Bone loss in chronic kidney disease: Quantity or quality?

    Bone loss in chronic kidney disease: Quantity or quality? Cai-Mei Zheng, Jin-Quan Zheng, Chia-Chao Wu, Chien-Lin Lu, Jia-Fwu Shyu, Hsu Yung-Ho, Mei-Yi Wu, I-Jen Chiu, Yuan-Hung Wang, Yuh-Feng Lin, Kuo-Cheng Lu PII: DOI: Reference:

S8756-3282(16)30084-9 doi: 10.1016/j.bone.2016.03.017 BON 11003

To appear in:

Bone

Received date: Revised date: Accepted date:

24 January 2016 18 March 2016 28 March 2016

Please cite this article as: Zheng Cai-Mei, Zheng Jin-Quan, Wu Chia-Chao, Lu Chien-Lin, Shyu JiaFwu, Yung-Ho Hsu, Wu Mei-Yi, Chiu I-Jen, Wang Yuan-Hung, Lin Yuh-Feng, Lu KuoCheng, Bone loss in chronic kidney disease: Quantity or quality?, Bone (2016), doi: 10.1016/j.bone.2016.03.017

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Bone Loss in Chronic Kidney Disease: Quantity or Quality?

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Cai-Mei Zheng1,2,3**, Jin-Quan Zheng3,4**, Chia-Chao Wu5, Chien-Lin Lu3, Jia‐‐ Fwu Shyu6, Hsu Yung-Ho1,2,3, Mei-Yi Wu1,2, I-Jen Chiu1, Yuan-Hung Wang3,7

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Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital,

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Taipei Medical University.

Department of Internal Medicine, School of Medicine, College of Medicine,

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Taipei Medical University.

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Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical

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University, Taiwan.

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Yuh-Feng Lin1,2,3, Kuo‐‐Cheng Lu3,5,8

Division of Pulmonary and Critical Care, Department of Critical Care Medicine,

Shuang Ho Hospital, Taipei Medical University. 5

Division of Nephrology, Department of Medicine, Tri-Service General Hospital,

National Defense Medical Center, Taipei, Taiwan. 6

Department of Biology and Anatomy, National Defense Medical Center, Taipei,

Taiwan. 7

Department of Medical Research, Shuang Ho Hospital, Taipei Medical iversity,

New Taipe Uni City, Taiwan 8

Division of Nephrology, Department of Medicine, Cardinal-Tien Hospital, 1

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.

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** Cai-Mei Zheng and Jin-Quan Zheng equally contributed to the work. Corresponding Author:

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Kuo‐‐Cheng Lu

No. 510 Zhongzheng Rd., Xinzhuang Dist., New Taipei City, 24205 Taiwan

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(R.O.C)

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Email address: [email protected]

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Abstract Chronic kidney disease (CKD) patients experience bone loss and fracture because

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of a specific CKD-related systemic disorder known as CKD–mineral bone disorder

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(CKD–MBD). The bone turnover, mineralization, and volume (TMV) system describes the morphological bone lesions in renal osteodystrophy related to

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CKD–MBD. Bone turnover and bone volume are defined as high, normal, or low, and

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bone mineralization is classified as normal or abnormal. All types of bone histology related to TMV are responsible for both bone quantity and bone quality loss in CKD

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patients. This review focuses on current bone quantity and bone quality loss in CKD

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patients and finally discusses potential therapeutic measures.

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Highlights

►Both bone quantity and quality loss are noted with progressive renal function

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impairment in chronic kidney disease patients. ►The mechanism of bone loss relies on systemic factors including vitamin D deficiency, mineral disturbances, inflammation, and uremic state. ► Local bone remodeling and bone turnover status also influence bone quantity and quality loss in these patients. ► Treatment of bone loss requires targeted therapy for both systemic factors and local bone remodeling.

Keywords: chronic kidney disease–mineral bone disorder (CKD–MBD); bone quantity and bone quality loss; bone remodeling; vitamin D therapy

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Contents 1. Introduction

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2. Bone Remodeling and Microenvironment 2.1. Normal Coupling of Osteoblasts and Osteoclasts during Bone Remodeling

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2.2. Abnormal Bone Remodeling in Chronic Kidney Disease 3. Bone Quantity Loss: Bone Mineral Density/Bone Mass Changes in Chronic

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Kidney Disease Patients

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3.1. High-Turnover Bone Disease-Associated Bone Quantity Loss 3.2. Low-Turnover Bone Disease-Associated Bone Quantity Loss 3.3. Immobilization and Lack of Mechanical Loading in Chronic Kidney Disease Patients 3.4. Vitamin D Deficiency-Related Bone Quantity Loss 3.5. Evaluating Bone Quantity Loss in Chronic Kidney Disease patients 3.5.1. Role of Imaging Studies 3.5.2. Bone Biopsy and Histomorphological Studies 3.5.3. Biomarkers of Bone Formation and Resorption 4. Bone Quality Loss: Abnormal Material Composition, Structural Failure, and Microdamage in Chronic Kidney Disease Patients 4.1. High-Turnover Bone Disease-Associated Bone Quality Loss 4.2. Low-Turnover Bone Disease-Associated Bone Quality Loss 4.3. Vitamin D Deficiency-Related Bone Quality Loss 4.4. Uremic Osteoporosis-Related Bone Quality Loss 4.5. Evaluating Bone Quality Loss in Chronic Kidney Disease Patients 4.5.1. Role of Imaging Studies 4.5.2. Role of Bone Biopsy and Histomorphometric Studies 4.5.3. Retained Uremic Toxins as Markers of Bone Quality Loss 5. Treatment Considerations of Bone Loss in Chronic Kidney Disease Patients 5.1. Vitamin D Supplementation 5.1.1. Nutritional Vitamin D (Cholecalciferol, Ergocalciferol) 5.1.2. 25-hydroxy Vitamin D (Calcifediol) 5.1.3. Active Forms of Vitamin D 5.1.4. Role of Uremic Absorbent AST-120 and Extensive Dialysis Therapy 6. Treatment of Specified Bone Disorders 6.1. High-Turnover Bone Disease 6.2. Low-Turnover Bone Disease 7. Conclusions 4

