Hepatic Osteodystrophy-Molecular Mechanisms Proposed to Favor Its Development

Abstract

Almost all patients with chronic liver diseases (CLD) show altered bone metabolism. Depending on the etiology, this manifests in a severe osteoporosis in up to 75% of the affected patients. Due to high prevalence, the generic term hepatic osteodystrophy (HOD) evolved, describing altered bone metabolism, decreased bone mineral density, and deterioration of bone structure in patients with CLD. Once developed, HOD is difficult to treat and increases the risk of fragility fractures. Existing fractures affect the quality of life and, more importantly, long-term prognosis of these patients, which presents with increased mortality. Thus, special care is required to support the healing process. However, for early diagnosis (reduce fracture risk) and development of adequate treatment strategies (support healing of existing fractures), it is essential to understand the underlying mechanisms that link disturbed liver function with this bone phenotype. In the present review, we summarize proposed molecular mechanisms favoring the development of HOD and compromising the healing of associated fractures, including alterations in vitamin D metabolism and action, disbalances in transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signaling with histone deacetylases (HDACs) as secondary regulators, as well as alterations in the receptor activator of nuclear factor kappa B ligand (RANKL)-osteoprotegerin (OPG) system mediated by sclerostin. Based on these mechanisms, we give an overview on the limitations of early diagnosis of HOD with established serum markers.

Keywords: bone metabolism; bone morphogenetic proteins (BMPs); hepatic osteodystrophy; histone deacetylases (HDACs); liver disease; osteopenia; osteoporosis; sclerostin; transforming growth factor beta (TGF-β); vitamin D metabolism.

Figure 1

Established serum markers for bone turnover in the context of (A) healthy liver and (B) diseased liver. Bone resorption markers: tartrate-resistant acid phosphatase isoform 5b (TRAP5b), matrix metalloproteinase isoforms 2, 9, 13, and 14 (MMPs), cathepsin K (CTSK), pyridinolin (PYD), desoxypyridinolin (DPD), helical peptide, type I collagen cross-linked C-telopeptide (ICTP), and C- and N-telopeptide crosslinks of type I collagen (CTX and NTX). Regulators of osteoclastogenesis: receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG). Bone formation markers: osteocalcin (OC) bone sialoprotein (BSP), osteopontin (OP), bone-specific alkaline phosphatase (BAP), hydroxyprolin (HYP), and type I collagen N- and C-terminal propeptides (PINP and PICP/CICP). Marker for liver/tissue damage: alkaline phosphatase (AP). Dotted arrows indicate expression. Red arrows indicate altered expression (up or down) in CLD.

Figure 2

Vitamin D (VitD) metabolism in the context of (A) healthy liver and (B) diseased liver. In the presence of ultraviolet B (UVB) irradiation and heat, 7-dehydrocholesterol (7-DHC) is processed to VitD in the skin. VitD is sequentially hydroxylated in the liver and the kidneys to its metabolites calcidiol (25(OH)D), calcitriol (1,25(OH)D), 24,25-dihydroxyvitamin D (24,25(OH)D), and 1,24,25-trihydroxy-vitamin D (1,24,25(OH)D). Enzymes involved in VitD metabolism: 7-dehydrocholesterol reductase (DHCR7), vitamin D 25-hydroxylase (CYP2R1), sterol 27-hydroxylase (CYP27A1), 25-hydroxyvitamin D 1-hydroxylase (CYP27B1), and 25-hydroxyvitamin D 24-hydroxylase (CYP24A1). VitD and its metabolites bind to the vitamin-D-binding protein GC (DBP) for transport in the blood. Other regulators: calcium (Ca²⁺), inorganic phosphate (Pi), fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH). Dotted arrows indicate expression. Red arrows indicate altered expression (up or down) in CLD.

Figure 3

Effects of transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) on bone in the context of (A) healthy liver and (B) diseased liver. Dotted arrows indicate expression. Red arrows indicate altered expression (up or down) in CLD.

Figure 4

Sclerostin as a possible regulator in the development of hepatic osteodystrophy (HOD). (A) Sclerostin serum levels were determined with the help of Sclerostin TECO^® ELISA (TECOmedical group, Neufahrn, Germany) in patients with healthy and diseased livers. (B) Receiver operating characteristic (ROC) curve with sclerostin as a marker for HOD. (C) Expression of SOST in healthy and diseased liver tissues. N ≥ 22, n = 2; statistical comparison with the Mann–Whitney U-test. Proposed regulatory mechanisms in the context of (D) healthy and (E) diseased liver. Dotted arrows indicate expression. Red arrows indicate altered expression (up or down) in CLD.