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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4325-4330
Copyright © 2004 by The Endocrine Society

Osteoporosis, Mineral Metabolism, and Serum Soluble Tumor Necrosis Factor Receptor p55 in Viral Cirrhosis

Jorge L. Gonzalez-Calvin, Francisco Gallego-Rojo, Ramon Fernandez-Perez, Francisco Casado-Caballero, Elena Ruiz-Escolano and Enrique G. Olivares

Department of Gastroenterology (J.L.G.-C., F.G.-R., R.F.-P., F.C.-C., E.R.-E.) and Immunology Unit (E.G.O.), University Hospital San Cecilio, 18012 Granada, Spain

Address all correspondence and requests for reprints to: Dr. Jorge L. Gonzalez-Calvin, Department of Gastroenterology, University Hospital San Cecilio, 18012 Granada, Spain. E-mail: jorgegonzalezc{at}meditex.es.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Liver cirrhosis is a risk factor for osteoporosis. Nevertheless, little is known about the mechanisms of bone mass loss in patients with viral cirrhosis. TNF{alpha} is a potent bone-resorbing agent. Serum concentrations of soluble TNF receptor p55 (sTNFR-55) correlate with clinical activity in liver cirrhosis. Our aim was to evaluate the possible role of sTNFR-55 in the pathogenesis of osteoporosis in patients with viral cirrhosis and its relationship with bone turnover markers. We studied 40 consecutive patients with viral cirrhosis and no history of alcohol intake and 26 healthy volunteers. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in the lumbar spine (LS) and femoral neck (FN). Patients with viral cirrhosis had reduced BMD (expressed as the z-score) in all sites [LS, –1.5 ± 0.22 (P < 0.001); FN, –0.37 ± 0.15 (P < 0.01)]. Serum concentrations of sTNFR-55 and urinary deoxypyridinoline, a biochemical marker of bone resorption, were significantly higher in patients with osteoporosis than in patients without osteoporosis (P < 0.001 and P < 0.05, respectively). Serum levels of sTNFR-55 correlated inversely with BMD in LS (r = –0.62; P < 0.005) and FN (r = –0.47; P < 0.05) and positively with urinary deoxypyridinoline (r = 0.72, P < 0.001). Our findings show that high serum concentrations of sTNFR-55 play a role in the pathogenesis of viral cirrhosis-associated bone mass loss and provide evidence of increased bone resorption related to the high serum sTNFR-55 levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS IS A complication of liver cirrhosis (1, 2, 3). However, the mechanisms by which chronic liver disease causes osteoporosis are not completely understood. Some studies have shown reduced osteoblastic function in alcoholic subjects with and without liver cirrhosis (4, 5, 6, 7, 8). In patients with viral cirrhosis who do not drink, increased bone resorption and high turnover osteoporosis have been described (3).

Nevertheless, the pathogenesis of osteoporosis associated with viral liver disease remains unknown. Of importance is the fact that elevated serum levels of several cytokines such as IL-1, IL-6, and TNF have been described in chronic liver disease (9, 10). Like other cytokines, TNF{alpha} has been shown to be a potent bone-resorbing agent that stimulates osteoclastogenesis (11, 12) and the activation of osteoclasts (13, 14, 15), and there is evidence that TNF and other cytokines are presumably causative agents of estrogen-deficient bone loss (16, 17). Liver disease and cytokines secretion might initiate and perpetuate bone loss in these patients.

TNF{alpha} exerts its biological function by binding to specific cell surface receptors (18). Two TNF receptors (TNFRs) of different molecular structures have been identified and cloned (19, 20). Soluble forms of both TNFRs present in serum [soluble TNFR p55 (sTNFR-55) and soluble TNFR p75 (sTNFR-75)] seem to play a role as modulators of the biological function of TNF{alpha} according to an agonist/antagonist pattern and can modify the function and availability of TNF{alpha} (21, 22).

Measuring sTNFRs in serum offers some advantages compared with direct quantification of TNF{alpha}, because TNF{alpha} is rapidly cleared from the circulation and is sometimes undetectable, and some assays are unable to detect TNF{alpha} bound to soluble TNFRs (23). sTNFRs are very stable, and their serum concentrations correlate well with those of TNF{alpha} (24, 25). In addition, serum levels of sTNFR-55 appear to reflect the activation state of the TNF{alpha}/TNFR system (26) and correlate with clinical activity in alcoholic cirrhosis and viral cirrhosis (27, 28) and with hepatic inflammation in chronic hepatitis B (29).

