TYPE Mini Review PUBLISHED 05 June 2023 DOI 10.3389/fphys.2023.1177829 Pathophysiology of bone disease OPEN ACCESS in chronic kidney disease: from EDITED BY Juan Miguel Díaz Tocados, Lleida Institute for Biomedical Research basics to renal osteodystrophy (IRBLleida), Spain REVIEWED BY and osteoporosis Eleanor DeLand Lederer, University of Texas Southwestern Medical Center, United States Armando Aguilar 1,2†, Laia Gifre 3†, Pablo Ureña-Torres 4, *CORRESPONDENCE Natalia Carrillo-López 5, Minerva Rodriguez-García 6, Jordi Bover, Elisabeth Massó 7,8, Iara da Silva 7,8, Víctor López-Báez 7,8, Jbover.ics@gencat.cat † Maya Sánchez-Bayá 7,8, Águeda Prior-Español 3, Marina Urrutia 7,8, These authors have contributed equally to this work Javier Paul 7,8, Misael C. Bustos 9, Anna Vila 7,8, Isa Garnica-León 2, RECEIVED 02 March 2023 Juan F. Navarro-González 10,11, Lourdes Mateo 3 and ACCEPTED 23 May 2023 PUBLISHED 05 June 2023 Jordi Bover 7,8* 1 CITATION Autonomous University of Chiapas, Tuxtla Gutiérrez, Mexico, 2Department of Nephrology, Mexican Aguilar A, Gifre L, Ureña-Torres P, Social Security, IMSS General Hospital of Zone No 2, Tuxtla Gutiérrez, Mexico, 3Department of Carrillo-López N, Rodriguez-García M, Rheumatology, Hospital Germans Trias i Pujol, Badalona (Barcelona), Catalonia, Spain, 4AURA Saint Ouen, Massó E, da Silva I, López-Báez V, Department of Nephrology and Dialysis and Department of Renal Physiology, Necker Hospital, University Sánchez-Bayá M, Prior-Español Á, of Paris Descartes, Paris, France, 5Bone and Mineral Research Unit, Instituto de Investigación Sanitaria del Urrutia M, Paul J, Bustos MC, Vila A, Principado de Asturias (ISPA), Oviedo, Asturias, Spain, 6Nephrology Clinical Management Unit, Central Garnica-León I, Navarro-González JF, University Hospital of Asturias (HUCA), Oviedo, Asturias, Spain, 7Department of Nephrology, University Mateo L and Bover J (2023), Hospital Germans Trias i Pujol (HGiTP), Badalona (Barcelona), Catalonia, Spain, 8REMAR-IGTP Group, Pathophysiology of bone disease in Research Institute Germans Trias i Pujol, Can Ruti Campus, Badalona (Barcelona), Catalonia, Spain, 9 chronic kidney disease: from basics to Department of Nephrology, Pontificia Catholic University of Chile, Santiago, Chile, 10Research Unit and renal osteodystrophy and osteoporosis. Nephrology Service, University Hospital of Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Islas Front. Physiol. 14:1177829. Canarias, Spain, 11Instituto de Tecnologías Biomédicas, Universidad de la Laguna, Islas Canarias, Spain doi: 10.3389/fphys.2023.1177829 COPYRIGHT © 2023 Aguilar, Gifre, Ureña-Torres, Carrillo-López, Rodriguez-García, Massó, da Silva, López-Báez, Sánchez-Bayá, Chronic kidney disease (CKD) is a highly prevalent disease that has become a Prior-Español, Urrutia, Paul, Bustos, Vila, public health problem. Progression of CKD is associated with serious Garnica-León, Navarro-González, Mateo complications, including the systemic CKD-mineral and bone disorder (CKD- and Bover. This is an open-access article distributed under the terms of the MBD). Laboratory, bone and vascular abnormalities define this condition, and all Creative Commons Attribution License have been independently related to cardiovascular disease and high mortality (CC BY). The use, distribution or rates. The “old” cross-talk between kidney and bone (classically known as “renal reproduction in other forums is permitted, provided the original author(s) osteodystrophies”) has been recently expanded to the cardiovascular system, and the copyright owner(s) are credited emphasizing the importance of the bone component of CKD-MBD. Moreover, a and that the original publication in this recently recognized higher susceptibility of patients with CKD to falls and bone journal is cited, in accordance with accepted academic practice. No use, fractures led to important paradigm changes in the new CKD-MBD guidelines. distribution or reproduction is permitted Evaluation of bone mineral density and the diagnosis of “osteoporosis” emerges in which does not comply with these terms. 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. Frontiers in Physiology 01 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 KEYWORDS CKD-MBD, renal osteodystrophy, osteoporosis, adynamic bone disease, sclerostin, RANKL (receptor activator for nuclear factor k B ligand), parathyroid hormone, Wnt Introduction mellitus, accelerated aging, female gender, and early menopause can additionally affect one or more bone properties. A detailed Chronic kidney disease (CKD) is a highly prevalent and description of all the pathophysiological pathways leading to progressive condition that affects more than 10% of the general different forms of ROD is beyond the scope of this article, and population around the globe (Kalantar-Zadeh et al., 2021; Csaba, we refer interested readers to excellent reviews elsewhere (Goltzman 2022). CKD has also emerged as one of the leading causes of et al., 2018). Nevertheless, in this narrative review we will briefly morbidity and mortality and represents significant challenges for address the relevant basics as well as evolving topics in bone healthcare systems and societies worldwide (Elshahat et al., 2020; pathophysiology of interest beyond nephrology. In fact, Kalantar-Zadeh et al., 2021; Alberto Ortiz, 2022; Csaba, 2022). important paradigm changes from ROD to OP have occurred in Importantly, progression of CKD is associated with a number of recent CKD-MBD guidelines and these need to be more widely serious complications, including mineral metabolism disorders and known. bone pathology, and these are independently associated with fractures, accelerated vascular calcification, cardiovascular disease, and dismal outcomes (Moe et al., 2006; Kidney Disease: Improving Bone cells Global Outcomes KDIGO CKD-MBD Update Work Group, 2017; Wang et al., 2018; Kidney Disease: Improving Global Outcomes The most important cells of bone tissue are osteoblasts (OBs), KDIGOCKD–MBD Work Group, 2009). Bone is no longer regarded osteoclasts (OCs), osteocytes, and bone-lining cells. simply as an organ that supports and protects internal organs and we even considered to be as a new endocrine organ at the heart of the a) OBs develop from pluripotential mesenchymal stem cells CKD-mineral and bone disorders (CKD-MBD) (Vervloet et al., (MSCs). MSCs can differentiate into adipocytes, chondrocytes, 2014). Bone is capable of secreting countless hormones and myocytes, or OBs depending on the transcription factor acting molecules essential for the normal physiology of many other on them. Bone morphogenic proteins (BMPs) and the Wnt body systems (Vervloet et al., 2014). Consequently, CKD-MBD is signaling pathway are related to OB differentiation. The a currently accepted term which refers to a systemic disorder of canonical Wnt signaling pathway induces transcription factors mineral and bone metabolism due to CKD manifested by various that favor OB differentiation, and the non-canonical Wnt laboratory, bone, and vascular abnormalities (Moe et al., 2006; pathway inhibits the differentiation of MSCs to other cell Kidney Disease: Improving Global Outcomes KDIGO CKD-MBD types, resulting overall in a positive balance towards OB Update Work Group, 2017; Kidney Disease: Improving Global formation. The main function of OBs is the formation of the Outcomes KDIGOCKD–MBD Work Group, 2009; Torregrosa bone matrix through the synthesis and secretion of type et al., 2022). 