INTRODUCTION

Solid organ transplantation is an effective alternative in the final stage of multiple chronic diseases, increasing patients´ survival. However, this improvement is associated with certain complications, such as a higher incidence of osteoporosis and an increased risk of fractures¹. Numerous studies have concluded that there is a loss of bone mass after transplantation, more marked between the first three and six months, which lasts up to a year after the same. Subsequently there is a stabilization and even recovery of bone mass in the two subsequent years^2-4.

Liver transplantation is considered an independent risk factor in the development of osteoporosis^1-3. In the case of patients with a liver graft, the incidence of fracture is estimated at 10-43%¹, with the spine location being the most frequent^2-4. Among the factors that contribute to the increased risk of osteoporosis and fractures in these patients are: prolonged treatment with immunosuppressants (mainly calcineurin inhibitors)^2,5-8 and glucocorticoids^9,10, vitamin D deficiency (very common due to malnutrition) and alterations in liver function found in most patients with cirrhosis^1-3.

The biochemical markers of bone remodeling offer information based on the dynamic prediction of the same, its accepted clinical application being the evaluation of the therapeutic response with antiresorptives^11,12 and its potential relationship with the risk of fracture. However, at present, there is no consensus regarding the determination of biochemical markers of bone remodeling in patients with liver transplantation³. Sclerostin (SOST) is a protein synthesized by the osteocyte that plays a central role in the regulation of bone remodeling, since it simultaneously acts as a negative regulator of bone formation and stimulates bone resorption through the RANK-ligand¹³. Its usefulness as a biochemical marker of bone remodeling, particularly in liver transplant patients, has not been established.

Thus, our study aims to assess the development of sclerostin levels in patients with liver transplantation, and investigate their relationship with other markers of bone remodeling.

PATIENTS AND METHODS

RESULTS

A total of 83 patients receiving a liver transplant (56 males and 27 females) were included in the study. The average age of the patients was 56.2±10.4 years. The group's average weight was 72.1±18.7 kg and its BMI was 27.7±7.5 kg/m².

Evolution of markers of bone remodeling

The basal levels of SOST were 0.76±0.35 ng/ml and decreased significantly early (0.55±0.22 ng/ml in the first month, p=0.034), a trend that was maintained until the end of the study. of the study (0.62±0.22 ng/ml, p=0.047) (Table 1). There were no significant differences between both sexes in the evolution of the aforementioned marker. The SOST levels did not correlate with the development of fractures. On the contrary, OC levels (17±10.35 ng/ml) showed a progressive and significant increase from the 3rd month after transplantation (31.85±26 ng/ml, p<0.01), which it was maintained until the end of the follow-up period (37.27±26.84 ng/ml, p<0.01). In both sexes, the evolution of OC levels was similar.

In relation to CTX, the levels prior to transplantation were 0.44±0.35 ng/ml. One month after transplantation, a significant increase was observed (0.81±0.47 ng/ml, p<0.01) that persisted until 6 months (0.62±0.34 ng/ml, p<0.01) compared to basal level. At 12 months, there was a marked decrease in CTX towards the value before transplantation (0.47±0.31 ng/ml, p=0.2). There were no differences regarding CTX development between both sexes but, since the third month, the group of women had significantly higher levels than men (0.94±0.62 ng/ml and 0.61±0,34 ng/ml, respectively, p<0.01). The levels of PA presented discrete variations throughout the study, without showing significant changes in any of the determinations (Table 1), nor differences between sexes.

Table 1. Development of sclerostin and the rest of the markers of bone remodeling throughout the study (mean ± standard deviation) 

OC: osteocalcin; AP: alkaline phosphatase; CTX: β-crosslaps; SOST: sclerostin.

There were no statistically significant correlations between the different markers of bone metabolism in the study.

DISCUSSION

In recent years it has been proposed that SOST, glycoprotein of 213 amino acids secreted by the osteocyte, and that produces an inhibition of bone formation by suppressing the Wnt/β-catenin intracellular signaling pathway, could be a biomarker of central importance in the evaluation of bone remodeling¹⁶. However, there is little information about SOST levels after a solid organ transplant, although patients undergoing this procedure suffer osteoporosis very often and, in particular, vertebral fractures. Thus, in a study carried out on bone biopsies of patients undergoing different types of transplantation (kidney, liver, heart), an increase in SOST expression evaluated by immunohistochemistry has been described¹⁷.