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8. References

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? 1. Introduction Chronic kidney disease (CKD) patients experience more susceptibility to fractures

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along with fracture-related mortality [1, 2]. Traditional osteoporosis, as defined by the National Institutes of Health [3], and/or CKD–mineral bone disorder

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(CKD–MBD)-related bone histological abnormalities (renal osteodystrophy [ROD])

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[4, 5] are noted in CKD patients. The World Health Organization (WHO) bone mineral density (BMD) (T score) criteria for osteoporosis can be used to diagnose

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osteoporotic fractures in early CKD stages as long as no CKD–MBD-related systemic and biochemical changes are present. Stage 3 CKD is subdivided into stages 3A

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(eGFR 60–30 mL/min−1) and 3B (eGFR 60–45 mL/min−1) because different derangements in the biochemical regulatory process occur between stage 3A and 3B

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CKD. Early CKD is characterized by a progressive rise in osteocyte-derived fibroblast

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growth factor 23 (FGF-23) and increasing parathyroid hormone (PTH) production in

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later CKD stages (3B and lower) [6–8]. Different quantitative bone histomorphometric changes related to systemic metabolic abnormalities (e.g., serum FGF-23, calcium, phosphate, and PTH levels) are noted [9]. Bone strength loss in CKD–MBD patients is associated with two components: loss of bone quantity (mass) and loss of bone quality (abnormalities in structure and material as well as microdamage) [10, 11]. Bone remodeling—cellular machinery that mediates the balance between bone formation and resorption—is the local biological process that specifically influences bone strength. The interconnections among the trabecular network, especially in trabecular bone, are also crucial determinants of bone strength. The accumulation of microdamage strongly influences bone strength. Moreover, “uremic osteoporosis,” possible uremic toxin-related bone quality loss, also presents as clinical fractures in CKD–MBD patients (Table 1). With progressive renal function impairment and dialysis therapy, the pattern of 6

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? ROD seems to be shifting from the classic secondary hyperparathyroidism presentation to one of low bone turnover bone disease. Patients also live longer when

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receiving dialysis therapy and are more likely to be able to engage in physical activities than if not receiving the therapy. CKD–MBD patients might experience

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more fractures related with physical activity because of weakened pathological bone.

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Moreover, their quality of life is influenced by musculoskeletal problems, including bone pain and muscle weakness [12]. Chronic musculoskeletal pain also significantly

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limits the physical activity and quality of life of renal failure patients [13].

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ROD-related bone pain initially presents as periarticular pain and later becomes diffuse and nonspecific, which might be related to weight bearing. Whether

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microfractures cause bone pain in these patients remains controversial, and why

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patients with aluminum-related bone disease experience more severe pain [14] is also unknown. Muscle weakness is also highly common in CKD patients, especially in

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those presenting proximal myopathy. The physiological basis for this weakness remains unclear [15].

In brief, complex systemic and local factors influence CKD patient bone strength and fractures, which finally determines their quality of life. Understanding these complex mechanisms might help clinicians to accurately diagnose and treat bone disease and fractures in these patients. 2. Bone Remodeling and Microenvironment Bone remodeling is a process by which old bone is removed and damaged bone is repaired to ascertain the mechanical integrity of the entire skeleton [16–18]. The process is performed within anatomically distinct sites (basic multicellular units [16]) and is orchestrated by cells of the osteoblast lineage and osteoclasts. With local bone damage, osteocyte apoptosis occurs; the lining cells and local factors released by dying osteocytes initiate osteoclast formation and activation. Osteoclastic resorption 7

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? of damaged bone is replaced by osteoblast bone deposition at the same site. Bone remodeling plays a crucial role in repairing microdamage, removing the areas with

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microcracks, and replacing them with new bone. 2.1. Normal Coupling of Osteoblasts and Osteoclasts during Bone Remodeling

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The regulation of bone remodeling is influenced by both systemic and local

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factors. The major systemic regulators include PTH, calcitriol, and other hormones such as growth hormone, glucocorticoids, thyroid hormones, and sex hormones.

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Insulin-like growth factors, prostaglandins, tumor growth factor-beta, bone

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morphogenetic proteins (BMPs), and cytokines are also involved in systemic regulation. Moreover, the mechanical loading applied by muscle on the bone provides

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an anabolic stimulus for the bone and is directly responsible for bone formation and

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remodeling [89]. Osteocytes are the main mechanosensing apparatus within bone, direct osteogenesis to the site where it is most required, and improve bone strength

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[19]. The osteocyte network control of osteoclast and osteoblast activity occurs through mechanical loading and unloading, during which bone resorption by osteoclasts and bone formation by osteoblasts occur [20]. Molecular-level bone remodeling regulation occurs through the receptor activator of nuclear factor κB (NF-κB) (RANK)/receptor activator of the NF-κB ligand (RANKL)/osteoprotegerin (OPG) system. The RANK on the surface of osteoclast cells causes osteoclast activation and proliferation when it is bound with the RANKL that is produced by osteoblasts [21, 22] and generates bone resorption. OPG, a protein secreted from osteoblast cells, is a decoy receptor for the RANKL, prevents the RANKL from binding with the RANK [21], and protects the skeleton from excessive bone resorption. Thus, through the RANKL/OPG system, bone resorption and bone formation are tightly coupled and maintain skeletal integrity. 2.2. Abnormal Bone Remodeling in Chronic Kidney Disease Patients 8

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Dysregulated bone remodeling in CKD patients results from an imbalance between osteoclastic bone resorption and osteoblast bone formation with resultant

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bone loss (Figure 1). A progressive rise in osteocyte-derived FGF-23 from as early as stage 2 CKD (eGFR of approximately 70–90 mL/min/1.73 m2) occurs, which causes

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early phosphaturia [23, 24]. This alteration of FGF23 expression in rat models reveals

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reduced bone mineralization [25]. Shalhoub et al. also demonstrated that FGF23 inhibits in vitro bone mineralization and osteoblast activity [26]. Furthermore,

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increased plasma FGF23 and its regulatory protein, osteocytic dentin matrix protein 1,

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were found to be correlated with the histomorphometric parameters of skeletal mineralization [27].

