Introduction

Osteoporosis is characterized by low bone mass and microarchitectural deterioration which is responsible for increased risk of bone fracture [1]. Altough osteoporosis is an important health problem in men as in women, it can be underestimated and undertreated [2]. Bone mineral density (BMD) is influenced by many factors such as ethnicity, gender, age, location, eating habits, and lifestyle [3]. Individuals of 65 years of age or older are included in the geriatric age group [4]. It was reported that the incidence of fractures in men increases particularly after the age of 75 years [5]. High-density structures at either the lumbar or femoral neck regions, such as soft tissue calcification, metallic objects, contrast media, osteoarthritis, etc., can result in wrong BMD measurements [6]. In these situations, the unaffected lumbar or femoral neck region gains the utmost significance for determination of osteroporosis. In this cross-sectional study which we performed in a Mediterrenean city (Mersin) of Turkey, we aimed to determine lumbar and femoral neck BMD values of geriatric and younger adult male populations, to compare BMD values of these two age groups, and to find the correlation, concordance, and discordance rates between the BMD values of these two main anatomic regions within both age groups.

Material and Method

Patient selection and obtaining patient data

In this prospective study, a total of 257 consecutive male individuals who did not have major risk factors that might affect bone mass and who underwent BMD evaluation as a routine outpatient procedure were recruited from 2010 to 2013. Patients with internal metallic fixators in their lumbar vertebrae (n=2), patients with BMD measurements of only the proximal femoral or lumbar regions (n=6), patients with only total body BMD measurements (n=3), and pediatric male patients (n=6) were excluded. The remaining adult males (n=240) were included and divided into two groups with respect to their ages. Those over 65 years of age (n=126) were included in the geriatric male group, while adult males under 65 years of age (n=114) were included in the non-geriatric male group. In both groups, patients were not taking any medication affecting bone metabolism (calcium, certain diuretics, estrogens, corticosteroids, anticonvulsants, vitamin D, heparin, etc.). All of the procedures were performed according to the World Medical Association Declaration of Helsinki (revised in 2000, Edinburgh). All the patients were informed about dual-energy x-ray absorptiometry (DXA) examination and informed consent was obtained from them. The mean ages of the geriatric and the non-geriatric male groups were 72.83±5.19 and 50.4±11.1 years, respectively. Weight, height and age of the patients were recorded at the time of BMD measurement. Body mass index (BMI) was calculated using the following formula: weight (kg)/height(m)² [7]. According to the mean value of BMI, which was 26.42±5.41 for the geriatric male group and 28.03±5.32 for the non-geriatric group, the overall weight status of the patients was determined as overweight [7].

Bone Mineral Density Measurement

In each patient, the lumbar spine (L1-4) BMD and left femoral neck BMD were measured by experienced technicians using a DXA device (Lunar Prodigy Advance; GE Medical Systems-Lunar, Madison, WI, USA). Daily quality control was carried out by measurement of an approved phantom. L1-4 measurements were done in the supine position with the legs elevated and supported below the knees to decrease lumbar lordosis. Femoral neck measurements were also performed in the supine position and femoral anteversion was corrected by rotating the foot internally. The BMD of the patients was defined as g/cm² and evaluated by using T-score (standard deviation of healthy young-adult mean) [8]. The World Health Organization (WHO) classification system was used; it defines normal BMD as T-score ≥ -1.0, osteopenia as T-score between -2.5 and -1, and osteoporosis as T-score ≤ -2.5 [1, 5, 8]. Concordance was described as obtaining lumbar and femoral T-scores that are in the same range of normal, osteopenic or osteroporotic. Minor discordance was described as having only one WHO diagnostic class difference between the lumbar and femoral regions, such as a normal T-score in one region and an osteopenic score in the other, or an osteopenic T-score in one region and an osteoporotic score in the other. Major discordance was described as detection of osteoporosis in one region when the other region was normal [9–11].

