Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis

Abstract

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

Keywords: CKD-MBD; RANKL (receptor activator for nuclear factor k B ligand); Wnt; adynamic bone disease; osteoporosis; parathyroid hormone; renal osteodystrophy; sclerostin.

FIGURE 1

Summary diagram of biochemical and skeletal abnormalies in CKD. Sclerostin rises from very early stages of CKD with TGF-β, uremic toxins, and inflammatory cytokines as main known stimuli. Elevated FG23, in the presence of sKlotho, increases the expression of Dkk1, a Wnt inhibitor; consequently, Wnt-β catenin signaling remains suppressed during the course of CKD. FGF23 decreases the levels of calcitriol, resulting in a stimulus for PTH synthesis and secretion which, on the other hand, decreases the effects of sclerostin. TGF-β, transforming growth factor beta; FGF-23, fibroblast growth factor-23; Vit D, vitamin D; DKK1, Dickkopf 1; PTH, parathyroid hormone; P phosphorus; Ca calcium.

FIGURE 2

Dual effect of PTH on bone (formation and resorption). Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the PTH/PTHrP type 1 receptor (PTH1R) with similar effects. This G protein-coupled receptor generates a dissociation of the α subunit. The most studied is the αs subunit and its main effector is adenylyl cyclase, which catalyzes the synthesis of the second messenger cyclic adenosine monophosphate (cAMP), which activates the cAMP-dependent protein kinase (PKA) pathway, phosphorylating several proteins that have diverse effects on bone and that we describe below: phosphorylation of cAMP response element-binding protein (CREB), increasing the expression of osteoblast-specific genes such as Runx 2, Osteocalcin and matrix metalloproteinase; stimulation of the Wnt-signaling pathway Wnt by means of the low-density lipoprotein receptor-related protein 6 (LRP6); phosphorylation and stabilization of β-catenin, suppression of Dickkopf 1 (DKK1) and glycogen synthase kinase 3 beta (GSK3β). Both are Wnt inhibitors, leading to the stimulation of the Wnt/B-catenin signaling pathway. All the aforementioned actions of PTH represent stimuli for bone formation (osteoanabolic effect). On the other hand, PTH in osteoblasts and osteocytes stimulates the production of receptor activator of nuclear factor Kβ ligand (RANKL) and decreases the production of osteoprotegerin (OPG), generating osteoclastogenesis and thereby stimulating bone resorption. In osteocytes, PTH suppresses the expression of sclerostin and this stimulates the Wnt/B-catenin signaling pathway, stimulating bone formation. PTH in osteocytes also stimulates the expression of nuclear receptor-related 1 protein (Nurr1), leading to an increase in the production of fibroblast growth factor-23 (FGF-23). PTH1R, in addition to coupling to αs, can also couple to αq/11, which activates the phospholipase C (PLC) by catalyzing the synthesis of its second messengers, inositol 1,4,5-trisphosphate (IP3); and diacylglycerol (DAG). In turn, PTH increases intracellular Ca2+ and activates protein kinase C (PKC) isozymes, PLC–PKC signaling pathway which is essential for osteoblast proliferation and for bone modeling and remodeling. Adapted from M. Bastepe, S. Turan and Q He (J Molec Endocrinol 2017; 58, R203-224).

FIGURE 3

Schematic representation of the Wnt-ß-catenin signalling pathway. (A) Activation of the intracellular cascade depending on the union between Wnt protein and its receptors. (B) Inhibition of Wnt signaling by its antagonists, blocking the union between Wnt protein and its receptors. Wnt: Wnt protein; Fz: frizzled; LRP5: low-density lipoprotein receptor (LDLR)-related protein 5 or LRP6; GSK-3b: glycogen synthetase kinase 3; APC: tumor suppressor adenomatous polyposis coli; Lef-1: Tcf/lymphoid enhancer-binding factor; Sfrp: secreted Fz-related-proteins; Scl: Sclerostin; Dkk1: dickkopf–related protein 1. Adapted from [Guañabens N, Curr Osteoporos Rep 2014].