Liver-bone crosstalk in non-alcoholic fatty liver disease: Clinical implications and underlying pathophysiology

Abstract

Osteoporosis is a common complication of many types of chronic liver diseases (CLDs), such as cholestatic liver disease, viral hepatitis, and alcoholic liver disease. Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic liver disease, affecting almost one third of adults around the world, and is emerging as the dominant cause of CLDs. Liver serves as a hub for nutrient and energy metabolism in the body, and its crosstalk with other tissues, such as adipose tissue, heart, and brain, has been well recognized. However, much less is known about the crosstalk that occurs between the liver and bone. Moreover, the mechanisms by which CLDs increase the risk for osteoporosis remain unclear. This review summarizes the latest research on the liver–bone axis and discusses the relationship between NAFLD and osteoporosis. We cover key signaling molecules secreted by liver, such as insulin-like growth factor-1 (IGF-1), fibroblast growth factor 21 (FGF21), insulin-like growth factor binding protein 1 (IGFBP1), fetuin-A, tumor necrosis factor-alpha (TNF-α), and osteopontin (OPN), and their relevance to the homeostasis of bone metabolism. Finally, we consider the disordered liver metabolism that occurs in patients with NAFLD and how this disrupts signaling to the bone, thereby perturbing the balance between osteoclasts and osteoblasts and leading to osteoporosis or hepatic osteodystrophy (HOD).

Anti-osteoporotic treatments in the era of non-alcoholic fatty liver disease: friend or foe

“…Moreover, Dichtel et al showed that decreased IGF-1 levels were correlated with higher histological severity of NAFLD (60). Decreased IGF-1 have been reported in both patients with osteoporosis and NAFLD, indicating the important role of IGF-1 in the liver-bone axis (58).…”

“…Insulin-like growth factor-1 (IGF-1) is mainly secreted by the liver while is also locally produced in small amounts by bones, affecting positively bone remodeling (58). Yao et al in their metanalysis demonstrated that IGF-1 levels were decreased in patients with NAFLD compared to healthy controls (59).…”

The associations of alcoholic liver disease and nonalcoholic fatty liver disease with bone mineral density and the mediation of serum 25-Hydroxyvitamin D: A bidirectional and two-step Mendelian randomization

“…The liver is the metabolic center involving not only in the metabolism of micro- and macro-nutrients (glucose, fat, protein, vitamins) nourishing the bones but also the synthesis of a variety of signaling molecules such as cytokines and enzymes into the circulation to modulate the metabolism and function of the bones [ 4 ]. Patients with chronic liver disease may experience abnormal metabolic changes in bones, known as hepatic osteodystrophy commonly manifested as decreased BMD and osteoporosis [ 5 , 6 ]. Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major types of chronic liver diseases marked by a variety of abnormalities in the liver, including fatty liver disease, liver fibrosis, and cirrhosis [ 7 ].…”