Statistical Analysis

The mean, standard deviation, and 95% confidence interval (CI) were calculated for all the quantitative variables. The frequencies of the patients with osteoporosis, osteopenia and normal BMD were expressed as percentages. The student t-test was used to determine whether there was a statistically significant difference between the geriatric and non-geriatric groups for the parameters (BMD, T-scores, BMI, age) measured. Within each group the Pearson correlation test was used to evaluate the relationship between T-scores of L1-4 and femoral neck. Also within each group, the Pearson correlation test was used to evaluate the relationship between BMI and all BMD measurements of L1-4 and femoral neck. P values < 0.05 were considered as statistically significant. All analyses were done with SPSS software (version 16.0: SPSS Inc, Chicago, IL).

Results

The mean BMI and BMD measurements in the geriatric group were significantly lower than those of the non-geriatric group (p<0.05) (Table 1). According to T-scores of L1-4, the percentage of osteoporosis in the geriatric and non-geriatric groups was 38% and 11.4%, respectively. According to T-scores of femoral neck, the percentage of osteoporosis in the geriatric and non-geriatric groups was 41.3% and 6.2%, respectively (Table 2a,b). The correlation between T-scores of L1-4 and femoral neck was significant both in the geriatric (r=0.560, p=0.000) and the non-geriatric (r=0.535, p=0.000) groups. In the geriatric group, concordance, minor discordance, and major discordance of T-scores were detected in 51.6% (n=65/126), 42.8% (n=54/126), and 5.6% (n=7/126) of the patients, respectively. In the non-geriatric group, concordance, minor discordance, and major discordance of T-scores were detected in 61.4% (n=70/114), 35.1% (n=40/114), and 3.5% (n=4/114) of the patients, respectively. The percentages of the regions that had lower T-scores in minor and major discordance are given in Table 3 for the geriatric and non-geriatric groups. In both the geriatric and non-geriatric groups, the correlations between the BMI and T-scores of L1-4 and femoral neck were statistically significant (p<0.05) (Table 4).

Discussion

For measuring BMD, today’s most widely used and most precise technique is DXA, which is a quantitative digital radiography with a precision of 1-2% [8]. In a study including 3469 patients, the incidence of vertebral fractures was found to increase two-fold for every 1 SD decrease in lumbar or femoral neck BMD values [12]. Femoral neck BMD measurement with DXA was determined as a strong predictor of hip fractures [13]. Diagnosis of osteoporosis, estimation of fracture risk, and follow-up of patients under treatment can accurately be done by DXA [1].

As the results of previous studies [14–17] and those of our study show, aging seems to have a great impact on BMD. In a large-scale study including 820 elderly men, the risk of multiple fractures in men older than 75 years was found to be about five times more than that of men who were between 60-64 years of age [17]. In our study, lumbar and femoral BMD values were significantly lower in the geriatric male group. Also, osteoporosis of the lumbar and femoral regions was detected 3.5 times and 6.7 times more, respectively, in our geriatric group as compared to our non-geriatric group. In addition to age, BMI is related to BMD; for example, low BMD associated fractures are closely related to low BMI [17, 18]. Doğan et al. [19] found a significant relationship between BMI and femoral BMD measurements in geriatric men. We also found statistically significant correlations between BMI and T-scores of L1-4 and femoral neck in both our geriatric and non-geriatric groups. Specifically, our geriatric group, who had lower mean BMD measurements compared to those of our non-geriatric group, also had lower BMI, which is consistent with the studies cited above.