1 collagen and other non-collagenous proteins which will later Previously, the term renal osteodystrophy (ROD) had been be mineralized. OBs also collaborate in this function by releasing coined in 1943 (Llach et al., 2000), 60 years after the phosphate contained in their vesicles and, together with the identification of an association between bone disease and kidney calcium and phosphate contained in the extracellular fluid, failure (Lucas, 1883; Llach et al., 2000). ROD was a very broad term compose the main mineral of cortical bone (calcium that classically included all the skeletal manifestations in patients hydroxyapatite crystals) (Day et al., 2005; Takada et al., 2007; suffering from CKD or end-stage kidney disease (CKD G5D) (Llach Guo et al., 2010). The N-terminal propeptide of type I et al., 2000). In children, rickets and skeletal deformities were also procollagen (P1NP) has been identified by the International included, while osteosclerosis and osteoporosis (OP) were globally Osteoporosis Foundation (IOF) and the International considered less common (Llach et al., 2000). Nevertheless, ROD is Federation of Clinical Chemistry (IFCC) to be one of the nowadays considered to be only one component of the wider reference markers of bone turnover (formation) for fracture complex CKD-MBD after a histomorphometric analysis of a risk prediction and monitoring of OP treatment (Vasikaran bone biopsy has been performed (Moe et al., 2006; Kidney et al., 2011). It is important to take into account the fact that Disease: Improving Global Outcomes KDIGO CKD-MBD only the measurement of intact P1NP is not affected by the Update Work Group, 2017). Derangements induced by CKD are decreased renal function in patients with CKD (Bover et al., multiple, ranging from the classically described disturbances of 2021a; Tridimas et al., 2021). Alkaline phosphatase (AP, vitamin D metabolism, calcium, and phosphate balance, through especially the bone isoform) can also be used to evaluate bone increased levels of parathyroid hormone (PTH) (secondary turnover in CKD (Bover et al., 2021a). Actually, AP can reflect hyperparathyroidism) to the more recently recognized increases not only OB activity in bone but also OB-like cell activity in the in fibroblast growth factor 23 (FGF23) and sclerostin, or decreased active process of ossification of vascular smooth muscle cells serum klotho levels, among others (Kidney Disease: Improving (Bover et al., 2018; Bover et al., 2021b). Global Outcomes KDIGO CKD-MBD Update Work Group, b) OCs derive from precursor cells of the monocyte-macrophage 2017; Llach et al., 2000; Hruska et al., 2017). Chronic metabolic lineage. OC differentiation and survival require the presence of acidosis, the use of drugs such as prednisone or calcineurin molecules such as the macrophage colony-stimulating factor inhibitors (used to treat certain kidney diseases), diabetes (M-CSF) and the important receptor activator of NF-κB Frontiers in Physiology 02 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 ligand (RANKL). OB-synthesized osteoprotegerin (OPG) acts as inverse association with survival in CKD patients (Gutiérrez a high-affinity decoy receptor for RANKL, inhibiting RANKL et al., 2008). action on the OC-RANK receptor (Wada et al., 2006). The ratio between RANKL and OPG determines the degree of osteoclastic differentiation (Gori et al., 2000), although blood measurements Normal bone anatomy and physiology are not of clinical use. It has been recently described another RANKL receptor, the leucine-rich repeat-containing G-protein- Two histologically different regions can be distinguished in coupled receptor 4 (LGR4), which competes with RANK to bind bone: a) cortical or compact bone, which represents up to 80% of RANKL and suppresses canonical RANK signaling during OC the skeleton, is composed mainly of calcium hydroxyapatite, and has differentiation (Luo et al., 2016). It also regulates OB the main function of providing mechanical support, and b) differentiation in vivo and in vitro (Luo et al., 2009). LGR4 is trabecular or cancellous bone, which is less abundant, is mainly also present in different tissues and consequently it has been composed of an organic matrix rich in type 1 collagen, has an linked with systemic roles from development to metabolic important endocrine function, and contains the bone marrow. regulation (Filipowska et al., 2022). Several biological processes occur in bone tissue during life. Bone undergoes modelling and remodelling in order to grow or The main function of the OC is bone resorption. OCs must be change shape (Katsimbri, 2017). Bone modelling is a process by activated by binding to the bone matrix, polarizing and forming which bones change shape or size in response to physiological podosomes and different membrane domains (the sealing zone, the influences or mechanical forces that are encountered by the characteristic ruffled border, and the functional secretory domain). skeleton (Katsimbri, 2017). Remodelling is the process which Each of these domains is extremely important for bone resorption, allows bone to maintain its mineral homeostasis and strength collagen degradation, and the return of calcium and phosphate to (Katsimbri, 2017). Once bone growth stops when adult age is the bloodstream (Luxenburg et al., 2007). Lysosomal enzymes reached (after bone formation and shaping), the bone tissue derived from OCs are responsible for breakdown of the requires dynamic remodelling to maintain adequate resistance collagenous bone matrix at specific sites (Bover et al., 2021a). and properties (Katsimbri, 2017). Old bone tissue is removed and Resultant products such as carboxy-terminal crosslinking replaced by new tissue through an organized process occurring telopeptide of type 1 collagen (CTX) are considered reference within temporary anatomical structures described as basic markers for bone resorption in the general population (Wheater multicellular units. Five stages are described in the remodelling et al., 2013). However, CTX is highly dependent on kidney function; process. They are widely known as activation, resorption, rest or therefore, the use of CTX cannot be recommended in patients with reversal, bone formation, and termination; however, a detailed CKD (Bover et al., 2021a). For this reason, tartrate-resistant acid description of these mechanisms is beyond the scope of this phosphatase 5b (TRAP5b) is gaining increasing importance, given review (Burger et al., 2003; Martin and Sims, 2005; Bonewald, that its concentration is not kidney dependent (Bover et al., 2021a). 2007; Bonewald and Johnson, 2008; Katsimbri, 2017). c) Osteocytes represent 95% of all bone cells. These cells are mature OBs that occupy the lacunar space and are surrounded by the Metabolic bone biopsy unmineralized osteoid matrix. After mineralization, these buried cells become osteocytes and acquire long dendritic-like processes, Bone dynamics can only be assessed by a bone biopsy, a classic giving them a star-shaped appearance. Dendritic processes procedure previously performed frequently by nephrologists in extend along the canaliculi in the bone matrix, interacting order to precisely distinguish among different forms of ROD with other osteocytes or with OBs on the surface. Osteocytes (e.g., high and low-turnover bone disease) (Moe et al., 2006; have a position that allows detection of both mechanical and Bover et al., 2021a). No biomarker or imaging studies can match metabolic signals and act accordingly, directly activating OBs and this gold standard (Bover et al., 2021a). Tetracycline labeling indirectly OCs, thus initiating the classic remodeling cycle. allows dynamic quantification, e.g., by analyzing the important Osteocytes influence OBs in two directions, either bone formation rate and the mineral apposition rate, among other upregulating them through the production of messengers such dynamic parameters. Many other static evaluations, such as the as nitric oxide and prostaglandin E2 or downregulating them osteoid area or the percentage of fibrosis, contribute to a precise through the secretion of sclerostin (Rochefort et al., 2010). As we diagnosis (Mazzaferro and Pasquali, 2021). Essentially, bone will discuss later, osteocytes and sclerostin have gained increased biopsies should evaluate bone turnover, mineralization and attention in bone pathophysiology, nephrology, and medicine in volume (following the useful acronym TMV) (Moe et al., general since their discovery and the development of new 2006). Thus, different patterns of ROD are usually described treatments for bone diseases such as OP. Osteocytes are also (see below): high-turnover osteitis fibrosa or mild the main source of FGF23, a pleiotropic hormone responsible of hyperparathyroidism, low-turnover adynamic bone disease suppressing phosphate reabsorption and calcitriol synthesis in (ABD) and osteomalacia, and the mixed form named uremic the kidney (Orlando, 2020). Although FGF23 monitoring is not osteodystrophy (Moe et al., 2006). yet included in the regular management of CKD-MBD, it is Bone biopsies are regaining importance in nephrology, important to emphasize its role in the development of left especially with the paradigm changes that have appeared in ventricular hypertrophy (Richter and Faul, 2018), among recent CKD-MBD guidelines (Kidney Disease: Improving other systemic effects (Vervloet, 2020), and its powerful Global Outcomes KDIGO CKD-MBD Update Work Group, Frontiers in Physiology 03 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 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. 