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Human genetic studies have highlighted the crucial role of WNT (wingless)

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signaling in bone mass regulation. WNTs are extracellular proteins that are linked to intracellular canonical and noncanonical WNT signaling pathways when activated.

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They were found to be implicated in osteoblast and osteoclastic differentiation and function [28], which is critical for trabecular and cortical bone mass. WNT signaling acts directly on osteoclast progenitors or indirectly by stimulating the release of OPG from osteoblasts [28]. WNT3a and WNT10b, acting through canonical signaling, and WNT16, acting through both canonical and noncanonical signaling, induce production of OPG in osteoblasts. OPG binds to the osteoclast-inducing cytokine RANKL and thereby inhibits osteoclast differentiation. Osteoblast WNT5a potentiates RANK-induced osteoclast differentiation by activating ROR2-dependent noncanonical signaling. By contrast, WNT4 and WNT16 act directly through noncanonical signaling on osteoclast progenitors to inhibit RANKL-induced osteoclast formation. WNT signaling also influences osteoblast differentiation and function during bone modeling. The osteocyte secretes sclerostin and Dickkopf-related protein-1, 9

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? which may inhibit osteoblast differentiation and maturation by inhibiting WNT signaling. Sabbagh et al. demonstrated that increased osteocytic sclerostin expression

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in CKD Jck mice [29] occurs during the early stages of CKD. Sclerostin is responsible for the suppression of bone formation and development of adynamic bone

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disease (ABD) [29] in early CKD stages. During this period, osteocytic

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WNT/β-catenin signaling is repressed and the osteoclastic RANKL is activated. In the later stages of CKD, PTH suppresses skeletal sclerostin expression and generates a

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high bone turnover status [29]. The sophisticated role of these signaling types in the

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CKD and end-stage renal disease (ESRD) population still requires exploration. High PTH levels during progressive CKD upregulate RANKL m-RNA and

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inhibit OPG gene expression in bone marrow stromal osteoblasts [30], increasing the

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quantity of osteoclasts and osteoblasts [31]. However, in a clinical setting, a significantly increased serum OPG level is present in predialysis patients, increases up

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to 3-fold in dialysis patients [32], and further increases with hemodialysis (HD) duration. OPG levels were determined to be significantly lower in ABD patients than in high-turnover bone disease or mixed osteodystrophy patients [33]. Thus, an OPG increment in uremic patients might protect against intensive bone loss by inhibiting osteoclastic activity and reducing the RANKL level [34], which is a compensatory mechanism for modulating bone remodeling in these patients [34]. In our previous study, we revealed that an increment in OPG levels was correlated with increased lumbar spine BMD after parathyroidectomy (PTX) in HD patients [35] and might be associated with suppression of osteoclastic bone resorption during that period. CKD patients have characteristically low 25 (OH) vitamin D (calcidiol), low 1,25 (OH) 2 vitamin D (calcitriol), and vitamin D resistance [36, 37]. Decreased ionized calcium, calcitriol, and hyperphosphatemia increase the synthesis and/or secretion of PTH (secondary hyperparathyroidism) when eGFR is lower than 60 10

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? mL/min [38]. With progressive loss of renal mass, limited 25 (OH) D enters the renal tubules and less 25 (OH) D is uptaken. Proteinuria and damaged proximal tubular

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cells reveal less megalin expression [39], impairing 25 (OH) D reabsorption. Moreover, impaired 25 (OH) D resorption results in the formation of less 1, 25 (OH)

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2D (calcitriol) in a substrate-dependent process [40]. The mitochondrial protein

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24-hydroxylase initiates the degradation of 25 (OH) D and 1, 25 (OH) 2D through hydroxylation of the side chain to form calcitroic acid. CKD, diabetes mellitus,

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increased FGF-23, and active vitamin D supplementation reduce the activity of

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25-hydroxylase and 1-α-hydroxylase and increase the activity of 24-hydroxylase [41, 42]. This reduces endogenous 25 (OH) D and 1, 25 (OH) 2D production and enhances

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their degradation. CKD patients with secondary hyperparathyroidism on high doses of

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active vitamin D may have aggravated 25 (OH) D deficiency [41], which may also reduce the availability of 25 (OH) D in extrarenal tissue, organs, and cells including

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osteoblasts, the parathyroid gland, muscles, and immune cells. Secondary hyperparathyroidism and elevated FGF-23 also promote the enzyme 24-hydroxylase and inhibit 1α-hydroxylase with resultant low active vitamin D formation. CKD is also characterized by vitamin D resistance when a progressive loss of vitamin D receptor (VDR) in the parathyroid gland occurs. The rising FGF-23 reduces PTH expression through the Klotho-FGFR1c receptor complex [43, 44]. However, downregulation of this complex occurs with progressive CKD, likely explaining why persistently high PTH levels occur despite increased FGF-23 in CKD patients [45]. According to animal studies, vitamin D deficiency is also clearly associated with impaired fracture healing [46], less resistance to torsional stress [46–48] , delayed union, increased bone fragility, and less callus and undermineralized bone [49]. Inflammation is a unique feature of advanced CKD patients [50–52], and many studies have proven that systemic inflammation might increase bone fracture risk in 11

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? these patients [53]. Among circulating inflammatory cytokines, interleukin-1beta and tumor necrosis factor alpha (TNF-α) play the most crucial role in bone remodeling

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[54]. These cytokines stimulate osteoclastogenesis by inducing the expression of the RANKL (i.e., a key trigger of osteoclast activation and bone resorption) [54–57].

