Bone loss in chronic liver diseases: Could healthy liver be a requirement for good bone health?

Abstract

Given that the liver is involved in many metabolic mechanisms, it is not surprising that chronic liver disease (CLD) could have numerous complications. Secondary osteoporosis and increased bone fragility are frequently overlooked complications in CLD patients. Previous studies implied that up to one-third of these individuals meet diagnostic criteria for osteopenia or osteoporosis. Recent publications indicated that CLD-induced bone fragility depends on the etiology, duration, and stage of liver disease. Therefore, the increased fracture risk in CLD patients puts a severe socioeconomic burden on the health system and urgently requires more effective prevention, diagnosis, and treatment measures. The pathogenesis of CLD-induced bone loss is multifactorial and still insufficiently understood, especially considering the relative impact of increased bone resorption and reduced bone formation in these individuals. It is essential to note that inconsistent findings regarding bone mineral density measurement were previously reported in these individuals. Bone mineral density is widely used as the “golden standard” in the clinical assessment of bone fragility although it is not adequate to predict individual fracture risk. Therefore, microscale bone alterations (bone microstructure, mechanical properties, and cellular indices) were analyzed in CLD individuals. These studies further support the thesis that bone strength could be compromised in CLD individuals, implying that an individualized approach to fracture risk assessment and subsequent therapy is necessary for CLD patients. However, more well-designed studies are required to solve the bone fragility puzzle in CLD patients.

Key Words: Chronic liver disease; Fracture risk; Hepatic osteodystrophy; Osteoporosis; Bone strength

Core Tip: Secondary osteoporosis and increased bone fragility are frequently overlooked complications in patients with chronic liver disease (CLD). Recent publications agree that CLD-induced bone fragility depends on the etiology, duration, and stage of liver disease, but certain ambiguities are still present. Importantly, etiopathogenetic mechanisms leading to CLD-induced bone loss are still insufficiently clarified. Given that available clinical tools for fracture risk assessment are not entirely reliable, evaluating small-length structural bone properties could improve understanding of the multifactorial nature of bone fragility in CLD patients, which could set a base for the development of more effective preventive and therapeutic strategies.

INTRODUCTION

The importance of a wide range of liver functions in the human body becomes the most visible in chronic liver disease (CLD). The most commonly known CLD complications are portal hypertension, hepatic encephalopathy, ascites, hepatorenal syndrome, variceal bleeding, and hepatocellular carcinoma[1,2]. However, CLD is also associated with changes in the skeleton, previously known as hepatic osteodystrophy[3,4]. Among CLD patients, substantial heterogeneity of skeletal changes was noted depending on the etiology, duration, and stage of the liver disorder[5,6]. Namely, osteoporosis was initially described as a complication of primary biliary cholangitis and primary biliary cirrhosis (cholestatic liver diseases)[7], while skeletal changes were later described in other (non-cholestatic) hepatic disorders as well[8,9]. It has been reported that approximately every second patient with viral hepatitis, hemochromatosis, and Wilson’s disease has osteoporosis or osteopenia[10-12], while up to 55% of patients with alcoholic liver cirrhosis have osteoporotic bone changes[3,13,14]. Interestingly, bone alterations in nonalcoholic fatty liver disease or nonalcoholic steatohepatitis have recently drawn researchers’ attention, revealing that up to one-third of these individuals could develop bone alterations[15,16].

Consequently, CLD individuals are at substantial risk for non-traumatic bone fractures[17-19], with a prevalence between 7% and 35%[20]. Recent data suggest that fracture incidence is two to three times higher in end-stage CLD patients compared to healthy controls[19,21], while others reported an eight-fold increase in the risk of bone fractures in these patients[22]. Regarding fracture localization, data suggest that vertebral fractures are most common in patients with end-stage CLD[19,23-26], given that more than one-third of these individuals experienced at least one vertebral fracture during their lifetime[8,23,27]. Moreover, CLD contributes to the age-associated increase in the risk of femoral fracture and subsequently its life-threatening complications[22]. It is important to emphasize that end-stage CLD patients are experiencing fragility fractures at a significantly younger age than most osteoporotic patients[22], considering that the cumulative fracture risk in CLD patients younger than 45 years corresponds to the risk of healthy controls over 75 years of age[22]. It is important to emphasize that CLD likely changes the sex distribution of fracture risk in the aged population, considering that CLD is more frequent in male patients[28], while osteoporosis and osteoporosis-related bone fractures are more likely to develop in older women[29].