2017; Torregrosa et al., 2022). The potential need for better Effects of parathyroid hormone on understanding of the consequences of the current more bone tissue aggressive use of anti-OP treatments in patients with CKD represents an additional reason for this trend (Kidney PTH plays a very important role in the dynamics of bone tissue. Disease: Improving Global Outcomes KDIGO CKD-MBD Several unanswered but important questions remain about the Update Work Group, 2017; Torregrosa et al., 2022). Thus, it skeletal actions of PTH, with differences between intermittent is currently considered reasonable to perform a bone biopsy if administration and constant exposure to high levels (Hock and knowledge of the type of ROD will impact treatment decisions Gera, 1992; Rendina-Ruedy and Rosen, 2022). Thus, constant high in patients with CKD G3a-G5D (not graded) (Kidney Disease: PTH levels can increase bone remodelling to exert a catabolic effect Improving Global Outcomes KDIGO CKD-MBD Update Work on cortical and, to some extent, trabecular bone (Goltzman, 2018). Group, 2017; Torregrosa et al., 2022). It was previously On the other hand, intermittent administration of PTH can exert an considered reasonable to perform a bone biopsy “in various anabolic effect on bone; this is especially the case for trabecular bone settings including, but not limited to: unexplained fractures, but also to some extent for cortical bone (Goltzman, 2018). We persistent bone pain, unexplained hypercalcemia, unexplained describe below some of the effects of PTH on bone cells and the hypophosphatemia, possible aluminum toxicity, and prior to remodelling stages. therapy with bisphosphonates in patients with CKD-MBD” (not graded either) (Kidney Disease: Improving Global Outcomes KDIGOCKD–MBD Work Group, 2009). A wider description of PTH and osteoblasts indications and the technical procedure is beyond the scope of this review and readers are referred to literature elsewhere PTH administration enhances bone formation by inducing (Salusky et al., 1988; Torres et al., 2014; Evenepoel et al., transcriptional changes in several OB pathways, being the via 2017). However, it should be emphasized that efforts are adenyl cyclase and protein kinase A (PKA) the most prominent currently being made to standardize the variable “normality” (Rendina-Ruedy and Rosen, 2022) (Figure 1). PTH also influences values used in different laboratories when performing the entire life cycle of OBs, from their differentiation from histomorphometric analysis (Sprague et al., 2016a). It is also pluripotent MSCs through to activation and even apoptosis. PTH being suggested that bone mineral density (BMD) testing should appears to increase the amount of OB precursors in the bone be used to assess fracture risk “if results will impact treatment marrow through a direct action. The bone marrow cells capable decisions” in patients with CKD G3a-G5D with evidence of of differentiating to OBs are the colony-forming units-fibroblast CKD-MBD and/or risk factors for OP (see later) (Kidney (CFU-F) and old studies already demonstrated that the Disease: Improving Global Outcomes KDIGO CKD-MBD administration of PTH (Kalantar-Zadeh et al., 2021; Csaba, 2022; Update Work Group, 2017; Torregrosa et al., 2022), since Alberto Ortiz, 2022; Elshahat et al., 2020; Moe et al., 2006; Kidney bone biopsy is not useful for fracture risk prediction. Disease: Improving Global Outcomes KDIGO CKD-MBD Update Frontiers in Physiology 04 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 Work Group, 2017; Wang et al., 2018; Kidney Disease: Improving protein) has also recently been approved for OP treatment (Paul Global Outcomes KDIGOCKD–MBD Work Group, 2009; Vervloet et al., 2016). Occasionally, teriparatide has also been used in the et al., 2014; Torregrosa et al., 2022; Llach et al., 2000; Lucas, 1883; treatment of ABD in CKD patients (Cejka et al., 2010; Sumida et al., Hruska et al., 2017; Goltzman et al., 2018; Day et al., 2005; Takada 2016). et al., 2007; Guo et al., 2010; Vasikaran et al., 2011; Tridimas et al., 2021; Bover et al., 2021a; Bover et al., 2018; Bover et al., 2021b; Wada et al., 2006; Gori et al., 2000; Luo et al., 2016; Luo et al., 2009; PTH and bone lining cells and osteocytes Filipowska et al., 2022; Luxenburg et al., 2007; Wheater et al., 2013; Rochefort et al., 2010; Orlando, 2020; Richter and Faul, 2018; Bone lining cells and osteocytes have properties which suggest Vervloet, 2020; Gutiérrez et al., 2008) to rats for 1 week resulted that they belong to the OB lineage, expressing many of their genes. It in the doubling of CFU-F compared with placebo-treated rats has been shown that PTH activates these lining cells, inhibits (Nishida et al., 1994). osteocyte apoptosis, delays the differentiation of OB to lining It is well known that PTH cross-talks with the cellular Wnt cells, and increases the conversion of lining cells to OBs (Jang signaling pathway, stimulating bone formation by increasing the et al., 2016). Osteocytes express receptors for PTH on their number of OBs. PTH also reduces the levels of sclerostin surface, in such a way that their morphology and function, (downregulating the SOST gene), thus providing another including cell retraction, mitochondrial congestion, and cell paracrine mechanism through which PTH can stimulate the death, seem PTH regulated (Heller et al., 1950; Cameron et al., differentiation of OBs (Bellido et al., 2005; Loots et al., 2005; 1967; O’Brien et al., 2008; Rhee et al., 2011). On the other hand, PTH Drake et al., 2010; Nagata et al., 2022). Within OBs, PTH upregulates osteocytic RANKL, and RANKL plays a critical role in stimulates the formation of a tertiary complex PTH/PTHrp the PTH-induced increases in bone resorption (see below) receptor and the Wnt co-receptor LRP6 (Wan et al., 2008), (Nakashima and Takayanagi, 2011; Xiong et al., 2011; Ben-awadh highlighting the importance of this complex since mice lacking et al., 2014; Xiong et al., 2014). LRP6 in OBs do not respond to iPTH (Wan et al., 2008). This signaling link between PTH and Wnt has also been strengthened by the observation that PTH reduces other Wnt inhibitors [such as PTH and osteoclasts Dickkopf 1 (Dkk1), secreted frizzled-related proteins (Sfrp) 1 and 4] (Carrillo-López et al., 2016), and that inhibition of Wnt signaling by OCs do not express receptors for PTH; therefore, PTH action is Dkk1 prevents the effects of PTH on bone (Li et al., 2006). It has indirectly mediated through OBs. M-CSF and RANKL are the two recently been reported that a newly identified osteogenic growth main cytokines that drive OC differentiation and function (Feng and factor, osteolectin/Clec11a, is required for the maintenance of Teitelbaum, 2013), and PTH has been shown to increase the skeletal bone mass during adulthood, and that the combined expression of these molecules (Itoh et al., 2000). In fact, there are administration of osteolectin and PTH, but not osteolectin and multiple cellular sources of these two cytokines in bone sclerostin inhibitor, additively increases bone volume (Zhang et al., (hypertrophic chondrocytes, marrow stromal cells, osteoblasts, 2021). These results demonstrate that PTH promotes osteolectin resident marrow lymphocytes, and osteocytes) (O’Brien et al., expression and that osteolectin mediates at least part of the effect of 2013), and RANKL is a well-studied PTH target gene in multiple PTH on bone formation. (Zhang et al., 2021). cell types (Fu et al., 2002; Fu et al., 2006; Kim et al., 2006; Kim et al., PTH also affects other important series of signaling pathways. 