We therefore conducted a controlled study of 40 men with viral cirrhosis and no history of alcohol intake and 26 male control subjects to evaluate the possible role of serum sTNFR-55 as a risk factor for osteoporosis in patients with viral cirrhosis. We also investigated the relationship between serum sTNFR-55 and bone metabolism markers in these patients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Forty consecutive male patients (mean age, 59 yr; range, 35–73 yr) with viral cirrhosis participated in this study. The diagnosis of cirrhosis was based on liver biopsy in 32 patients; in the remaining eight patients diagnosis was based on the following clinical and laboratory data and clinical findings: physical stigmata of chronic liver disease, reduced prothrombin activity, hypoalbuminemia, signs of chronic liver disease on echography and esophageal varices on endoscopy. All 40 patients had positive serological markers for viral hepatitis (31 hepatitis C virus antibody-associated and nine hepatitis B surface antigen-associated), and they had a body mass index greater than 20 kg/m2. Five patients had ascites. Patients with malignancy; endocrine, cardiac, or lung disease; physical signs of hypogonadism (gynecomastia and testicular atrophy by physical examination); and serum creatinine concentrations greater than 0.15 mmol/liter were excluded. None had received calcium, vitamin D, corticosteroids, or any medication related to mineral metabolism. None had a family history of osteoporosis. We selected only patients whose previous alcohol consumption had not exceeded three drinks per week. They were classified into three groups according to the Child-Pugh score of severity of liver disease (30), as follows: group A, 16 patients (mean age, 57 yr; range, 37–67 yr); group B,14 patients (mean age, 59 yr; range 42–73 yr); and group C, 10 patients (mean age, 61 yr; range, 46–70 yr).

Twenty-six healthy male volunteers comprised the control group; none of these participants consumed more than three alcoholic drinks per week. Their mean age was 58 yr (range, 35–72 yr).

All patients and control subjects received complete information and gave their informed consent to participate in the study. The protocol was approved by our hospital’s ethics committee.

Laboratory analyses

Blood and urine samples were drawn in the morning after an overnight fast. Biochemical liver function tests and serum calcium (corrected for albumin concentration) and inorganic phosphate were measured with an automatic technique. Serum was assayed using commercially available kits for sTNFR-55 [with an enzyme-amplified immunocytometric assay (STNF-RI EASIA) from BioSource Europe (Nivelles, Belgium)], bone Gla protein (BGP; 125I RIA, Incstar Corp., Stillwater, MN), bone alkaline phosphatase [b-AP; Tandem-T, Ostase, immunoradiometric assay (IRMA), Hybritech Europe, Liege, Belgium], intact PTH (IRMA, Incstar Corp.) 25-hydroxyvitamin D (25OHD; RIA, Incstar Corp.), IGF-I (RIA, Nichols Institute, San Juan Capistrano, CA), testosterone (RIA, Sorin Biomedica, Saluggia, Italy), and SHBG (IRMA, Farmos Diagnostica, Olunsalo, Finland). The free testosterone index (FTI) was calculated with the following formula: total hormone x 100/SHBG (31). Urine was analyzed for calcium (atomic absorption spectrophotometry) and creatinine (standard automated techniques). Urinary free deoxypyridinoline (D-Pyr) was measured with a commercial kit from Metra Biosystem (Mountain View, CA) that uses a competitive ELISA test, according to a previously described method (32). Urinary excretion was expressed in terms of urinary creatinine as the ratio of D-Pyr to creatinine. Intra- and interassay precision ranged from 4.5–9% in our laboratory for all biochemical tests.

BMD measurements

Bone mineral density (BMD) was measured by dual x-ray absorptiometry (QDR1000, Hologic, Inc., Waltham, MA). Measurements were made of the usual L2–L4 area at the lumbar spine (LS) and femoral neck (FN). The values were expressed as z-score (number of SD adjusted by age and sex) compared with a healthy Spanish reference population (1221 males and 1331 females) (33, 34). The precision of the method had a long-term coefficient of variation less than 2% at lumbar and femoral sites of measurement. Osteoporosis was defined as a BMD 2.5 SD or more below the young adult mean at the spine or proximal femur according to WHO criteria (35).