Though significant correlations between T-scores of lumbar vertebrae and femoral neck were demonstrated [20, 21], discordance between these two regions was also reported in many studies [9–11, 20–22], as was the case in our study. In their study with 649 males over 50 years of age, Özdemir et al. [10] reported the percentages of concordance, minor discordance, and major discordance of T-scores as 59.6%, 37.6%, and 2.8%, respectively. Mounach et al. [22] determined the percentages of concordance, minor discordance, and major discordance of T-scores among 608 male participants as 58.3%, 38%, and 3%, respectively. In their large-scale study with 4188 patients including males and females, Moayyeri et al. [11] reported the percentages of concordance, minor discordance, and major discordance of T-scores as 58.3%, 38.9%, and 2.7%, respectively. We obtained similar results in both of our study groups. We detected minor discordance in four of every ten patients and major discordance in one of every 18-28 patients. Regarding the geriatric men in our study, the percentages of femoral regions with lower T-scores in patients with minor and major discordance were higher than those of non-geriatric men. This can be explained by the tendency to have both cortical and trabecular bone loss in aged patients [10, 23]. Spondylotic changes or aortic calcifications in the elderly might also cause relatively increased lumbar BMD measurements [10]. Discordance can occur because of physiological reasons, due to disease processes such as aortic calcification; as a result of anatomical factors; because of artifacts such as metallic objects; and/or technical factors such as operator-dependent variations in the examination technique [9]. In a study including 348 postmenopausal women, Singh et al. [24] detected that lumbar BMD was lower than femoral BMD in patients with discordance. This finding and our above-mentioned result makes us consider that not only aging but also male gender might have contributed to measurement of lower femoral T-scores in discordant patients. But we think that detailed comparative studies with larger groups including both genders are needed to further exhibit the effect of male gender on femoral BMD in discordant elder patients. As a challenging issue in the diagnosis of osteopenia and osteoporosis, the problem of discordance can be solved by measurement of both lumbar and femoral regions at the same session and by taking the region with lower T-score into consideration [10]. But when we have to rely on a single region (i.e. for patients with large internal metallic fixators in lumbar vertebrae, metallic hip prostheses, scoliosis, or compression fractures of vertebrae, etc.), being aware of the significant correlation between T-scores of lumbar vertebrae and femoral neck will help us in assessing the status of the site that is unavailable for BMD measurement. On the other hand, though the percentage of major discordance is relatively low as reported in previous studies and in our study, we should also be careful not to make a false negative diagnosis in a patient with regional osteoporosis at the site that is unavailable for optimal BMD measurements, as mentioned above.

Our study has some limitations. We could not use fracture risk assessment tool (FRAX), an algorithm that has recently been introduced to assess fracture risk by giving the 10-year probability of hip fracture and major osteoporotic fracture, and that has successfully been used by Gültekin et al. [25] in postmenopausal Turkish women. In our study we excluded patients with metallic internal fixators, but we could not exclude patients with spondylosis, scoliosis, coxarthrosis and/or aortic calcifications because we could not obtain plain radiographs or computed tomography images of the patients. This might have contributed to T-score discordance in some patients. Though we used a standardized BMD measurement technique, involvement of different DXA technicians during the study period might have caused operator-dependent T-score discordance in some BMD measurements. We also could not compare our results with those of females within similar age groups to assess the effect of gender on concordance and discordance of T-scores.

In conclusion, using DXA we demonstrated that the geriatric male population had decreased BMD and an increased rate of osteoporosis as compared to the non-geriatric male population. Though the correlation between T-scores of L1-4 and femoral neck was significant both in geriatric and non-geriatric men, we also detected either minor or major discordance in a considerable number of patients; this should be taken into consideration during evaluation of DXA results.

Competing interests

The authors declare that they have no competing interests.

References

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Introduction

Pulmonary embolism (PE) is a common and potentially fatal condition. Most patients who die from pulmonary embolism do so within the first few hours without accurate diagnosis. Patients with PE often have nonspecific symptoms and the diagnosis is often delayed [1]. Earlier diagnosis of PE may decrease the morbidity and mortality. There are still difficulties in the diagnosis of PE [2]. Noninvasive diagnostic tests such as plasma D-dimer measurement, lower limb deep vein compression ultrasonography (CUS), ventilation-perfusion scintigraphy (V/Q scan), and chest multi detector computed tomography pulmonary angiography (CTPA) have been used for the diagnosis of PE [3]. Plasma D-dimer measurement, a noninvasive diagnostic tool, is frequently used. It is a degradation product produced by plasmin-mediated proteases of cross-linked fibrin. It is the most reliable tool for excluding pulmonary embolism in younger patients who have no associated comorbidity or history of venous thromboembolism and whose symptoms are of short duration [4]. Advanced age, pregnancy, active malignancy, recent surgical interventions, liver failure, rheumatoid arthritis, and the presence of infection may result in false positive plasma D-dimer measurement. Anti-coagulation therapy, the presence of small clots, isolated small pulmonary infarcts, and existing symptoms persisting for more than 5 days may lead to false-negative plasma D-dimer measurement results [5]. Therefore, new tests should be identified in order to exclude PE and to reduce the number of these advanced imaging tests performed.