2007). During OC-mediated bone resorption, growth factors such as For example, PTH stimulates Runx2, an essential transcription TGF-ß1 and IGF-1 are released. IGF-1 is maintained in the bone factor in bone required for OB differentiation (Arumugam et al., matrix in complex with binding proteins (IGFBP) and OC bone 2019). PTH stimulates the synthesis of growth factors including remodelling leads to IGFBP cleavage and subsequent IGF-1 release insulin-like growth factor (IGF)-1 and FGF, both of which are (Crane and Cao, 2014). Finally, recent translation studies highlight required for the anabolic effects of iPTH (Bikle et al., 2002; the potent amplificatory action of T-cell on PTH-induced bone Hurley et al., 2006; Wang et al., 2007). Another PTH target gene resorption in parathyroid disease (Neale, 2017). PTH acts on CD4+ that has been extensively studied in OBs is the matrix T-cell to drive up TNFα and IL-17, further amplifying osteoblastic metalloproteinase 13 (MMP13) gene, the expression of which is RANKL production and down-regulating OPG, establishing mediated through an intricate signaling pathway involving PKA, favorable conditions for osteoclastic bone resorption (Neale, 2017). Runx2, sirtuin-1, and others. Thus, PTH upregulation of MMP13 plays an important role in how OBs remodel old bone matrix as they synthesize new type I collagen. (Shimizu et al., 2010; Disorders of bone remodelling in CKD Shimizu et al., 2014; Fei et al., 2015). PTH has also been shown to induce T lymphocytes in the bone marrow microenvironment to Despite previous descriptions of “late rickets associated with produce cytokines that stimulate the differentiation of OBs albuminuria” by Lucas in The Lancet in 1883 and “tumor of the (Terauchi et al., 2009). Finally, one of the most important effects parathyroid gland” by MacCallum in 1905 (Llach et al., 2000), it was of PTH in OBs is inhibition of OB apoptosis (Allan et al., 2008; De not until 1924 that a study of a patient with severe bone Pasquale et al., 2008). All these positive actions of PTH on OBs and demineralization and multiple fractures led to the discovery that bone formation represent the basis on which today recombinant the disease resided in the parathyroid gland (Albright and PTH (teriparatide) constitutes an alternative in the treatment of OP Reifenstein, 1948). In 1925 the first resection of a parathyroid (Neer et al., 2001). Abaloparatide (an analog of human PTH-related adenoma was performed (Albright and Reifenstein, 1948). It Frontiers in Physiology 05 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 1933 Langmead suggested for the first time that parathyroid et al., 2018). Surgical parathyroidectomy and calcimimetics seem hyperplasia was secondary to advanced CKD (Llach et al., 2000). to reverse some of these untoward effects (Massy et al., 2014; Other patients began to be diagnosed with this new disease and there Komaba et al., 2015; McMahon et al., 2015; Komaba et al., 2022). was a need to study derangements in divalent ion metabolism, Regarding bone, PTH levels are actually only indirectly vitamin D, and the molecule produced by the parathyroid glands associated with bone formation (a secondary impact), and they that caused so much damage to the bone tissue (Albright and probably represent parathyroid activity at a certain time point much Reifenstein, 1948; Handler et al., 1954; Llach et al., 2000). In the better than bone dynamics (Pablo and Covic, 2020). Moreover, 1960s, Stanbury and Lamb as well as Dent and co-workers (Llach unlike most other biomarkers or regulators of bone turnover, such as et al., 2000) linked abnormalities of divalent ion metabolism, PTH, APs or P1NP, PTH secretion is not dictated by local bone demands and vitamin D with the bone abnormalities observed in CKD. With (triggered on osteocytes via mechanical stimuli) (Bover et al., 2018). the advent of radioimmunoassays for PTH (Brewer and Ronan, Actually, the major determinants of PTH synthesis and secretion are 1970; Niall et al., 1970; Llach et al., 2000), high circulating levels of calcium, phosphate, vitamin D, and FGF23 levels (Levin et al., 2007; PTH were detected at earlier stages of CKD (Llach et al., 2000); Sturgeon et al., 2017). In fact, according to current guidelines, the however, it was not until 1970 that characterization of the PTH measurement of both serum PTH and bone AP can be used to molecule was completed, which helped to its cloning in 1983 evaluate bone disease in CKD patients because markedly high or low (Brewer and Ronan, 1970; Niall et al., 1970; Vasicek et al., 1983). values predict underlying bone turnover (Kidney Disease: In the 1990s, highly sensitive immunoassays were developed and its Improving Global Outcomes KDIGO CKD-MBD Update Work receptor was finally cloned in 1991 (Jüppner et al., 1991; Abou- Group, 2017; Jørgensen et al., 2022a). Combination of PTH and APs Samra et al., 1992). We now know that at least very low or very high significantly increases both the sensitivity and the specificity of the levels of PTH (i.e., less than 2X or more than 9X the upper normal histopathological diagnosis (Ureña et al., 1996; Bover et al., 2018). limit for the used assay) are associated with low or high-turnover These biomarkers offer the possibility of more frequent serial bone disease (ABD or osteitis fibrosa, respectively) in dialysis measurements that can guide us on therapeutic decision-making patients; both extremes increase not only the risk of fractures but and follow-up. However, despite it has been recently recognized that also mortality by different means (Kidney Disease: Improving diagnostic performance of biochemical markers of bone turnover is Global Outcomes KDIGO CKD-MBD Update Work Group, acceptable, with clinical utility in ruling out both high and low 2017; Kidney Disease: Improving Global Outcomes turnover bone disease, biomarkers do have some limitations such as KDIGOCKD–MBD Work Group, 2009; Torregrosa et al., 2022). the scarcity of data available to consider precise target figures, their It was considered previously that the elevation of PTH was the biological variability and the inherent disparity of trials leading to main responsible for skeletal abnormalities in CKD; however, recent different reference ranges and cut-offs (Jørgensen et al., 2022a; evidence has shown that changes in bone tissue occur from early Jørgensen et al., 2022b). stages (Sabbagh et al., 2012; Baron and Kneissel, 2013a). The While the parathyroid glands can be affected by a primary increase in sclerostin and FGF23 levels, two molecules secreted disease, such as parathyroid adenoma or the rare parathyroid by osteocytes, and the consequent repression of Wnt-β catenin neoplasms, secondary (or even tertiary) hyperparathyroidism is signaling pathway represent a clear mechanistic example frequently observed during the course of CKD (Kidney Disease: explaining the impairment of bone health from the onset of CKD Improving Global Outcomes KDIGO CKD-MBD Update Work (Figure 1) (Cejka et al., 2012; Moysés and Schiavi, 2015; Drüeke and Group, 2017; Torregrosa et al., 2022). Below we describe the two Massy, 2016). Increasing PTH, to a certain extent, may thus appear most common histologic patterns, which derive from very high as an adaptive mechanism to maintain not only normal serum (osteitis fibrosa) and relatively low levels of PTH (ABD). calcium, phosphate and/or calcitriol levels but also a normal bone remodeling (Torregrosa et al., 2022). Another molecule that is elevated in the early stages of CKD and causes changes in bone Osteitis fibrosa dynamics is activin A (ActA), a member of the TGF-β superfamily that is secreted by renal fibroblasts. ActA activates receptors on the The first report of this disease derived from very high PTH surface of OCs, leading to the activation of the intracellular protein levels was made by von Recklinghausen in 1891 (Von Smad2. ActA also increases the expression of RANKL by OBs which Recklinghausen, 1891), but the full report of “osteitis fibrosa binds to RANK on the surface of OCs, stimulating the expression cystica” was not provided until 1936, by Albright and co- and phosphorylation of c-Fos. Together with smad2, these workers (Llach et al., 2000). CKD-associated molecules form a complex that enters the nucleus of OCs hyperparathyroidism was considered by far the most prevalent generating osteoclastogenesis and bone resorption form of ROD until recently, especially among advanced CKD and (AgapovaFangSugatani et al., 2016; Sugatani et al., 2017; dialysis patients. However, current patterns show a lower Cianciolo et al., 2021). prevalence ranging from 20% to 40% (Bover et al., 2014). The PTH also alters metabolic homeostasis through its actions in pathophysiology of secondary/tertiary hyperparathyroidism is other cells and tissues, and myriad non-skeletal metabolic or beyond the scope of this review and interested readers are