Statistical analysis

All results were expressed as the mean ± SEM. Normal distribution of values in controls and cirrhotic patients were verified with the Kolmogorov-Smirnoff test. The mean values in different groups were compared by one-way ANOVA and unpaired two-tailed t tests or nonparametric Mann-Whitney U test as appropriate. A one-sample t test was used to assess the differences between the mean BMD z-score at each site and zero. Correlation studies were performed with Pearson standard linear regression analysis (normal distribution) or the Spearman test (nonnormal distribution). Risk factors for the development of osteoporosis were analyzed by backward stepwise regression analysis. Variables entered into the model included the patient’s age, FTI, and serum values of 25OHD, IGF-I, PTH, and sTNFR-55. Variables with threshold P < 0.2 were retained in the regression model.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows biochemical data. No significant differences were found between control subjects and the three groups of cirrhotic patients for body mass index (Table 2Go) and age.


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  		TABLE 1. Biochemical data in control subjects and viral cirrhotic patients

 

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  		TABLE 2. Body mass index (BMI), serum concentrations of sTNFR-55, and biochemical parameters of bone mineral metabolism in control subjects, patients with cirrhosis, and patients classified according to Child-Pugh score

 
BMD

Osteoporosis was found in 56% of the patients. When patients were classified according to the severity of liver disease, the percentages of osteoporosis were: Child A, 38.2%; Child B, 58.3%; and Child C, 65.8%. BMD in the LS and FN, expressed as the z-score, were significantly lower in patients with liver cirrhosis (LS, –1.5 ± 0.22; FN, –0.37 ± 0.15) than in the reference population at both sites (P < 0.001 for LS and P < 0.01 for FN). Figure 1Go shows that BMD of the LS was significantly lower in the Child B and Child C groups than in the Child A group (P < 0.01). No significant differences were found between Child B and C patients or between patients with ascites and patients without ascites. Bone mass loss in trabecular bone (lumbar spine) was more severe than that in cortical bone (FN; P < 0.001). The percentage of patients with osteoporosis in LS was 39.5%, the percentage with osteoporosis in FN was 35.37%, and the percentage of patients with osteoporosis in both sites was 18.8%



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  		FIG. 1. BMD values (z-score) in patients with viral cirrhosis classified according to Child-Pugh score. A, Child-Pugh A; B, Child-Pugh B; C, Child-Pugh C. Data are shown as the mean ± SEM. *, P < 0.01 vs. Child A.

 
Relationship among serum sTNFR-55 concentrations, BMD, and biochemical markers of bone turnover rate

Table 2Go shows that all three groups (Child A, B, and C) had significantly higher serum sTNFR-55 values than the control group (P < 0.001). Child B and C patients also had higher serum sTNFR-55 than Child A patients (P < 0.01). Urinary D-Pyr excretion was significantly higher in Child B and C groups than in the Child A group (P < 0.05) and control subjects (P < 0.01). Figures 2Go and 3Go show that patients who had osteoporosis had higher serum sTNFR-55 and urinary D-Pyr values than patients without osteoporosis (P < 0.01 and P < 0.02, respectively).



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  		FIG. 2. Serum sTNFR-55 in control subjects and patients with viral cirrhosis (VC) with and without osteoporosis. Data are shown as the mean ± SEM. *, P < 0.001 vs. control; {dagger}, P < 0.01 vs. VC without osteoporosis.

 


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  		FIG. 3. Urinary D-Pyr in control subjects and patients with viral cirrhosis (VC) with and without osteoporosis. Data are shown as the mean ± SEM. *, P < 0.01 vs. control; {dagger}, P < 0.02 vs. VC without osteoporosis.

 
We found a highly significant inverse correlation between BMD-LS and serum sTNFR-55 (r = –0.79; P < 0.001). We also found other significant correlations: BMD of FN and serum sTNFR-55 (r = –0.47; P < 0.05), BMD of LS and urinary D-Pyr (r = –0.6; P < 0.03), and BMD of FN and urinary D-Pyr (r = 0.57; P < 0.03). There was a strong positive correlation between serum sTNFR-55 and urinary D-Pyr (r = 0.72; P < 0.001). Serum b-AP concentrations were higher in Child B and C groups than in controls (P < 0.05 for both). For serum BGP, only Child C patients had lower values than controls (P < 0.05).