The urokinase plasminogen activator receptor (uPAR) is a three domain membrane bound receptor, mainly expressed on immunologically active cells (e.g. neutrophils, activated T cells, macrophages) and vascular endothelial cells [6, 7]. The soluble form of uPAR (suPAR) can be generated when uPAR is cleaved from the surface of such cells during inflammatory stimulation. It is linked to cellular and vascular inflammatory processes [8]. With its ligand, urokinase plasminogen activator (uPA), it participates in numerous immunologic functions including migration, adhesion, angiogenesis, fibrinolysis, and cell proliferation [9]. SuPAR is a measurable protein in the circulating blood of all individuals. It has been tested as a prognostic and diagnostic tool in a number of infectious and inflammatory conditions. In contrast to most pro-inflammatory and acute response biomarkers, circadian changes in plasma suPAR are minimal and the in vitro stability of suPAR is high [10, 11]. Numerous observational studies have shown increased suPAR in patients with cancer and various infectious and inflammatory diseases, including infections with human immunodeficiency virus (HIV), malaria, tuberculosis, central nervous system infections, arthritis, liver fibrosis, and inflammatory bowel disease [12]. Recent studies have pointed to its association with atherosclerosis and the development of cardiovascular disease (CVD) [13, 14].

In the Malmö Diet and Cancer Study population, one study reported that development of venous thromboembolism was higher in individuals with higher suPAR levels [15]. However, less is known about the relationship between suPAR and PE.

The goal of this study was to compare the suPAR levels between PE patients and healthy people and to investigate the value of suPAR in the diagnosis and prognosis of PE.

Material and Method

Study Design

Thirty patients hospitalized and monitored with a PE diagnosis in the Chest Disease Clinic of Suleyman Demirel University Hospital were enrolled in the study. The diagnosis of pulmonary thromboembolism was made based on its compatibility with a filling defect of PTE on spiral computerized tomographic pulmonary angiography according to a predefined standard protocol. The local ethics committee approved the present study. Patients with hypertension, diabetes mellitus, chronic renal failure, liver disease, heart failure, acute or chronic infection, accompanying autoimmune disease, and malignancy were excluded. 29 consecutive sex- and age-matched healthy individuals without relevant current status and medical history were included. The exclusion criteria in the control group were the same as those in the patient group. In patients, plasma D-dimer examinations were performed usig a automatic coagulation analyzer and the immune turbidimetry method, with reference values of 69–243 ng/ml.

Plasma suPAR Measurement

Whole EDTA-blood samples were centrifuged at 3,000 x g for 10 minutes. The plasma samples were transferred in separate tubes and stored at 80°C. The suPARnostic ELISA Standard Kit (ViroGates A/S, Birkerød, Denmark, Code No. A001) was used for the quantitative determination of suPAR levels in plasma samples. The levels of plasma suPAR were determined according to the manufacturer’s instructions. The absorbance of samples was measured at 450 nm using an Organon Teknika 530 Microplate Reader. The suPAR concentrations of each specimen were determined by interpolation on the standard curve that was created by the absorbance of the standards. The suPAR concentrations of each specimen were expressed as ng/mL. The detection limit of the assay was estimated to be 0.1 ng/mL.

Statistical analysis

Statistical analysis was performed using SPSS 15.0. Normal distribution of data was analyzed using the Kolmogorov-Smirnov test, and the Mann-Whitney U-test was used to compare the groups. Statistical significance was set at p < 0.05. In addition, receiver operating characteristic (ROC) curve analysis was performed.