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TNF-α also directly inhibits osteoblast function by promoting osteoblast-specific

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transcription factor Runx2 degradation [58, 59] and inhibiting Runx2 expression [60]. The regulation of osteoblast apoptosis is now recognized as a major mechanism for

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determining bone formation rates. Circulating proapoptotic proteins including TNFα,

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IL-1, BMP-2, and advanced glycosylated end products (AGEs) are increased in CKD patients (Figure 1).

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Commonly used unfractionated heparin during dialysis is also related to low

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BMD development in patients with osteoporosis through its effects on bone remodeling. Heparin binds to OPG and inhibits its interaction with the RANKL, thus

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enhancing osteoclastic bone resorption [61]. Grzegorzewska et al. [62] revealed a lower femoral neck BMD in dialysis patients who received regular LMWH, antiplatelet agents, or both (Figure 1). 3. Bone Quantity Loss: Bone Mineral Density and Bone Mass Changes in Chronic Kidney Disease Patients The prevalence of osteoporosis (low bone density) varies according to CKD stage. Fractures in early-stage CKD patients (stage 1–3A CKD) are mostly associated with traditional osteoporosis rather than CKD–MBD. Most patients with stage 4 or 5 CKD exhibit alternations in metabolic bone disorders and/or decreases in BMD [63, 64]; at the time of dialysis initiation, up to 50% of patients have experienced a fracture [65, 66]. Together, vitamin D deficiency, poor nutrition, inactivity, myopathy, and peripheral neuropathy play a role in muscle weakness and falls [67] (Table 2).

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? 3.1. High-Turnover Bone Disease-Associated Bone Quantity Loss High-turnover bone disease is associated with reduced BMD because of

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multifactorial causes, including acid–base disturbances as well as impaired vitamin D

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and PTH homeostasis. High-turnover bone lesions, including osteitis fibrosa and

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mixed uremic osteodystrophy, are common in patients with serum intact PTH levels >400 pg/mL. Huang et al. revealed that advanced age, low body weight, a low serum

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albumin level, and high ALP and iPTH levels are associated with low bone mass in HD patients [68]. Continuously high PTH stimulates osteoclastic resorption and

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remodeling rates [69]. Excessive osteoblast viability and activity because of persistent hyperparathyroidism may follow to compensate for the bone resorption, with resultant

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osteosclerosis [70]. Metastatic calcification and vascular calcification occur as a result

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of increased calcium and phosphate solubility product in extracellular fluid [71]. Increased bone resorption and defective mineralization may lead to reduced bone

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mass. Recently, Nickolas et al. [72] reported that patients with CKD have rapid cortical bone loss with significant losses of areal BMD at total hip and ultra-distal radii of −1.3% and −2.4%, respectively, as detected using dual‐energy X‐ray absorptiometry (DXA) [72].

3.2. Low-Turnover Bone Disease-Associated Bone Quantity Loss Low-turnover bone disease includes osteomalacia, aluminum-induced bone disease, and ABD. ABD becomes common in dialysis centers with increasing use of calcium and potent vitamin D analogs to suppress PTH. PTH resistance is unique to CKD and occurs because of PTH receptor downregulation and osteoblast dysfunction [73, 74] by persistently elevated PTH and excessively low 1,25-dihydroxy vitamin D levels [75]. Growing awareness of the relationship between ABD and abnormal 13

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? calcium balance [76] with possible links to calcific arteriolopathy [77] and cardiovascular disease [78] have been noted. This type of ROD is common in elderly

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patients [79] and patients receiving chronic peritoneal dialysis. It is also associated with diabetes mellitus patients, in whom hyperglycemia and hypoinsulinemia act

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synergistically to inhibit PTH release [80].

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3.3. Immobilization and Lack of Mechanical Loading in Chronic Kidney Disease Patients

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Physical immobilization and lack of exercise are extremely common among advanced CKD patients and those under maintenance dialysis [81] and are largely

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responsible for low bone mass and fractures in these patients. Physical exercise may promote bone growth and suppress bone loss not only through the mechanical load

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applied to the skeleton but also by modifying several endocrine axes [82, 83]. Several

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energy-associated hormones, myokines, adipokines, and neurotransmitters finely

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regulate the bone remodeling in response to energy availability and exercise needs [84]. Irisin, a newly discovered exercise-mediated myokine, was determined to be reduced with progressive CKD [85] and was found to be lowest among stage 5 CKD patients [86]. A recent study revealed that active ESRD patients with ABD have greater mineralized bone volume than less active patients do [87]. The beneficial effects of exercise on the bone tissue are largely determined by both structure (macroarchitecture and microarchitecture) and intrinsic bone quality (mainly involving hydroxyapatite and collagen content, which is not the focus of this review). Simple, low-impact, weight-bearing exercises, such as walking and resistance exercise (strength training), are encouraged as daily physical activities for CKD patients to improve their bone strength. 3.4. Vitamin D Deficiency-Related Bone Quantity Loss

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Vitamin D is required for normal bone formation and normal mineralization, which play a critical role in bone biology. Altered vitamin D metabolism plays a

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crucial role in secondary hyperparathyroidism along with other mineral metabolism changes (Table 4). Increased bone turnover, bone loss, and mineralization defects

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have been noted with serum 25-(OH) D levels <50 nmol/L [88, 89]. In a retrospective

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study, Coen et al. [90] found that ESRD patients with 25 (OH) D deficiency (<15 nmol/L) had a lower bone formation rate and trabecular mineralization surface

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independent of PTH and calcitriol levels [90]. A study conducted by Ambrus et al. [91]

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also revealed the association between fractures and significantly low vitamin D status among maintenance HD patients [91]. In another study, Mucsi et al. [92]

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demonstrated a positive relationship between 25 (OH) vitamin D levels and radial

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bone BMD in HD patients. Lower 25 (OH) vitamin D levels have been determined to be associated with subperiosteal resorption and reduced BMD in ESRD patients [93,