Relationship between other biochemical parameters and BMD

Table 2Go shows that Child B and C patients had significantly lower PTH and 25OHD concentrations than control subjects (P < 0.05) and Child A patients (P < 0.05). FTI and serum levels of IGF-I were significantly lower in all Child groups than in controls (P < 0.001). We found positive significant correlations between BMD-LS and serum IGF-I (r = 0.33; P < 0.05), BMD-LS and serum 25OHD (r = 0.36; P < 0.05), and BMD of FN and serum 25OHD (r = 0.37; P < 0.05). Cirrhotic patients with osteoporosis had lower serum IGF-I levels [7.2 ± 1.5 ng/ml (7.2 ± 1.5 µg/liter)] than cirrhotics without osteoporosis [12.1 ± 2.1 ng/ml (12.1 µg/liter); P < 0.05]. No significant differences were found between cirrhotic patients with osteoporosis and cirrhotic patients without osteoporosis for serum concentrations of PTH, BGP, 25OHD, and b-AP and for FTI.

Stepwise regression analysis

The results of the stepwise regression analysis determining the main predictor of LS and FN osteoporosis are shown in Table 3Go. Only variables with P < 0.05 are shown. sTNFR-55 was the most important independent variable of both LS and FN (P < 0.004).


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  		TABLE 3. Backward stepwise regression analysis defining the main predictor of osteoporosis in viral cirrhotic patients

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study shows that in male patients with viral cirrhosis, without a history of alcohol consumption, the prevalence of osteoporosis is high even in patients with well-compensated liver disease, and BMDs in the LS and FN are significantly lower than those in the reference population. These results confirm the findings of a previous report (3).

The mechanism of liver disease-associated bone mass loss is not fully understood, but several factors are likely to contribute. Diminished bone formation has been suggested to be the main factor responsible for osteoporosis in alcoholic subjects with and without liver cirrhosis (4, 5, 6, 7, 8, 9), but there are few published data on patients with viral cirrhosis without a history of alcohol consumption (3).

Several studies have shown increased serum concentrations of sTNFR-55 in the serum of patients with chronic liver disease (26, 27, 36). Our results agree with those described previously, and like others (26, 27), we found high serum sTNFR-55 levels in patients with viral cirrhosis, which were related to the severity of the liver disease. Nevertheless, as far as we know this is the first published study that has evaluated serum sTNFR-55 levels in patients with osteoporosis associated with chronic liver disease. We have found that patients with viral cirrhosis and osteoporosis had serum sTNFR-55 levels higher than patients without osteoporosis, and BMD in LS and FN was inversely correlated with serum levels of sTNFR-55. Furthermore, stepwise regression analysis showed that the serum concentration of sTNFR-55 was the major determinant of osteoporosis at both skeletal sites, LS and FN, in our patients after adjustments for the patients age, Child-Pugh score, FTI, and serum levels of 25OHD, IGF-I, PTH, BGP, and albumin. On the basis of these findings and the known effects of TNF{alpha} on bone metabolism, we suggest that circulating levels of sTNFR-55 play an important role in the development of osteoporosis in patients with viral cirrhosis.

We measured urinary D-Pyr as a biochemical marker of bone resorption, which has some advantages over other markers of osteoclastic function in patients with liver cirrhosis because it is found almost exclusively in bone and dentine, but not in human liver fibrosis. Hence, most of the D-Pyr in urine is assumed to originate from bone (37, 38, 39). One study in patients with primary biliary cirrhosis (PBC) showed that urinary D-Pyr correlated with the serum amino-terminal propeptide of type III collagen, an index of liver fibrogenesis, suggesting that D-Pyr may correlate with liver collagen metabolism (40). Nevertheless, this positive correlation could be due to an increased bone resorption in patients with PBC (41), which is related to the severity of hepatic disease (42). Thus, elevated urinary D-Pyr levels in patients with PBC might only reflect high bone turnover. In contrast with other markers of osteoclastic function, D-Pyr in the diet does not appear to be absorbed (43), this obviates the need for dietary restraints during urine collection. We found that urinary D-Pyr values were higher in patients with osteoporosis than in patients without osteoporosis. Also of importance is the fact that we found an inverse correlation between BMD and urinary D-Pyr and a strong positive correlation between urinary D-Pyr and serum sTNFR-55. These associations provide evidence of increased bone resorption related to the elevated serum sTNFR-55 concentrations found in patients with viral cirrhosis.