Results

Fifty nine individuals (30 patients with PE and 29 healthy subjects) were enrolled in the study. Demographic characteristics (age and sex) in the PE and control groups were similar. There was a total of 30 patients, of whom 14 (46.7%) were female and 16 (53.3%) were male. The mean age of the patients was 61.73 (±17.4) years. The PE group’s clinical characteristics are shown in Table 1. The median (95% CI) suPAR level measured in the PE group was 6.4 (6.4-10.5) ng/mL, compared to 3.3 (2.9-4.2) ng/mL in the control group (P<0.001, Figure 1). suPAR levels were significantly higher in the patients with PE (P<0.001). Receiver operating characteristic (ROC) curve analysis was performed to determine cutoff thresholds in discriminating between PE and control group plasma suPAR levels. The area under the ROC for that purpose was 0.871 (95% CI; 0.776-0.965). A suPAR cutoff point in patients with PE > 4.3 ng/mL had specificity and sensitivity of 83% and 82%, respectively (Figure 2). Patients with higher suPAR (4.3 ng/ml) had significantly longer hospital stays than patients with lower suPAR. The median days of hospital stay was 8 in patients with higher suPAR levels and 6 in patients with lower suPAR levels. This difference was statistically significant (p=0.049). There was a statistically significant positive correlation between D-dimer and suPAR (r=0.530, P=0.004).

Discussion

The present study has novel findings: serum suPAR levels were significantly higher in patients with PTE than in healthy controls. There was a statistically significant positive correlation between D-dimer and suPAR. In addition, patients with higher suPAR levels had significantly longer hospital stays than patients with lower suPAR levels.

The suPAR level indicates both an active systemic inflammation and a low grade inflammation [16]. It has been suggested that suPAR is involved in the plasminogen-activating pathway, inflammation and modulation of cell adhesion, migration, and proliferation [7]. Systemic levels of suPAR were significantly higher in critically ill patients compared to healthy controls [11, 17]. suPAR has been linked to endothelium dysfunction, damaged cardiac microcirculation, increased vascular stiffness, and finally, more extensive atherosclerosis [18]. Elevated levels of suPAR were associated with increased risk of future CVD independently for traditional risk factors and subclinical organ damage [19]. Several longitudinal population-based studies have reported an association between plasma suPAR levels and increased risk of CVD [13, 20].

Endothelial damage is one of the causes of thrombus formation in PE. suPAR was found to be positively correlated with the number of neutrophils, leucocytes, monocytes, and eosinophils. This supports suPAR as a marker associated with inflammation. In our study, suPAR levels were significantly higher in the patients with PE compared to healthy controls. These results may be due to the fact that suPAR is produced from endothelial cells and has an important role in the fibrinolytic system [7, 21].

Several studies have investigated the prognostic value of suPAR. High systemic levels of suPAR were associated with the need for ICU admission [11]. Studies involving patients with myocardial ischemia (acute coronary syndrome or MI) have demonstrated that suPAR is associated with mortality [20, 22]. One study involving 449 patients with acute chest pain and suspected non-ST-elevation acute coronary syndrome demonstrated suPAR to be a strong and independent marker of all causes of mortality over the mid- and long-term [23]. We did not find an association between suPAR levels and mortality.

Plasma D-dimer measurement is commonly used as the first test in patients suspected of having acute PE. Several factors other than PE or deep vein thrombosis (DVT) are associated with positive D-dimer results. The positive predictive value of D-dimer with advanced age, malignancy, pregnancy, heart failure, pneumonia, sepsis, and kidney failure is quite low [2,24]. Specificity is reported to be between 40% and 60% [25]. A suPAR cutoff point > 4.3 ng/mL showed 83% specificity and 82% sensitivity in patients with PE. Also, D-dimer levels were significantly correlated with suPAR levels.

The present study has several limitations. First, the study involves a relatively small number of patients and controls. Second, we used a cross-sectional design for this study. Third, the large number of exclusion criteria may also be a limitation of this study, decreasing the utility of this test as an effective adjunct to guide the diagnosis of PE relative to other conditions that also may alter suPAR levels.

Consequently, we suggest that plasma suPAR may be a biomarker with good sensitivity and specificity for diagnosis of PE. However, further prospective studies with a larger population are required to demonstrate the diagnostic and prognostic significance of suPAR.

Competing interests

The authors declare that they have no competing interests.

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