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94]. Vitamin D deficiency also causes frailty [95–97] because of muscle weakness, nonvertebral and hip fractures [98–100], and all-cause mortality [101–103]. 3.5. Evaluating Bone Quantity Loss in Chronic Kidney Disease Patients The Kidney Disease Outcomes Quality Initiative guidelines distinguish the following six types of bone disorder on the basis of the turnover, mineralization, and volume system: hyperparathyroid bone disease (high turnover, normal mineralization, and any bone volume), mixed bone disease (high turnover with mineralization defect and normal bone volume), osteomalacia (low-turnover bone with abnormal mineralization and low-to-medium bone volume), ABD (low-turnover bone with normal mineralization and low or normal bone volume), amyloid bone disease, and aluminum bone disease [104–106]. 3.5.1. Role of Imaging Studies 15

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Bone density scanning (DXA or bone densitometry) is a standard measure for predicting fracture risk in members of the general population with bone loss. However,

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the role of DXA in predicting fracture risk in patients with CKD is controversial. The DXA measurement of “areal” density does not measure true “volumetric” density and

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cannot differentiate cortical bone from trabecular bone. Moreover, DXA does not

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predict the type of ROD in CKD patients. By contrast, femoral BMD is correlated with cortical porosity histomorphological samples from stage 5 CKD patients

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receiving dialysis [107]. The Kidney Disease: Improving Global Outcomes guidelines

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recommend DXA measurements for fracture risk assessment in patients with stage 1 to early stage 3 CKD [108]. A reduction in bone mass is associated with increased

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fractures but might not be linked to CKD [109]. However, DXA cannot measure bone

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microstructure or quality, which influence fracture risk [110]. DXA may underestimate the fracture risk in later stages of CKD (stages 4 and 5 CKD) [111, 112];

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some recent studies have used two-dimensional as well as three-dimensional DXA to predict fracture risk in patients with severe CKD [113–115] but still yielded inconclusive results.

The WHO’s Fracture Risk Assessment Tool (FRAX) combines 10 clinical risk factors with or without femoral neck BMD to estimate the 10-year absolute risk of major osteoporotic or hip fractures in the general population [116]. In CKD patients, the clinical utility of FRAX remains unclear. FRAX did not predict fractures in patients with ESRD receiving HD [117]. Naylor et al. [118] reported that the discrimination and calibration of FRAX do not significantly differ in CKD patients for fracture assessment. Quantitative computed tomography (QCT) can be employed to more accurately quantify BMD, and it measures the volumetric BMD and geometry of both cortical and trabecular compartments. HR-pQCT is a noninvasive tool that being used to 16

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? clarify the microstructural basis of CKD-related fragility in predialysis patients receiving HD and after kidney transplantation. 3DHR-pQCT measures the strength of

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the entire bone or individual cortical and trabecular compartments. Recently,

120] as well as trabecular plate and rod structure [121].

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advanced HR-pQCT methods have been used to characterize cortical porosity [119,

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3.5.2. Bone Biopsy and Histomorphological Studies

Transiliac crest bone biopsy with a histomorphological study is the most

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sensitive and specific method of assessing bone strength in those with renal bone

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disease [122–125] and is also the gold standard for excluding age-related osteoporosis as a cause of ROD. For prior tetracycline labeling that is attached to calcium [122,

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123], the fluorescence is determined under a fluorescent microscope, and the width

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between double fluorescence is measured to quantify certain dynamic parameters of bone turnover. However, routine use of bone biopsy is not practicable because it is

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invasive, expensive, and not widely available. 3.5.3. Biomarkers of Bone Formation and Resorption Because bone biopsies are invasive and technician-dependent, noninvasive high-resolution imaging techniques and bone biomarkers are regarded as more feasible for predicting fractures in CKD patients. Bone formation markers including bone-specific alkaline phosphatase (BSAP), osteocalcin, and procollagen type-1 N-terminal propeptide (P1NP) are markers of osteoblast function. Bone resorption markers such as tartrate-resistant acid phosphatase 5b (Trap-5b) and C-terminal telopeptides of type I collagen (CTX) are markers of osteoclast number and function. Trap-5b and BSAP are not cleared by the kidneys and are mostly used in CKD patients as useful biomarkers. Serum intact PTH(iPTH) and BSAP are most commonly used as markers of turnover to discriminate renal bone disease [126]. High serum intact PTH(iPTH) and BSAP indicates high-turnover bone disease, whereas 17

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? low serum intact PTH(iPTH), low BSAP, and normal vitamin D levels occur in ABD patients. Low vitamin D and PTH levels in conjunction with high levels of BSAP are

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correlated with osteomalacia. Osteocalcin, P1NP monomer, and CTX are cleared by the kidneys, and their usefulness in treating CKD patients remains unclear.

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Serum PTH and BTM also assist in predicting bone loss and fractures in CKD

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patients. High levels of PTH and BTM were shown to be associated with cortical and trabecular density as well as thinner cortices and trabeculae [127] (21). P1NP,

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osteocalcin, CTX, and Trap-5b levels predict fractures [127]. Low (<150 pg/mL) or

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high (>300 pg/mL) PTH levels along with higher BSAP levels [117] are associated with a higher fracture risk in ESKD patients. PTH levels ≥130 pg/mL at 3 months

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post transplantation also predict incident fractures in kidney transplant recipients

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[128]. Nutritional markers (e.g., prealbumin, nPNA, and BMI) were found to predict BMD in chronic PD patients and were determined to be associated with fracture risk