We found increased concentrations of serum b-AP only in patients with advanced liver disease (Child-Pugh stages B and C), which confirms the findings of a previous report (3) and may reflect higher bone formation rates in response to high rates of bone resorption. For serum BGP, only Child C patients had lower values than controls, and there was no correlation between serum BGP and serum b-AP changes, in agreement with other studies (3, 44). The lack of parallelism between serum BGP and b-AP may be a consequence of advanced liver failure or may reflect low BGP synthesis caused by low serum levels of 25OHD (45).

Bone mass loss in viral cirrhosis is probably multifactorial, and several risk factors may be involved. Changes in PTH concentrations seem to have only minor influences on the development of osteoporosis in patients with liver cirrhosis of different causes (2, 3, 4). In this study only patients with advanced liver disease had lower serum PTH levels than control subjects, and we found no differences between patients with osteoporosis and patients without osteoporosis. No correlation was found between serum PTH and BMD. Hence, its role in bone mass loss in these patients remains unclear. Serum 25OHD concentrations were decreased in Child B and Child C patients, consistent with previous findings for patients with chronic liver disease of different causes (1, 2, 3). We found a poor positive correlation between serum 25OHD and BMD, and regression analysis showed that serum 25OHD was not a predictor of osteoporosis in these patients. We suggest that low serum 25OHD concentrations can have some influence on bone mass loss in patients with viral cirrhosis.

Serum IGF-I is known to be a major determinant of BMD in healthy men (46), and decreased serum IGF-I levels have been described in idiopathic osteoporosis (47). We found low serum IGF-I concentrations in Child A, B, and C patients, which correlated with BMD in LS, but not in FN. Patients with osteoporosis had lower serum IGF-I values than patients without osteoporosis. Nevertheless, regression analysis showed that serum IGF-I was not a predictor of osteoporosis in our patients. We suggest that low serum IGF-I can play a role in the development of osteoporosis in viral cirrhosis.

Hypogonadism is a well-known risk factor for osteoporosis (48). In our study, patients with physical signs of hypogonadism were excluded. Child A, B, and C patients had lower FTI values than controls, but we have not found correlation between FTI values and BMD. There were no differences in FTI between patients with and without osteoporosis, and regression analysis showed that FTI was not a predictor of osteoporosis. Therefore, we were unable to show an independent effect of low FTI on BMD in our patients.

In our study only five patients had ascites, so we do not know the possible implications of ascites for BMD measurements.

We found that bone mass loss is more severe in trabecular bone (LS) than in cortical bone (FN), which can be explained by the fact that the rate of turnover in cortical bone is much lower than that in trabecular bone (49), and probably some risk factors for osteoporosis have lesser deleterious effects on bone with lower rates of turnover.

In conclusion, this study confirms that viral cirrhosis is a major cause of osteoporosis in humans. The pathogenesis of osteoporosis seems to be multifactorial, and we show for the first time that bone mass loss is closely related to the high serum sTNFR-55 concentrations found in these patients. Advanced liver disease and low serum levels of 25OHD and IGF-I could also be considered risk factors for osteoporosis in these patients. Our results provide evidence of increased bone resorption in viral cirrhosis associated with serum levels of sTNFR-55. High serum sTNFR-55 concentrations may therefore play a role in bone mass loss in patients with viral cirrhosis.


   Acknowledgments
 
We thank K. Shashok for checking the use of English in the manuscript.


   Footnotes
 
This work was supported by Grant FIS 01/0942 from Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Spain.

Abbreviations: AP, Bone isoenzyme alkaline phosphatase; BGP, bone Gla protein; BMD, bone mineral density; FN, femoral neck; IRMA, immunoradiometric assay; LS, lumbar spine; 25OHD, 25-hydroxyvitamin D; PBC, primary biliary cirrhosis; sTNFR-55, soluble TNF receptor p55.

Received January 16, 2004.

Accepted May 17, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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