.02; p = .012) (). The multivariate regression analysis of these five factors revealed that age (OR 1.11; p = .02) and DISH (OR 5.99; p = .0003) were independently associated with PVF ().
Table 3. Factors associated with the presence of vertebral fractures in the univariate and multivariate regression analyses.
Discussion
In this study, DISH diagnosed based on CT images was found in 36.6% (49/134) of the overall study population of elderly males with CNPC. Moreover, when limited to patients with PVF, 68.9% (20/29) had DISH. A multivariate analysis of clinical factors associated with PVF revealed that aging and DISH were positively associated with PVF, and that these statistically significant associations were independent of BMI, VFA, or TH-BMD. The results suggest that the presence of DISH may not be negligible when assessing the risk of vertebral fracture before the initiation of treatment for prostate cancer.
The reported prevalence of DISH varies widely between 2.9% and 25% [Citation11,Citation15,Citation17]. It has been pointed out that this variability may be due to differences in race, age, gender, medical history, and diagnostic modalities in different research groups [Citation20]. Previous studies have suggested that DISH is prevalent in elderly patients, males, patients with obesity, and patients with type 2 diabetes [Citation13,Citation14]. Furthermore, although DISH was only diagnosed by X-rays in past reports, CT is often used to diagnose DISH at the present time [Citation23]. CT provides detailed images around the spine, including the disc space [Citation23]. In a report analyzing chest CT scans of 3013 Japanese people (female, n = 1261; male, n = 1752) with a mean age of 65 years, the prevalence of DISH in males was 13% [Citation16]. In our study, the prevalence of DISH in CNPC patients of ≥65 years of age was 36.6%. We hypothesized that the relatively high prevalence of DISH was due to the high mean age of our cohort (mean; 75.2 vs. 65 years), the relatively high mean VFA (126.6 cm2 [significantly higher than 100 cm2, which is the definition of visceral obesity in Asia [Citation24]]) and the fact that the evaluation of DISH was performed using chest to pelvic CT in our study. Generally, patients with prostate cancer are elderly and have changes in body composition, including an increase in visceral fat with aging. In addition, many epidemiological and basic studies have revealed that obesity is involved in the progression of prostate cancer [Citation3,Citation18,Citation19,Citation25]. These characteristics of patients with prostate cancer are common with males, aging, and obesity, which are clinical factors suggested to be associated with DISH. Therefore, patients with prostate cancer may potentially have a higher prevalence of DISH. It may be valuable for further research in large cohorts in the future.
Previous studies have reported that the prevalence of DISH increases with age [Citation11,Citation12,Citation15,Citation23]. It has also been pointed out that DISH may be associated with modern lifestyle diseases, such as diabetes and components of metabolic syndrome [Citation26–28] In this study, DISH patients were significantly older than those without DISH (p = .0272), as reported previously. On the other hand, there were no significant differences in VFA, hypertension, dyslipidemia, or hyperglycemia, which are components of metabolic syndrome. However, although significant differences were not seen, DISH patients tended to have high VFA, high HbA1c, high FPG, and a high prevalence of diabetes and dyslipidemia. The prevalence of hypertension was almost same between the two groups. The small sample size of this study may have influenced this result. Moreover, DISH was significantly associated with low TH-BMD in this study. It is suspected that immobility and the effect of stress shielding reduce bone formation in patients with DISH. In general, the BMI has a strong positive correlation with bone density, in particular, the density of the femur, and a consistent correlation is obtained regardless of gender [Citation29,Citation30]. Furthermore, previous studies have suggested a negative correlation between the blood insulin concentration and bone density in insulin-resistant males after adjustment for age, weight, and height [Citation31], and dyslipidemia was a risk factor for reduced bone density in the femur [Citation32]. As the DISH patients in this cohort were old and tended to have lower BMI values, impaired glucose tolerance (high HbA1c and high FPG), and higher rates of diabetes and dyslipidemia, it is possible that these factors affected the low TH-BMD.
In this study, 68.9% of the patients with PVF had DISH. This indicated that two in three vertebral fracture patients had DISH. This result was higher than the previously reported rate of DISH in Japanese vertebral fracture patients of 24–101 years of age, which was 33.9% (54/159) [Citation20]. Besides, it was found that aging (OR 1.11; p = 0.02) and the presence of DISH (OR 5.99; p = .0003), but not components of metabolic syndrome or SFA or L-BMD, were positively associated with PVF, and that this positive association was independent of BMI, VFA, and TH-BMD (). In contrast, although the results of the multivariate analysis were not statistically significant (OR 0.98; p = .062), the VFA was negatively correlated with PVF in the univariate analysis (OR 0.98; p = .016) (). These findings suggest that visceral fat accumulation, which plays an important role in triggering metabolic syndrome, has a protective effect against vertebral fracture. Previous retrospective studies and recent prospective studies investigating the relationship between the visceral fat mass assessed by CT and prostate cancer have shown a positive association between visceral fat accumulation and prostate cancer development [Citation18,Citation19]. The results of our multivariate analyses suggest that the increased risk of VF associated in patients with DISH may have a greater impact than the reduced risk of VF that can be expected with visceral fat accumulation in prostate cancer patients.
In general, prostate cancer patients may experience ADT leading to CTIBL for 1–10 years or longer, depending on the stage and risk of progression. The prognosis of prostate cancer is long in comparison to other cancers. Given this background, urologists should confirm the presence or absence of DISH as early as possible. DISH is usually asymptomatic at the time of its diagnosis [Citation33]. According to previous reports, the diagnosis of DISH is often delayed, and the diagnosis may be triggered by delayed paralysis due to vertebral fracture [Citation20,Citation34]. It has been pointed out that it is difficult to detect fractures because of bone changes due to DISH [Citation35], because patients with mild pain are often reluctant to see a doctor, and because patients with back pain cannot distinguish back pain from fracture pain [Citation20]. For patients with prostate cancer, whole-body CT is performed to detect metastasis at the time of the cancer diagnosis. Thus, with the help of orthopedic surgeons and radiologists who are skilled in the diagnosis of the spine, urologists can make an accurate diagnosis of DISH early. This may help to avoid delays in the diagnosis of DISH, such as the confirmation of DISH at the time of skeletal-related events in the course of cancer treatment.
This study was associated with some limitations. First, since this study was retrospective in nature and performed in a single-center, the evaluated sample sizes were not large enough to draw definitive conclusions. A large-scale multicenter study is required to verify the findings. Second, the CNPC patients registered in this study were all Japanese. It is known that the prevalence of diabetes, the degree of obesity defined by BMI, and fat distribution in Asians differ from other races, including Caucasians [Citation36–39]. Our findings may not apply to other races. With these limitations, we believe that the new information provided by this study for prostate cancer patients can increase urologists' understanding of DISH.
In conclusion, in elderly patients with prostate cancer, DISH was independently associated with PVF, as well as aging. Our study suggests that it may be better to screen for DISH before the start of treatment when assessing the risk of vertebral fracture in prostate cancer patients.
Disclosure statement
The authors declare no conflicts of interest in association with this study.
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