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.

Keywords: Bone strength; Chronic liver disease; Fracture risk; Hepatic osteodystrophy; Osteoporosis.

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).

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.

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.