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in a cross-sectional study [129]. Additional prospective studies are required to evaluate the role of BTM in fracture risk assessment and determine the optimal time interval for bone disease monitoring. 4. Bone Quality Loss: Abnormal Material Composition, Structural Failure, and Microdamage in Chronic Kidney Disease Patients Bone is composed of inorganic minerals (mainly calcium and phosphate hydroxyl apatite crystals) and type I collagen [130]. Tissue mineral density produces bone stiffness, and collagen crosslinking generates tensile strength. Variations in bone tissue mineral density and in collagen crosslinks affect both bone strength and function. Deteriorated bone elastic mechanical and mineral properties have been shown to be associated with CKD [105, 131, 132]. AGEs associated with oxidative stress and chronic inflammation [133] were determined to be correlated negatively with the rates of bone formation and mineral apposition [134] in CKD patients. 18

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Structural arrangement and orientation of bone minerals and matrices also influence bone quality. Interactions among chronic abnormal parathyroid function, impaired

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bone turnover, uremia-related toxins, and vitamin D deficiency generate “bone quality loss” in CKD patients. A recent study conducted by Malluche et al. [135] proved that

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a high-turnover status produced more changes in material composition and

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nanomechanical properties, whereas a low-turnover status resulted in more changes in microstructural parameters. Although no definitive data exist regarding the bone

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microdamage [136] in CKD patients, an abnormal rate of microdamage formation and

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repair is noted in both high- and low-turnover CKD patients, with resultant microscopic and macroscopic cracks presenting clinically with bone fractures (Table

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3).

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4.1. High-Turnover Bone Disease-Associated Bone Quality Loss High-turnover bone disease in CKD patients is characterized by increased

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osteoclast activity with disturbed bone remodeling (more bone resorption than bone formation) and bone architectural changes. The degree of mineralization is impaired in those with a high-turnover status because the recently formed bone is removed rapidly without adequate mineralization [137]. Bones from a high-turnover state have lower mineralization and lower trabecular microhardness than do bones from normal or low-turnover states [135, 138]. A low mineral-to-matrix ratio [135] and low carbonate-to-phosphate ratio [139] reduce bone toughness. Moreover, collagen crosslinking abnormalities have been observed in both serum and soft tissue [134, 140], which were believed to influence the bone microstructural parameters [141–145] in the patients. High PTH generates microstructural alterations at both the cortical and trabecular levels in CKD patients. Specifically, chronic excess PTH secretion is catabolic for cortical bone with decreased cortical thickness, whereas increased trabecular thickness has been observed [146–148] but with disturbed trabecular 19

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? quality. Amling et al. [149] demonstrated that reduced trabecular connectivity and trabecular perforations occur in ESRD patients. Another study [150] revealed a

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marked loss of both trabecular bone mass and thinning of the cortical shell in the vertebra of CKD animals with high PTH, suggesting that high-turnover CKD disease

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also compromises the mechanical properties of vertebra [150]. Furthermore, bone

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deformities in a high-turnover status increased microdamage generation [151, 152], which also produces thinner cortices or reduced trabecular connectivity.

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4.2. Low-Turnover Bone Disease-Associated Bone Quality Loss

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In low-turnover bone disease, disturbed bone remodeling occurs with decreased bone resorption and bone formation. Osteoblast apoptosis is a major mechanism that

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suppresses bone formation [153]. The amount of interchangeable calcium and

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phosphate are reduced with a lower turnover status, generating more serum minerals, which are principally associated with vascular and soft tissue calcification. Compared

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with high or normal turnover states, low-turnover states were determined to have more microstructural abnormalities including lower cancellous bone volume and reduced trabecular thickness [135]. Similar to high bone turnover in patients, low bone turnover in patients with CKD is also associated with a reduced carbonate-to-phosphate ratio [135]. The rate of bone microdamage repair is reduced in low-turnover CKD patients [151, 152] and causes clinical fractures. 4.3. Vitamin D Deficiency-Related Bone Quality Loss Vitamin D deficiency is associated with an impaired bone mineralization phase, resulting in a larger unmineralized bone matrix, called an osteoid. Recently, a group of U.S. and German scientists [154] demonstrated that vitamin D deficiency speeds the premature aging of existing bone and reduces its quality [154]. Apart from overall reduced mineralization, changes in remaining mineralized bone are also associated with a higher degree of mineralization as well as a mature collagen crosslink ratio and 20

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? carbonate-to-phosphate ratio, which are characteristics of aging and brittle bone [154]. Moreover, vitamin D deficiency inhibits the normal bone remodeling in remaining

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mineralized bone tissue [154, 155]. Vitamin D deficiency is associated with significant loss in the mechanical integrity and toughness of human cortical bone,

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which can also be explained by tissue aging [154]. Furthermore, vitamin D-deficient

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tissue has a straighter crack path with fewer crack bridges compared with normal bone, which is more prone to fractures (Table 4). Thus, vitamin D levels should be

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maintained at well-balanced levels to maintain the structural integrity of bone,

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especially in CKD patients.

4.4. Uremic Osteoporosis-Related Bone Quality Loss

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ESRD patients also have an extremely high risk of bone fractures because of the

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high incidence of uremic osteoporosis and MBD. Compared with the normal population, uremic patients are more prone to having low bone mass, a disarranged

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microarchitecture, skeletal fragility, and abnormal bone metabolism [156]. Several uremic toxins exert noxious effects on bone metabolism and function [157, 158] (Table 5). Indoxyl sulfate (IS) is a representative uremic toxin that accumulates with progressive renal dysfunction in CKD patients. A study revealed a positive correlation between IS levels and bone formation rate, osteoid volume, osteoblast surface area, and bone fibrosis volume [159]. Multivariate regression analysis confirmed the associations between IS levels and osteoblast surface area, bone fibrosis volume, and bone formation rate [159]. The concept of “uremic osteoporosis” was recently introduced by Fukagawa et al. [160, 161] to explain the role of uremic toxins in changing bone quality in CKD patients. They determined that the mineral-to-matrix ratio and carbonate substitution increased with the number immature crystals in CKD rats [160]. The enzymatic crosslink ratio was also abnormally increased. Accumulated uremic toxins, especially IS, might also be responsible for pathological 21

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? collagen crosslinks with disturbed orientation and deteriorated mechanical properties [160] in CKD patients. Oral absorbent AST-120 [160] significantly reduces serum IS

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levels and can abolish the bone effects noted in CKD animals. A recent animal study [162] suggested that IS exacerbates low bone turnover bone disease by inhibiting

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formation through skeletal resistance to PTH and other unknown mechanisms.