In the present observational prospective study, the evolution of the levels of sclerostin (SOST) and other markers of bone remodeling during 12 months after a liver transplant was evaluated. Our results show a significant decrease in the serum levels of SOST, as opposed to an increase in the rest of remodeling markers (OC and CTX).

These results are similar to those described in patients with kidney transplantation, in whom a marked decrease (30-60%) in serum levels of SOST after transplantation is observed¹⁸,¹⁹, especially in the first 2 months after the intervention. In our study the most marked decrease also occurs in the first month. Until now, it has not been possible to establish a relationship between the levels of SOST in patients with kidney transplants and the risk of fractures or cardiovascular events, although it does occur with the presence of vascular calcifications²⁰.

In renal transplantation, one of the main factors that justify the initial reduction of SOST could be an increased loss of urine due to tubular dysfunction due to overload, typical of the initial period after transplantation²¹. In the case of the liver, previous studies have shown that in certain diseases that may require transplant, such as primary biliary cirrhosis, patients had increased sclerostin levels²². Among the possible factors that would justify the initial decrease in SOST could be the imporved pro-inflammatory situation after surgery and immunosuppression.

Regarding inflammation, in our study CRP levels were basally elevated and decreased significantly throughout the year (although there was no correlation between the value of SOST and that of CRP). However, in the literature there are examples in which the possible relationship between SOST and inflammation has not been confirmed. Thus, in a previous study in patients with rheumatoid arthritis treated with TNF inhibitors (tumor necrosis factor) no effect of anti-inflammatory treatment on the levels of SOST was evidenced²³.

The decrease in SOST observed in the patients of our study could be one of the causes that justifies the improvement in mineral metabolism after the intervention, just as it has been considered in patients undergoing a kidney transplant18,19. One of the proposed hypotheses is that the changes in the SOST would reflect the optimization of osteocyte function after transplantation²⁴.

In a study previously carried out in kidney transplant patients, men had a similar SOST level than women before surgery¹⁷. Similarly, in our study we did not observe any difference between SOST serum concentrations in both sexes, neither at the beginning of the study nor during the follow-up.

Regarding the rest of the bone remodeling markers, in our study we observed an increase in markers of bone formation (OC), as well as those of bone resorption (CTX). These results are consistent with those already presented in the literature, after liver transplantation25. Recently, an increase in CTX and N-terminal propeptide of type I procollagen (P1NP) was observed 6 months after liver transplantation²⁵. These results, similar to those of our group, seem to confirm the existence of a high bone remodeling in patients undergoing a transplant. In this context, it is worth highlighting the influence of steroids (as part of the treatment after transplantation), favoring resorption and suppressing bone formation, especially during the first six months after surgery⁹,¹⁰.

In addition to the determination of bone remodeling markers, in our study a high 25 (OH) D deficiency rate prior to transplantation (82.1%) was also confirmed. After adequate supplementation, a significant improvement in 25 (OH) D levels was observed, until the mean value was placed in the insufficiency range. In parallel, slightly elevated levels of PTH were observed (in a probable context of hyperparathyroidism secondary to vitamin D deficiency) before surgery, with normalization at 12 months, after improvement in the 25 (OH) D figures. There are multiple factors that influence the insufficient levels of 25 (OH) D prior to transplantation: proinflammatory state, higher prevalence of malnutrition, loss of liver contribution by hydroxylation of its precursor, etc.3 Several previous studies have reported high rates of 25 (OH) D deficiency, although not as high as those shown in our cohort. Thus, in a group of patients undergoing liver transplantation, a deficiency rate of 25 (OH)D of 37% was observed, improved at 6 months, with a deficiency rate of 17%²⁵.

Our study presents several strengths. First, its optimal sample size (n=83) and the fact that this is a longitudinal and prospective study. Finally, it is the first study that includes SOST determination after liver transplantation. Despite this, the study has certain limitations. Bone mineral density was not evaluated, nor the etiology of the liver disease that motivated the transplant. On the other hand, the low number of fractures observed does not allow us to draw conclusions about the real impact of these changes on the risk of post-transplant osteoporosis²⁶.

In summary, our results show a decrease in SOST levels after liver transplantation, which goes in the opposite direction to the variations observed in other remodeling markers such as CTX and OC.

Deficiency of 25 (OH) vitamin D pre-transplant is high and improves after supplementation. More studies are needed to determine if these changes have a significant impact on the occurrence of osteoporosis or longterm cardiovascular disease in patients undergoing transplantation.