Despite the significant number of studies that have assessed various characteristics of bone deterioration in CLD individuals, many unknowns should be elucidated to understand this topic entirely.

OSTEODENSITOMETRY FINDINGS IN CLD PATIENTS

Most studies dealing with bone changes in CLD patients used dual-energy X-ray absorptiometry as the most valuable tool in the clinical assessment of fracture risk[30]. Interestingly, opposite results were yielded. Namely, dual-energy X-ray absorptiometry assessment revealed significantly lower bone mineral density (BMD) in patients with viral, autoimmune, and primary biliary cirrhosis[31-33]. At the same time, other authors failed to show a significant BMD decrease in CLD of the same etiology[34,35]. Multiple studies showed reduced dual-energy X-ray absorptiometry-obtained BMD values, suggesting osteopenia or osteoporotic changes of the lumbar spine and femoral neck in patients with alcohol-induced CLDs[36-38], while other research teams failed to show these bone alterations in individuals prone to chronic alcohol abuse[17,39,40]. Given that the primary source of these contradictory data could be in the study design (cross-sectional study design), selection criteria, and the number of participants included in the study, future well-designed prospective studies are required to fully understand BMD alterations in CLD patients.

BONE TURNOVER BIOMARKERS IN PATIENTS WITH CLD

As a non-invasive and cost-effective tool for indirect assessment of bone remodeling dynamics, bone turnover biomarkers (BTMs) are a complementary method in the clinical management and follow-up of the treatment effects in patients with osteoporosis and osteoporosis-related bone fragility[41]. Automated or manual immunoassays using blood or urine samples are utilized to measure a specific combination of these protein or protein-derivative biomarkers[42], which are considered indicative of the dynamic relationship between osteoblast activity (bone formation markers) and osteoclast activity (bone resorption markers)[41,43]. The most frequently investigated bone formation markers are osteocalcin, bone alkaline phosphatase, and N-propeptide of type I collagen[41]. On the other side, commonly interpreted bone resorption markers are C-terminal and N-terminal telopeptides of type I collagen, deoxypyridinoline, and tartrate-resistant acid phosphatase isoform 5b[41] (Figure 1).

Figure 1 Schematic representation of the most frequently analyzed bone turnover markers. The emphasis is placed on the difference between bone turnover markers released by catabolic osteoclast activity (bone resorption markers) and anabolic osteoblast activity (bone formation markers).

The interpretation of BTM levels has been of clinical utility in age-related osteoporosis[43], while its role in the clinical management of CLD-induced bone loss is still modest. Some data suggest that serum levels of osteocalcin and bone alkaline phosphatase are decreased in individuals with CLD[25,36,44], while others failed to show significant differences between individuals with CLD and the control group[45,46]. Moreover, contradictory data regarding the level of β-CTX and deoxypyridinoline were noted in CLD patients[36,45,47,48]. It is important to note that liver dysfunction could affect serum concentrations of BTMs, which reveals excessive bone matrix degradation, indicating that its assessment allows only limited conclusions in CLD individuals[10,49]. Multiple limitations of BTM assessment are among the reasons why CLD-induced bone changes are recognized and treated after a patient experiences non-traumatic fracture[10], suggesting that further investigation is required to elucidate the role of BTMs in developing novel, adequate preventive and treatment strategies.

ASSESSMENTS OF MICROSCALE BONE PROPERTIES IN CLD INDIVIDUALS

The World Health Organization recommended BMD as the primary parameter for the diagnosis of osteopenia and osteoporosis and for clinical fracture risk assessment[50]. However, considering that the occurrence of fragility fractures primarily requires the action of several bone strength determinants and their mutual interaction, it is evident that increased bone fragility could not be solely explained by BMD decrease[51,52]. In other words, low BMD should only be considered an applicable and non-invasive clinical surrogate marker of bone fragility[52,53]. Namely, it has been known that only up to one-third of non-traumatic fractures are attributable to low BMD values, indicating that many individuals with bone fractures have BMD in the referent range[54].