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4.5. Evaluating Bone Quality Loss in Chronic Kidney Disease Patients 4.5.1. Role of Imaging Studies

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Because of recent advances in imaging methods, these methods can be used to

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detect bone quality loss, including altered bone material and structure as well as microdamage, from the macroorgan level to the nanoscale level. Fourier transform

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infrared (FTIR) spectroscopy provides material-relevant information regarding bone

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minerals and matrices from the bone biopsies of different turnover states in stage 5D CKD patients [135] and detects the mineral-to-matrix ratio (relative mineralization),

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carbonate-to-phosphate ratio (crystal purity), crystallinity (crystal size and perfection), and collagen crosslinking ratio (the relative proportion of mature to immature collagen crosslinks) [135, 163–165]. Raman spectroscopy is complementary to FTIR and measures chemical bonds that are rarely detected through FTIR. Raman spectroscopy also measures the carbonate-to-phosphate ratio, crystallinity, and mineral-to-matrix ratio [165]. Quantitative backscatter electron imaging, high-performance liquid chromatography, and energy-dispersive X-ray spectroscopy might also be able to detect material composition, but their usefulness in treating CKD patients remains controversial. 4.5.2. Role of Bone Biopsy and Histomorphometric Studies Bone quality microstructural parameters determine the load-bearing competency of bone. As previously described, iliac crest bone biopsy and histomorphometry is the gold standard for both quantifying and qualifying the bone structure of patients with 22

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? CKD–MBD [166]. Bone volume, trabecular thickness, trabecular separation, trabecular number, cortical thickness, cortical porosity, and collagen texture are

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detected. Bone activation frequency, bone formation rate, and osteoblast and osteoclast surface and number determine bone turnover status, whereas osteoid thickness,

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osteoid maturation time, and mineralization lag time can determine mineralization

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nature. Micro-CT has been determined to be less effective than bone histomorphometry in differentiating ROD from normal bone [167, 168].

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4.5.3. Retained Uremic Toxins as Markers of Bone Quality Loss

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Serum BSAP is used with PTH levels to identify patients with low bone formation (e.g., BSAP < 20, PTH < 100 pg/mL). Uremic retention solutes in CKD

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patients act as uremic toxins and interact with normal biological functions. Uremic

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toxins are involved in kidney–bone–vascular axis disorders and might be useful as biomarkers of bone loss in patients with these disorders. Some crucial uremic toxins

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believed to be involved in kidney–bone disorders are phosphate, FGF-23, PTH, AGEs, β2-microglobulin, and protein-bound substances including IS and paracresyl sulfate. Whether these uremic toxins alone or in combination with bone turnover markers can be used to differentiate bone quality changes in CKD patients still requires investigation.

5. Considerations for Treating Bone Loss in Chronic Kidney Disease Patients As described previously, BMD is strongly related to fracture risk in patients with traditional osteoporosis but only weakly related to fracture risk in CKD patients [169]. In CKD patients, cortical bone loss is the primary type of bone loss, whereas in osteoporosis patients, both cortical and trabecular bone is lost. CKD–MBD patients have abnormal vascular changes in addition to changes in circulating minerals, electrolytes, enzymes, and signaling factors, which are not observed in ordinary osteoporosis patients. Therefore, those providing therapy should consider multiple 23

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? pathophysiological conditions in addition to the short-term and long-term effects on the bone. Fractures in early-phase CKD patients without systemic and biochemical

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changes can be treated as osteoporosis-related fractures, but patients with later stage CKD require more sophisticated therapies for treating their systemic CKD–MBD

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disorders. Therapies that are designed according to bone quality and quantity changes

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that result from low- or high-turnover bone disease may be more effective for preventing fractures in CKD patients.

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Theoretically optimal therapeutic measures for preventing CKD include using

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medicines that serve the following functions: increase bone mass; improve skeletal architecture by increasing bone size and dimension, particularly in cortical bone;

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increase trabecular number and thickness; restore connectivity; improve the material

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properties of bone simply by, for example, normalizing turnover and increasing mineralization; and optimally perform these functions without impairing the ability to

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repair microdamage (Figure 2).

5.1. Vitamin D Supplementation Two nonmutually exclusive strategies for using vitamin D to treat CKD patients are using nutritional vitamin D (cholecalciferol, ergocalciferol) and active vitamin D (calcitriol or analogs). Treatment for vitamin D insufficiency or deficiency reduces fracture risk as well as suppresses the renin–angiotensin system, inflammatory pathways, myocardial hypertrophy, and glucose intolerance, all of which might play crucial roles in CKD patients. Treating CKD patients with active vitamin D (calcitriol or analogs) improves secondary hyperparathyroidism (Figure 2). 5.1.1. Nutritional Vitamin D (Cholecalciferol and Vitamin D3) Deficient or insufficient 25-hydroxy vitamin D levels can be restored using nutritional vitamin D3 (cholecalciferol) because vitamin D2 (ergocalciferol) is much less potent and has a shorter duration of action relative to vitamin D3 [170]. Because 24

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? serum 25-hydroxy vitamin D levels are a reliable and accurate measure of vitamin D stores, these levels should be used as a guide in vitamin D replacement therapy [171,

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172]. Specifically, 25-hydroxyvitamin D levels are 16–30 ng/mL (40–75 nmol/L) in those with vitamin D insufficiency, 5–15 ng/mL (12–37 nmol/L) in those with mild

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vitamin D deficiency, and <5 ng/mL (12 nmol/L) in those with severe vitamin D

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deficiency. Because serum levels that are lower than 30 ng/mL are associated with increased intact PTH [173, 174], reduced BMD, and increased rates of hip fractures, a

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recommended level of >30 ng/mL could be extrapolated to the CKD population.