anabolic effects have been attributed to PTH (Rendina-Ruedy referred elsewhere (Llach et al., 2000; Cunningham et al., and Rosen, 2022). However, in addition PTH has been 2011; Lunyera and Scialla, 2018). After increased synthesis considered a uremic toxin in CKD patients with secondary and secretion of PTH by multiple stimuli (hypocalcemia, hyperparathyroidism because of many pleiotropic detrimental hyperphosphatemia, decreased calcitriol, etc.), PTH binds to effects that can be attributed to this molecule (Ureña-Torres its receptors in bone tissue (mostly PTHR1), which are located Frontiers in Physiology 06 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 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). on the surface of OBs and osteocytes. PTHR1 belongs to the mineralization, as is the case with osteomalacia (Malluche et al., B-family of G protein-coupled receptors, and once the PTH 1982; Feng and McDonald, 2011; Hruska et al., 2017). molecule has bound to its receptor, it triggers a series of Furthermore, in hyperparathyroidism there is activation of intracellular signaling events (Figure 2). fibroblast-type mesenchymal cells that give rise to peritrabecular In OBs, binding of PTH to its receptor induces the production of fibrosis (Lotinun et al., 2005; Lowry et al., 2008). The overall results M-CSF and RANKL, responsible for the differentiation and is a loss of cortical bone secondary to the accelerated resorption, activation of OCs (Kondo et al., 2002; Feng and Teitelbaum, which far exceeds bone formation, and in the place of a laminar 2013). PTH also induces the production of osteocytic RANKL, osteoid, a fibrous tissue even containing cysts is present (Naji Rad potentiating the differentiation and activation of OCs and Deluxe, 2022). (Nakashima and Takayanagi, 2011; O’Brien et al., 2013; Ben- awadh et al., 2014; Xiong et al., 2014). The persistent and constant elevated PTH increases the bone resorption units, Adynamic bone disease resulting in a considerable increase in resorptive areas and leading to negative bone balance (Malluche et al., 1982; Ma et al., In the 1980s the term “aplastic” or “adynamic” bone disease was 2001; Silva and Bilezikian, 2015). Increased osteoblastic activity introduced (Malluche and Faugere, 1986). Aluminum intoxication leads to an unparalleled increase in the production of osteoid by was previously the most frequent cause of low-turnover bone disease OBs. Nevertheless, this osteoid does not have an orderly and laminar (aluminum-induced osteomalacia) since aluminum decreases the disposition, as in normal bone. This is known as woven bone, and activation of OB and OC and causes an important defective this increase in osteoid is known as hyperosteoidosis, which occurs as mineralization (Malluche and Faugere, 1986; Nebeker and a consequence of increased remodelling and not due to a delay in Coburn, 1986). ABD is characterized by suppressed bone Frontiers in Physiology 07 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 formation, low cellularity, and thin osteoid seams, the last- A crucial aspect of low remodelling is that it promotes longer mentioned being the most important difference with secondary mineralization, which may lead to brittle bones. It should osteomalacia (wide osteoid volume) since mineralization is be known that the osteoid mineralization process is carried out in normal in ABD (Parfitt et al., 1987; Moe et al., 2006; Nagy et al., two stages: primary mineralization, over the course of days, during 2022). Minimodeling has been shown to potentially contribute to which 50%–79% of the maximum mineralization is reached, and bone formation in dialysis patients with ABD, in the absence of afterwards secondary mineralization begins (Ruffoni et al., 2007; remodelling stimulated by PTH, and this is especially the case in Bala et al., 2010). Secondary mineralization is a slow process and young patients with positive activities of daily living (Ubara et al., develops in the course of months, contributing to the maximum 2005). Minimodeling refers to the formation of bone by the action of mineralization and to an increase in the quantity and size of the OBs without prior resorption by OCs. Bone modeling can be divided crystals (Boivin and Meunier, 2003). Secondary mineralization into macromodeling or minimodeling depending on whether it is occurs inversely to bone turnover. Thus, the greater the turnover developed in cortical or cancellous bone, respectively. This process, the shorter the time in which secondary mineralization develops, which is very important during fetal and neonatal life, generates and the lower the turnover the longer the duration of secondary convex bone formation on smooth cement lines which do not mineralization (Boivin et al., 2009). In addition, the suppression of express tartrate-resistant acid phosphatase, the hallmark of OC bone turnover can cause micro fissures that are difficult to repair in activity when bone formation is preceded by resorption. The first the presence of a low bone formation rate (Ng et al., 2016; Dong to use this term was Frost (Frost, 1966), and it was postulated later et al., 2019). In this context, the 2009 KDIGO CKD-MBD guideline that minimodeling may continue in trabeculae throughout life recommended a bone biopsy prior to antiresorptive therapy in (Frost, 1990). It seems to contribute to a significant percentage of patients with CKD G4 to G5D, low BMD, and/or fragility bone volume in special conditions such as CKD, fractures (Kidney Disease: Improving Global Outcomes parathyroidectomized and/or patients with ABD, and it has been KDIGOCKD–MBD Work Group, 2009). The rationale was that popularized with the advent of new dual medications against OP, low BMD may be due to CKD-MBD (e.g., high PTH) and that such as romosozumab (Yamamoto et al., 2021). Increased lowering PTH is a safer and more appropriate therapy than an mineralization of the minimodelling surface at the endocortical antiresorptive (Kidney Disease: Improving Global Outcomes surface has also been observed in dialysis patients with ABD KDIGOCKD–MBD Work Group, 2009). Moreover, there was treated with the non-calcium-based phosphate binder lanthanum concern that bisphosphonates could induce ABD, although this carbonate (Yajima et al., 2013). hypothesis was based upon a single cross-sectional study (Amerling The prevalence of ABD used to be much lower than that of et al., 2010). In the intervening period, studies in patients with CKD osteitis fibrosa, but this pattern of bone damage has increased have not definitely demonstrated that bisphosphonates are a direct significantly, and in most recent studies it is described as the cause of ABD (Kidney Disease: Improving Global Outcomes most prevalent (Frazão and Martins, 2009; Malluche et al., 2011; KDIGO CKD-MBD Update Work Group, 2017; Torregrosa Nagy et al., 2022). It has even been proposed that ABD may be the et al., 2022). Suppression of bone turnover is inherent to predominant bone pattern in early stages of CKD (Massy and bisphosphonates and most treated patients develop a low bone Drueke, 2017). The rising prevalence is probably due to patient’s formation rate (Evenepoel et al., 2021a), yet this treatment increasing age and a higher prevalence of diabetes mellitus (relative prevents fractures (Kidney Disease: Improving Global Outcomes hypoparathyroidism) (Jara et al., 1995; Brandenburg and Floege, KDIGO CKD-MBD Update Work Group, 2017). Suppression of 2008). In fact, however, the etiology of ABD is multifactorial and bone turnover by bisphosphonates occurs even in the absence of there are many other potential causes, including iatrogenic factors, CKD and there is no evidence that the level of remodelling malnutrition-inflammation syndrome, gonadal dysfunction, and the suppression in CKD is greater than that in non-CKD antagonistic effect of retained PTH fragments, among many others counterparts (Allen and Aref, 2017). In any case, the implications (Brandenburg and Floege, 2008; Bover et al., 2014). Calcium of drug-induced suppression of bone turnover for bone strength are overload (oral or contained in the dialysate bath) and an intensely debated (Evenepoel et al., 2021a). As we mentioned excessive use of antiparathyroid (vitamin D or calcimimetics) previously, low PTH levels as a proxy of low-bone turnover in agents have also been closely associated with ABD due to CKD