Moreover, various bone properties are recognized as important determinants affecting bone strength (ability to resist fracture)[55]. Thus, current studies suggested that multiscale analysis of various bone properties (with respect to the hierarchical structure of the bone, Figure 2) could contribute to a better understanding of increased bone fragility in elderly individuals with chronic comorbidities, including a variety of CLDs[56]. The importance of assessing these bone properties is highlighted by the fact that some pharmaceutical agents were proven to improve bone strength and reduce fracture risk without increasing BMD[57,58], indicating the potential for developing new and effective treatment strategies[52].

Figure 2 Multiscale approach in the assessment of bone strength determinants. The importance of the various bone properties that contributes to increased bone fragility, and up-to-date methodologies are used to assess these bone strength determinants. The emphasis is placed on the difference between factors that were previously assessed and those factors that require further investigation in patients with chronic liver disease. CLD: Chronic liver disease.

Initially, histomorphometry studies using optic microscopy assessment of iliac bone biopsies showed deteriorated trabecular bone architecture in CLD patients[59,60]. In addition, some novel clinical studies confirmed these results on the tibia and radius of CLD patients, using a newer methodology called peripheral quantitative computed tomography[33,61,62]. Since osteoporosis is not uniform throughout the skeleton[63] it was crucial to assess CLD-induced microstructural decline in lumbar vertebrae and proximal femora[38,64]. Similarly to previous findings, our research group used microcomputed tomography with an isotropic resolution of 10 µm to observe impaired microarchitectural integrity of lumbar vertebrae and proximal femora collected from CLD individuals[9,38,64]. On the trace of altered trabecular and cortical microarchitecture, we demonstrated reduced mechanical bone competence in these individuals[38,65], indicating that altered bone matrix content could be involved in CLD-induced bone fragility.

Future state-of-the-art studies should focus on a precise nanoscale morphostructural estimate of the inorganic (mineral) and organic component of the bone extracellular matrix (collagen fibers) to elucidate its role in increased bone fragility among CLD individuals (Figure 2). Finally, the long-term benefit of small-length bone studies could develop a specific diagnostic algorithm that will help to reliably predict bone strength based on the information available in the clinical context of each patient.

THE MOLECULAR MECHANISMS INVOLVED IN ETIOPATHOGENESIS OF CLD-INDUCED BONE LOSS

Bone loss in CLD patients is commonly described as a consequence of bone remodeling disturbance[8], but the particular contribution of increased bone resorption and decreased bone formation still needs to be thoroughly explained. Nowadays, a common understanding is that the etiopathogenetic mechanisms of bone loss are dependable on the etiology of liver disease[3,8]. Previous data revealed that osteoblast dysfunction and decreased bone formation play a central role in the etiopathogenesis of bone loss in patients with cholestatic liver disease, Wilson’s disease, and hemochromatosis[7,12,48,66]. Conversely, viral CLD displays a more dominant effect on increased osteoclast activity, inducing high-turnover osteoporosis[21,32,67].

On a molecular level, low-turnover osteoporosis in CLD patients is commonly associated with toxic effects of biliary stasis and copper/iron accumulation on differentiation, maturation, and proliferation of osteoblasts (Figure 3)[68-70]. Also, previous studies suggested that osteoblast dysfunction in patients with cholestatic forms of CLD could be mediated by insulin growth factor-1 or oncofetal fibronectin[66,70,71], while direct toxic effects of alcohol on osteoblastic function contribute to bone loss among patients within alcohol-induced CLD[72,73]. During the process of bone formation, osteoblasts become embedded within the bone matrix, continuing to function as bone remodeling orchestrators or osteocytes[74]. Osteocytes form a global network throughout the bone tissue by intercellular channels (gap junctions), most frequently formed by connexin 43[75]. Reduction in osteocytic expression levels of connexin 43 and minor disruptions in the osteocyte lacunar network was noted in CLD individuals (Figure 3), suggesting that the mechanosensing potential and molecular transduction might be defective in those patients with CLD[65,76]. In addition, increased bone expression levels of sclerostin (an osteocyte-derived negative regulator of bone formation) were noted in CLD individuals[65,76], which was in accordance with previous clinical studies[77,78]. These data indicate that treatment targeting sclerostin may be an interesting strategy to fight osteoporosis in CLD patients[10]. Still, possible therapeutical utilities in CLD patients are yet to be thoroughly investigated in the years ahead.

