In our study, osteopenia frequencies in cirrhotics (20%) and chronic alcoholics without liver disease (29%) were similar to controls (33%). Thus in our male cirrhotic patients liver disease did not predispose osteopenia. We suggest that the reason for the low frequency of osteopenia in the cirrhotic group was probably due to the fact that the study population consisted completely of men and the relatively low mean age of the study population, taking into consideration the late onset of the tendency for osteoporosis in men [19
]. In the present study, our male cirrhotic patients and chronic alcoholics without liver disease have normal testosterone levels in contrast to the usual expected decrease in cirrhotics [20
]. Although we did not measure, it is well known that estrogen levels in male patients with cirrhosis is increased due to reduced metabolism from the liver and increased conversion of testosterone and androstenedione to estrone and estradiol in the peripheral tissues [21
]. The possible excess estrogen in our male patients with cirrhosis in combination with proven normal serum testosterone levels may protect our cirrhotic patients from bone loss. Another factor which might have affected results of our study was the fact that healthy controls had a lesser habit of cigarette smoking and alcoholic cirrhotic patients consumed less caffeine containing food. Cigarette smoking probably increases the tendency for the development of osteoporosis, associated with its common use in alcoholics.
In our study, no significant difference was observed between cirrhotic patients with osteopenia and without osteopenia, with regards to serum cytokine levels. The normal levels of serum IL-1, IL-8, and TNF-α
in our study in cirrhotic patients with osteopenia compared to the controls indicated that these cytokines do not play a role in the pathogenesis of hepatic osteodystrophy. To our knowledge, the relationship of serum IL-8 to hepatic osteopenia has not been previously investigated. The current study is the first to report a lack of significant association between serum IL-8 and bone mineral density. The high IL-2 and IL-6 levels in our cirrhotic patients suggest that these cytokine may play a role in the pathogenesis of hepatic osteoporosis. However, no significant difference was demonstrated between cirrhotic patients with and without osteopenia with regards to IL-2 and IL-6 levels. A previously conducted in vitro
study was also demonstrated that IL-2 had no effect on osteoclasts [22
The serum levels of IL-6, IL-8, and IL-18, were reported to be increased secondary to systemic endotoxemia, in patients with alcoholic liver disease and steatohepatitis [23
]. The serum IL-6 levels of our alcoholic cirrhotic patient group were also found to be increased compared to controls and chronic alcohol user. However, there was no significant difference between alcoholic cirrhotic patients with and without osteopenia. On the other hand, chronic inflammation may show some difference in the degree of activity during the course of time. This means that an osteopenic cirrhotic patient may present with severe active hepatitis for many years and then demonstrate inactive cirrhosis during the course of the study. Serum cytokines evaluated during this period may show normal values, while bone mineral loss may be prominent despite normal cytokine levels. Cross-sectional evaluation of serum cytokine levels may have probably been obscuring a possible relationship.
In accordance with our findings, another recent study by Mitchell et al. failed to detect an association between serum cytokines IL-6 and TNFα
and bone mineral density or bone turnover and levels of IL-6 and TNF did not differ between those with and without reduced bone density [24
]. However, they found that low body mass index (BMI), increased bone turnover, and low IGF-1 were independent predictors of low spinal bone density. Despite prevalent elevations of TNFα
and IL-6, levels did not correlate with degree of bone loss. Similarly, in another study in which the osteoporosis percentages did not significantly differ between viral cirrhotics and controls, although the serum levels of sTNFR were elevated, the researchers did not find any relationship between this cytokine receptor level and bone mass [25
]. Although this study support our findings in which the osteopenia prevalences was not different from controls, they explain the possibility of absence of negative effect of TNF on bone mass as the elevated serum levels of both osteoprotegerin and serum estradiol on bone of their female patient population.
In a study conducted by Goral et al., IL-6 and TNF-α
were found to be elevated in cirrhotic patients with osteopenia compared to controls [26
]. However, the mean age of their cirrhotic patient population is about a decade older than controls. Probably when corrected for ages, maybe, Goral et al. would not find any difference between their older cirrhotic patients and younger controls. Similarly, Antonio Díez-Ruiz et al. suggested that the decrease in bone mass in their alcoholic cirrhotic patients could be related to elevated serum levels of TNF-alpha and IL-2 [27
]. On the other hand, in both of these two studies, serum osteocalcin levels as well as the IGF-1 were also found to be reduced. So, it is difficult to interpret from the results of these studies whether elevated serum levels of cytokines contribute to bone loss in cirrhotic patients.
Although our patients did not have a higher frequency of osteoporosis compared to controls, we demonstrated that osteoblastic activity was in a decreasing state. In this study, the level of osteocalcin was found to be low in viral and alcoholic cirrhotic patients, as well as in chronic alcoholic patients without cirrhosis. This finding suggested that osteoblastic activity did not decrease only in cases with liver disease, but also in chronic alcoholics without liver disease probably due to the direct toxic effect of ethanol osteoblasts [28
]. In our study, we could not detect any decrease in 25-OH vitamin D serum levels in cirrhotic patients with or without osteopenia. The normal values of serum vitamin D, phosphorus, and 24-hour urinary calcium and phosphorus levels in our patients suggested that the decreased serum calcium levels were mostly related to decreased albumin levels.
The smaller number of cirrhotic patients in our study compared to other studies was considered as a limitation of our study. In addition, collection of cross-sectional instead of longitudinal cytokine levels may also be misleading. However, selection of only male patients and the presence of a low prevalence of osteoporosis in cirrhotic patients included in the study irrespective of the disease stage demonstrated that the incidence of hepatic osteodystrophy was lower than what was previously anticipated. We also concluded that the serum cytokines IL-1, IL-2, IL-6, IL-8, and TNF-α did not play a role in the pathogenesis of hepatic osteodystrophy.