patients have been associated with increased fracture risk excessive suppression or inadequate normalization of PTH levels (Coco and Rush, 2000; Nitta et al., 2004) but it remains a matter of in CKD (Bover et al., 2014). The combination of relatively low levels debate whether low bone turnover per se or the disease causing low of PTH and APs currently represents the best clinical basis for bone turnover accounts for the perceived ABD-induced risk of assessment of potential ABD beyond the gold standard bone biopsy fracture or adverse outcomes (Evenepoel et al., 2021a; Nagy (Couttenye et al., 1996; Moore et al., 2009; Sprague et al., 2016b; et al., 2022). Bover et al., 2018). In fact, multifactorial hyporesponsiveness to It is noteworthy that in ABD there is a state of imbalance PTH is a well-documented consequence of CKD (Evenepoel et al., between the low circulating levels of bone anabolic factors such as 2016; Bover et al., 2021c) and a certain degree of secondary IGF-1 and the increased expression of inhibitors of bone turnover hyperparathyroidism is beneficial in CKD patients, not only such as sclerostin and Dkk1. This imbalance favors suppression of because of the positive PTH phosphaturic effect but also in order bone formation through inhibition of the Wnt-catenin pathway to maintain a normal bone formation rate (Ketteler et al., 2022; (Tanaka et al., 2015; Massy and Drueke, 2017). New treatments for Torregrosa et al., 2022). ABD has also been associated with a higher OP with a dual action (anti-sclerostin antibodies with anabolic and mortality, occasionally attributed to an increased number of antiresorptive properties) were shown to be promising in a rat model fractures and accelerated vascular calcification (Bover et al., 2014). of progressive ROD (Moe et al., 2015). It is noteworthy that these Frontiers in Physiology 08 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 authors found efficacy in improving rat bone properties only when Work Group, 2009). However, as mentioned previously, an the PTH levels were low, also preventing calcium-induced vascular important shift occurred in the 2017 KDIGO CKD-MBD calcification, while no significant effect was observed in animals with guidelines in the opposite direction (evidence 2B). Thus, it was high PTH levels. now suggested that BMD testing could be used to assess fracture risk in patients with CKD G3a-G5D if results would impact treatment decisions (Kidney Disease: Improving Global Outcomes KDIGO Osteoporosis CKD-MBD Update Work Group, 2017); the rationale being that new evidence had appeared, demonstrating that DXA does predict OP is defined as a systemic skeletal disease characterized by low fractures also in patients with CKD (Kidney Disease: Improving bone mass and microarchitectural deterioration of bone tissue, Global Outcomes KDIGO CKD-MBD Update Work Group, 2017; leading to an increase in bone fragility and therefore a higher Kidney Disease: Improving Global Outcomes KDIGOCKD–MBD susceptibility to bone fractures (Compston et al., 2019). Work Group, 2009; Pimentel et al., 2021). The same suggestion has Consequently, the definition of OP includes not only bone since been adopted in other national guidelines (Torregrosa et al., quantity (mass) but also bone quality (microstructure), in 2022). In fact, at least 4 prospective cohort studies using dual-energy addition to the important clinical outcome of fragility fractures X-ray absorptiometry (DXA) BMD and incident fractures (Compston et al., 2019). This concept was developed in 1993 by an demonstrated that DXA BMD predicted incident fractures across International Consensus of experts, and the diagnostic criteria, the spectrum from CKD G3a to G5D (Kidney Disease: Improving which were also adopted by the WHO in 1994, use standard Global Outcomes KDIGO CKD-MBD Update Work Group, 2017). deviation (SD) scores of BMD in relation to the peak bone mass Nevertheless, it is important to recognize that DXA does not reached by young healthy women (WHO, 1994). distinguish among different forms of ROD and it essentially Briefly, in postmenopausal women, OP was defined as a BMD evaluates quantity as opposed to quality of bone (Kidney Disease: T-score lower than −2.5 SD below the average of young healthy Improving Global Outcomes KDIGO CKD-MBD Update Work women, and osteopenia as a BMD T-score between −1 and −2.5 SD Group, 2017; Pimentel et al., 2021). Consequently, BMD does not below this average value (WHO, 1994). Thus, there is a significant offer information either on bone microarchitecture [the trabecular relationship between BMD and fragility fractures, with a 1.5 to 2.6- bone score (TBS) may provide some additional clues] (Silva et al., fold increase in fracture risk for every SD decrease in BMD (Siris 2014; Yun et al., 2020), bone turnover or mineralization, and cannot et al., 2004). Importantly, the diagnostic criteria recognize the differentiate between OP, ABD, osteomalacia or osteitis fibrosa importance of BMD in the pathogenesis of fragility fractures and (Ginsberg and Ix, 2022). However, as mentioned before, BMD also provide a tool to quantify the prevalence of OP (bone does predict fractures and may support decision-making together densitometry) (Compston et al., 2019). However, the utility of with bone biomarkers (Jørgensen et al., 2022a), even in the absence BMD as the sole clinical indicator for OP is limited since BMD of a bone biopsy, according to recent guidelines which also draw is only one of multiple risk factors for fracture development. attention to the associated vital risk (Kidney Disease: Improving Actually, the majority of fragility fractures occur in individuals Global Outcomes KDIGO CKD-MBD Update Work Group, 2017; with BMD values above this threshold (less negative) (Siris et al., Torregrosa et al., 2022). 2004; Compston et al., 2019). Accordingly, the National Bone Health Bone metabolism in CKD patients differs from that of the Alliance Working Group published a position statement in general population, depending on CKD stage, and type of kidney 2014 which included not only BMD but also the presence of replacement therapy (i.e., hemodialysis, peritoneal dialysis, or fragility fractures and the fracture risk assessed by the Fracture kidney transplantation), among many other pathophysiological Risk Assessment Tool (FRAX) for the clinical diagnosis of OP (Siris factors including bone location and histologic structure (Chen et al., 2014). Apart from the BMD criteria, these experts also defined et al., 2014). Thus, cross-sectional analysis showed a significantly OP as the presence of a hip fragility fracture (with or without BMD), lower BMD at femoral neck and total hip and a significant higher a non-hip fragility fracture (including vertebral, proximal humeral, serum PTH along with CKD stages (Cailleaux et al., 2021). Baseline pelvic, and distal forearm fractures) plus densitometric osteopenia, age, gender, low body mass index, tobacco, and high PTH levels were and a high fracture risk just based on a nationally-adapted FRAX significantly associated with low BMD (Cailleaux et al., 2021). score (Siris et al., 2014). Since bone quality is probably another Interestingly, the longitudinal bone loss observed in patients with important aspect to be taken into account which may be additionally CKD during the mean 4.3-year follow-up revealed a significant bone affected in the presence of CKD (Tasnim et al., 2021), new tools are loss at the radius only, whereas BMD changes at the femoral neck being developed to improve its assessment and improve fracture risk were not associated with CKD stages or basal PTH levels (Cailleaux prediction both in the general population and in CKD patients et al., 2021). These data invite to a better definition of the skeletal site (Bover et al., 2021a). and the monitoring schedule of serial BMD measurements in patients with CKD, and to investigate the changes of BMD and microarchitecture with high-resolution techniques, which may Osteoporosis and chronic kidney disease broaden the understanding and differential role of PTH on trabecular and cortical bone, especially in CKD patients Studies assessing the presence of densitometric OP in patients (Cailleaux et al., 2021). with CKD are scarce since BMD assessment was not recommended Different drugs in patients with this clinical condition (including in the previous 2009 KDIGO CKD-MBD guidelines (evidence 2B) glucocorticoids) may also affect bone metabolism, and it has to be (Kidney Disease: Improving Global Outcomes KDIGOCKD–MBD taken into account that extensive vascular calcification or the Frontiers in Physiology 09 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 presence of an arteriovenous fistula may additionally affect the CKD-MBD Update Work Group, 2017; Torregrosa et al., diagnosis of OP (Evenepoel et al., 2021a; Pimentel et al., 2021). 