Figure 3 Schematic representation of possible pathophysiological mechanisms leading to bone loss in chronic liver disease patients. The role of multiple factors leading to bone loss and osteoporosis in individuals with chronic liver disease places an emphasis on the difference between factors that cause osteoblast dysfunction (reduced bone formation) and factors that stimulate osteoclast activity (increased bone resorption). Green arrows indicate an activating effect, while red arrows indicate a deactivating effect. c-fms: Colony-stimulating factor-1 receptor; Cx43: Connexin 43; IGF-1: Insulin-like growth factor 1; IL: Interleukin; LRP5/6: Low-density lipoprotein receptor-related protein 5/6; M-CSF1: Macrophage colony-stimulating factor 1; MMPs: Matrix metalloproteinases; OC: Osteocalcin; OPG: Osteoprotegerin; PTH: Parathyroid hormone; RANK: Receptor activator for nuclear factor kappa B; RANKL: Receptor activator for nuclear factor kappa B ligand; TNF: Tumor necrosis factor.

Previous studies revealed that bone loss in CLD individuals could be explained by a strong link between systemic hyperproduction of inflammatory mediators and increased bone resorption (Figure 3)[21,32,67]. Most commonly, it is understood that tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-7, IL-11, IL-13, IL-15, and IL-17, produced by immune cells, could directly activate osteoclast precursors or display an indirect effect by osteoblasts[8,10,72]. Namely, increased secretion of receptor activator for nuclear factor kappa B ligand (RANKL), the disturbed ratio between RANKL and osteoprotegerin, matrix metalloproteinases activity, and cathepsin K are described as contributing factors in CLD-induced bone loss via increased bone resorption (Figure 3)[10,79-81]. The recent recommendation for therapy targeting RANKL advocates the importance of the RANK-RANKL-osteoprotegerin system in bone loss among CLD patients[20,82]. In addition, increased circulating macrophage colony-stimulating factor 1 in CLD patients could promote bone resorption due to its role in priming a larger number of monocytes to form osteoclasts in these patients[6].

Lastly, low vitamin D levels, unbalanced diet (low calcium and protein intake), malabsorption, disruption in the homeostasis of the intestinal microbiome, coupled with a variety of hormonal and metabolic disruptions (such as increased levels of parathyroid hormone, hypogonadism, and hypercorticism) were identified as factors that contribute to bone loss in CLD individuals[20,72,83]. Based on these data, new nutritional support guidelines were recently introduced by the European Association for the Study of the Liver[20,84]. However, given that bone changes in CLD patients are undoubtedly present, it is vital to further investigate more direct etiopathogenetic mechanisms involved in the relationship between liver and bone disorders.

CONCLUSION

Bone alterations are a common complication in patients with CLD, especially in those with liver cirrhosis. Over the previous period, numerous studies have contributed to understanding bone fragility in CLD patients. However, numerous ambiguities are still present due to the modest reliability of clinical diagnostic methods, which could lead clinicians to doubt whether or when it is necessary to start treating CLD-induced skeletal alterations. Thus, evaluating small-length structural bone properties could improve understanding of the multifactorial nature of bone fragility in CLD patients. All these data could set a base for developing a patient-specific diagnostic algorithm that will reliably predict bone strength based on the information available in a clinical context. Additionally, specific clinical guidelines for preventing, diagnosing, and treating skeletal disorders in patients with CLD need to be established in the near future.