2022; Bover et al., 2019; Casado and Neyro, 2021). Moreover, drugs approved for OP are not simply the subject of theoretical concerns (ABD); rather some restrictions on use may be stipulated in their summary of product characteristics (SmPC) when New bone metabolic pathways-new decreased renal function is present (an example being treatments bisphosphonates). However, growing experience with OP medications in patients with CKD has increased the confidence In recent years, we have learned more about the role of certain in using antiresorptive therapy in patients with low BMD and a high cell signalling pathways in the regulation of bone metabolism, risk of fracture (Kidney Disease: Improving Global Outcomes examples being the OPG/RANKL (LGR4) system and the KDIGO CKD-MBD Update Work Group, 2017; Torregrosa canonical Wnt-ß-catenin pathway. It is important that knowledge et al., 2022). on these two pathophysiological pathways is further expanded, given that the latest approved antiosteoporotic treatments aim to modulate these signalling routes. Denosumab is an antibody Chronic kidney disease and fractures against RANKL and romosozumab is an antibody against sclerostin. They are not specifically contraindicated in renal It seems clear that patients with CKD sustain more fragility failure and therefore they may become a real therapeutic target fractures than the general population (Pimentel et al., 2021), for OP even in patients with CKD, also bearing the absence of and the risk of fragility fracture has been reported to be up to chronic accumulation (Festuccia et al., 2017; Miller et al., 2022; 5 times higher in individuals with an estimated glomerular Suzuki et al., 2022). filtration rate (eGFR) of less than 15 ml/min/1.73 m 2 compared to those in whom the eGFR exceeds 60 ml/min/ 1.73 m 2 (Naylor et al., 2015; Pimentel et al., 2021). Wnt-β-catenin signaling Additionally, it should be noted that the worse the CKD stage, the higher the fracture risk (Naylor et al., 2015). For We have already mentioned that the Wnt-β-catenin is an example, the Canadian Multicentre Osteoporosis Study intracellular signaling pathway that has emerged as a key regulator (CaMos) reported a fracture incidence ranging from 15.0/ of osteoblastogenesis (Gordon and Nusse, 2006). Its regulation occurs 1,000 person-years in CKD G1 up to 46.3/1,000 person-years mainly through its antagonists, sclerostin and Dkk-1, which are in CKD G4 (Naylor et al., 2015). Many other factors are primarily expressed by osteocytes (Gordon and Nusse, 2006). In involved in the increased fracture risk associated (or not) brief, when the Wnt protein binds to the dual receptor complex, with CKD such as age, gender (the risk is higher in women), which comprises frizzled (Fz) and either low-density lipoprotein history of prior hip fracture, urine albumin levels, low body receptor (LDLR)-related protein 5 (LRP5) or LRP6, ß-catenin is mass index, long dialysis vintage, and/or high and low-turnover accumulated in the cytoplasm and enters the nucleus, where it is bone disease (Pimentel et al., 2021). On the other hand, studies associated with a transcription factor, regulating the expression of assessing the prevalence of vertebral fractures among canonical Wnt target genes such as WISP1 and RUNX2 (Gordon individuals with CKD are scarce and clearly seem to and Nusse, 2006) (Figure 3). Consequently, the activation of Wnt underestimate such fractures, as the published rates have signalling finally induces the differentiation of OB precursors towards ranged between 1% and 20% (Pimentel et al., 2021). mature OBs and prevents OB (and osteocyte) apoptosis, resulting in Furthermore, it should be underlined that there is a higher increases in bone mass. However, when sclerostin or Dkk-1 binds to the mortality risk after a fragility fracture (hip and non-hip Wnt receptors (LRP-5/6 membrane), they prevent the binding of the fractures) in patients with CKD G4-G5 as compared to Wnt protein to its receptors, and the cytoplasmatic ß-catenin protein is controls with an eGFR over 60 ml/min/1.73 m 2 (de Bruin phosphorylated and degraded. Therefore, ß-catenin cannot enter the et al., 2020). Like many other authors, we have shown in a nucleus and cannot activate osteoblastogenesis. Other inhibitors, such recent study that the presence of vertebral fractures is correlated as the Sfrp 1and 4, (upregulated in CKD) do not specifically bind to with poorer survival and that these fractures are independent LRPs but compete with the Wnt ligand for the binding to the receptor predictors of all-cause mortality (Castro-Alonso et al., 2020). (Gordon and Nusse, 2006). As a consequence, the inhibition of Wnt Consequently, current nephrology guidelines have removed the signalling (by the absence of Wnt protein or the presence of antagonists) requirement for bone biopsy prior to the use of antiresorptive leads to downregulation of bone formation, probably leading to a lower drugs for OP because their use must be individualized in bone mass (Gordon and Nusse, 2006; Baron and Kneissel, 2013b). In patients with CKD (Kidney Disease: Improving Global addition, Wnt-ß-catenin signalling is critical not only for Outcomes KDIGO CKD-MBD Update Work Group, 2017; osteoblastogenesis but also for the regulation of osteoclastogenesis Torregrosa et al., 2022; Ketteler et al., 2017), and the risk/ (Wijenayaka et al., 2011) through the RANKL/OPG system (Figure 3). benefit ratio may be favourable also in these patients (Bover et al., 2019; Casado and Neyro, 2021; Torregrosa et al., 2022). Actually, it has been proposed that it is “time for action” even in Sclerostin the absence of randomized clinical trials (Moe and Nickolas, 2016), although it is still prudent to use these drugs with caution Sclerostin is a 22-kDa protein that is a member of the cystatin (Kidney Disease: Improving Global Outcomes KDIGO knot family of proteins and the product of the SOST gene Frontiers in Physiology 10 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 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]. (Brandenburg et al., 2019). Loss of function mutations of the SOST individuals undergoing hemodialysis (Moysés and Schiavi, 2015). gene have been reported in van Buchem disease (sclerosteosis; a Curiously, it seems that peritoneal dialysis decreases sclerostin hereditary sclerosing bone dysplasia) (), and this represented the circulating levels (as 2.5 times higher values have been found in starting point for development of an anti-sclerostin antibody which the dialysate compared to urine), whereas after a conventional has recently been approved for the treatment of OP (Baron and hemodialysis session the circulating levels of sclerostin remain Kneissel, 2013b). As mentioned above, sclerostin downregulates unaltered (Figurek et al., 2020). In this context, a small osteoblastogenesis but also promotes osteoclastogenesis through prospective study has shown suppression of the increase in activation of the RANKL/OPG system; thus the antibody offers a sclerostin level in hemodialysis using a medium cut-off dialysis unique dual positive action (Wijenayaka et al., 2011). Sclerostin is filter (Ahn et al., 2021). also expressed by osteoclast precursors, hepatocytes, and renal and The pathophysiology of sclerostin in CKD and its consequences vascular cells, but little is known about the systemic effects of this are not clear yet. On the one side, sclerostin is overexpressed by molecule [186]. osteocytes and by injured kidney cells (Moysés and Schiavi, 2015), In postmenopausal women, increased circulating sclerostin while on the other hand there is an increased tubular excretion of values have been associated with OP and an increased risk of sclerostin with a reduction in renal function (Moysés and Schiavi, fragility fractures (Clarke and Drake, 2013). It has also been 2015; Figurek et al., 2020). It is well known that after kidney described an increase of circulating sclerostin values in some transplantation serum sclerostin values are rapidly restored to the clinical conditions associated with OP such as type 2 diabetes normal range (Moysés and Schiavi, 2015). Altogether suggests that a mellitus, glucocorticoid treatment, multiple myeloma or CKD; sclerostin accumulation occurs in CKD, and it has been reported whereas decreased values of sclerostin have been described in that it may be present even at early CKD stages in an attempt to patients with hyperparathyroidism and under osteoanabolic prevent bone loss (Massy and Drueke, 2017) as a result of both a treatment with teriparatide (Moysés and Schiavi, 2015). multifactorial increase in expression and a decrease in elimination (Moysés and Schiavi, 2015). Moreover, it seems that sclerostin also intervenes in the relationship among phosphate, FGF23 and bone in Sclerostin in chronic kidney disease CKD. Thus, a positive correlation has been described between sclerostin, serum phosphate, and FGF23, while, conversely, a In CKD, circulating levels of sclerostin increase as kidney negative relationship with PTH has been reported (Moysés and function declines (Moysés and Schiavi, 2015; Massy and Drueke, Schiavi, 2015; Figurek et al., 2020). Additionally, high sclerostin 2017; Figurek et al., 2020). Thus, the level has been reported to be levels have been associated with PTH resistance or 5 times higher in patients with CKD G5D (Figurek et al., 2020). hyporesponsiveness to PTH in CKD (Massy and Drueke, 2017; Additionally, increased sclerostin values have been described in Figurek et al., 2020; Bover et al., 2021c). Other molecules beyond Frontiers in Physiology 11 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 PTH and phosphate (and probably FGF23) also seem to regulate the 2022). Consequently, in case that a cessation of treatment is deemed expression of sclerostin, such as calcitriol, BMPs, TNF, and necessary either by patient’s decision, or medical reasons such as low prednisone (Moysés and Schiavi, 2015), suppressing sclerostin adherence, or after reaching a determined T-score at BMD, or after expression from osteocytes, and increasing the rate of bone completing the 12-month treatment (in the case of romosozumab), remodelling (Figurek et al., 2020). guidelines recommend different approaches and/or sequential Finally, an inverse relationship has been described between treatments which are more detailed and specific after denosumab sclerostin and bone AP (Figurek et al., 2020). A recent study suppression (Tsourdi et al., 2017; McClung et al., 2020; Kendler et al., assessed the relationship between bone histomorphometric 2022; Kim et al., 2022). parameters from patients with CKD G3-G4 and circulating levels In summary, CKD is a highly prevalent condition and recent years of the Wnt antagonists sclerostin and Dkk-1 (Neto et al., 2021). It have witnessed important advances in the understanding of the was observed that individuals with low-turnover bone disease associated mineral metabolism disorders. The systemic complex CKD- (diagnosed by bone biopsy) had higher circulating sclerostin MBD has already been universally accepted because of its clear levels and lower DKK-1 and RANKL levels as compared to association with cardiovascular disease and extremely high mortality individuals with high-turnover bone disease or normal bone rates. CKD-MBD includes a bone component which is no longer just histology (Neto et al., 2021), demonstrating an association represented by the classical ROD or disorders of bone remodelling. In between higher circulating sclerostin values and lower bone fact, it is now very well known that CKD is associated with a higher risk of remodelling (low bone turnover). Additionally, in a CKD animal falls and fractures, and higher mortality rates when a fracture occurs. New model of ABD, high dietary phosphate intake was associated with guidelines suggest that BMD should also be assessed in CKD patients if high osteocyte SOST expression (Antoine et al., 2020). While more results will impact clinical decisions (i.e., individualized prescription of studies are needed to assess the usefulness of the circulating values of anti-OP drugs). Several illustrative algorithms for CKD patients have sclerostin as a clinical tool to identify patients with low-turnover already been published, broadly calling for a shift from nihilism to bone disease in CKD, taking into account all the data it may be pragmatism (Pimentel et al., 2017; Evenepoel et al., 2021b; Evenepoel concluded that blocking sclerostin could be an interesting treatment et al., 2021c; Pimentel et al., 2021; Casado et al., 2022; Ginsberg and Ix, target for those patients with low-bone turnover or at least some 2022; Haarhaus et al., 2022). However, it is still prudent to use these drugs CKD patients with OP due its dual positive action (Antoine et al., (bisphosphonates, denosumab, recombinant PTH and romosozumab) 2020). Romosozumab has recently been approved for the treatment with caution, especially in advanced kidney disease, balancing the risk/ of postmenopausal OP, although in Europe it carries a black box benefit ratio, since, as documented in this article, pathophysiological warning that it should not be initiated in patients with myocardial pathways are extremely intricate and not completely unraveled yet. infarction or stroke in the preceding year (Anthony, 2019). Initial positive experiences in CKD patients are being currently published (Sato et al., 2021; Miller et al., 2022; Suzuki et al., 2022). Author contributions AA Preparation of the draft (first version). LG Preparation of the Denosumab and romosozumab draft (first version). PU-T, NC-L, MR-G, EM, IdS, VL-B, MS-B, AP- E, MU, JP, MB, AV, IG-L, JN-G, and LM, Critical review of the We have already briefly discussed both the OPG-RANKL-RANK article with important contributions to its intellectual content and system and the Wnt-β-catenin signaling pathway, and that these approval of the final version to be published. JB Preparation of the monoclonal antibodies (anti-RANKL and antisclerostin, respectively) draft (first version), Critical review of the article with important are not contraindicated in CKD or dialysis patients with OP. contributions to its intellectual content and approval of the final Nevertheless, their use in CKD may be associated with specific version to be published. All authors contributed to the article and problems (at least in advanced stages), which are described elsewhere approved the submitted version. (Festuccia et al., 2017; Bover et al., 2019; Miller et al., 2022; Suzuki et al., 2022)”. Briefly, hypocalcemia is more frequently observed in CKD patients and therefore an adequate repletion of calcium and vitamin Acknowledgments D is recommended (Miller et al., 2022), especially in dialysis patients. Most importantly, the favorable skeletal effects of these monoclonal Some authors belong to the SGR program of “Generalitat de antibodies may reverse quickly upon discontinuation, especially after Catalunya” (2021-SGR-00187 REMAR Group), and the RICORS denosumab withdrawal, because of a vast increase of OC number and 2040 (kidney Disease) (Redes de Investigación Cooperativa activity, which may lead to a subsequent profound increase of bone Orientadas a Resultados en Salud), IDI-2021-000080 or RD21/ turnover to pre-treatment or even above pre-treatment values, a 0005/0009 and RD21/0005/0013, ISCIII, Instituto de Salud Carlos phenomenon commonly described as “rebound phenomenon” III, Spain. (Casado and Neyro, 2021). In the case of denosumab, subsequent multiple vertebral fractures have been described upon discontinuation (Tsourdi et al., 2017; McClung Conflict of interest et al., 2020). Risk was similar to that observed in the placebo group in the randomized clinical trials (Kim et al., 2022). A recent new hypothesis for The authors declare that the research was conducted in the the rebound effect after denosumab cessation is by the phenomenon to absence of any commercial or financial relationships that could be OB recicling from osteomorphs, a newly described cell state (Kim et al., construed as a potential conflict of interest. Frontiers in Physiology 12 frontiersin.org Aguilar et al. 10.3389/fphys.2023.1177829 Publisher’s note organizations, or those of the publisher, the editors and the reviewers. 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