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Several studies have revealed that lower 25 (OH) D levels are related to an increased risk of ESRD [175] and early mortality in dialysis patients [176].

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Single-center studies have also revealed a modest decrease in serum PTH levels

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following nutritional vitamin D treatment in CKD patients [177–179]. Martin et al. reported that treatment with 50,000 IU of ergocalciferol weekly significantly

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increased 25-hydroxy vitamin D levels and reduced intact PTH levels without affecting serum calcium or phosphate levels in stage 3–4 CKD patients with 25-hydroxy vitamin D levels <30 ng/mL and hyperparathyroidism during 6 months of therapy [177]. Thus, in CKD patients with GFR of 20–60 mL/min/1.73 m2, the recommended daily allowance of vitamin D for preventing vitamin D deficiency is 800 IU for those over 60 years and 400 IU for younger adults. No evidence of vitamin D overload or renal toxicity [180, 181] is noted in advanced CKD patients who are treated with 10,000 IU of ergocalciferol for more than 1 year. In those with severe vitamin D deficiency with 25 (OH) D levels <5 ng/mL (12 nmol/L), rickets, or osteomalacia, 50,000 IU of ergocalciferol should be given weekly for 12 weeks and monthly thereafter [182]. Optimal dosing regimens in HD patients remain unknown. An ergocalciferol-prescribing dosing regimen for stage 3–4 CKD patients failed to achieve repletion or maintenance of normal vitamin D levels in HD patients [183]. 25

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? 5.1.2. 25-hydroxy Vitamin D (25 (OH)-VitD; Calcifediol) Compared with active vitamin D (calcitriol), 25-hydroxy vitamin D (calcifediol)

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has a longer plasma half-life and less potency, with fewer effects on hypercalcemia; thus, it has become a crucial agent for vitamin D replacement in CKD patients. A

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previous study of the pharmacokinetics of oral cholecalciferol and calcifediol revealed

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that calcifediol given daily, weekly, or as a single bolus is approximately 2–3 times more potent in increasing plasma 25 (OH) D3 concentrations than cholecalciferol is

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[184]. A study on the use of calcifediol in HD patients with severe secondary hyperparathyroidism [185] revealed not only improvement in biochemical parameters

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but also healing of severe subperiosteal resorption at a 1-year follow-up. Another study of HD patients showed that calcifediol not only effectively suppresses PTH

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levels but also reduces the bone histological manifestations of hyperparathyroidism in

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patients with high iPTH levels (active bone). Moreover, patients with low iPTH

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(inactive bone) exhibited improved mineral appositional rates and bone formation rates, suggesting that calcifediol restores osteoblast viability. One year of calcifediol treatment improves BMD and bone biopsy indexes in continuous ambulatory peritoneal dialysis patients [186]. Furthermore, calcifediol could also prevent the development of renal bone disease in CKD patients who have not yet received dialysis [187]. Recently, a modified-release oral formulation of calcifediol was designed to gradually raise serum 25-hydroxyvitamin D to minimize the induction of CYP24 (the cytochrome P-450 enzyme that specifically catabolizes vitamin D and its metabolites) [188] and was found to reduce iPTH more effectively in patients with secondary hyperparathyroidism [189]. 5.1.3. Active Forms of Vitamin D Various active forms of vitamin D are used in clinical practice, including calcitriol, paricalcitol, doxercarciferol, 1-α calcidiol, and 22-oxacalcitrol. The decision 26

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? to use active vitamin D is based on PTH and calcium levels [190, 191]. In patients with PTH levels between 150 and 250 pg/mL and hypocalcemia, low doses of

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calcitriol (e.g., 0.25–0.5 mcg orally) can be given. Low doses of paricalcitol are used (i.e., 3–6 mcg orally three times per week) with higher PTH. When serum PTH more

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than 600 pg/mL, intravenously administered paricalcitol is used three times per week

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in a total weekly dose of at least 15 mcg. Preventing and treating mineral metabolism disturbances and related bone disease in CKD patients remains a great challenge.

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5.1.4. Role of Uremic Absorbent AST-120 and Extensive Dialysis Therapy

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Because accumulated uremic toxins adversely affect bone quality in CKD patients, reducing serum uremic toxin levels might be essential for reducing bone

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fractures in these patients. An oral adsorbent, AST-120, is currently used clinically to

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retard renal function deterioration by lowering serum IS levels in CKD patients. AST-120 administration was found to abolish cortical bone effects in CKD animals

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[160]. Whether the clinical use of these uremic absorbents or frequent extensive dialysis to remove accumulated uremic toxins improves bone quantity and quality in CKD patients is yet to be determined. 6. Treatment of Specified Bone Disorders Management of osteoporosis does not differ among members of the general population with stage 1–3 CKD as long as there is no biochemical evidence of CKD–MBD. DXA accurately predicts fracture risk for patients with stage 1–3 CKD [112]. All the registered agents for osteoporosis, including selective estrogen receptor modulators, bisphosphonates, denosumab, and teriparatide, can be used to treat early stage CKD patients (Figure 2). Because DXA underestimates the fracture risk in patients with later stage CKD (stages 4 and 5), HRpQCT of the forearm or tibia has been used as a superior predictor of fracture risk in these patients [72, 114]. Currently, HRpQCT is not widely 27

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? used clinically; thus, combining DXA with the risk factors for clinical fractures can be used as an alternative method for determining management. Evidence of the

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effectiveness of using ordinary osteoporosis medications to reduce fracture risk in patients with severe CKD is lacking, and these medications likely produce more side

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effects [192–194]. Denosumab has no GFR restrictions; however, evidence for its

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effectiveness in reducing fractures among patients with stage 4 and 5 CKD is still lacking. No data are available on the effectiveness of using teriparatide to treat

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patients with stage 4 or 5 CKD or with histologically proven renal ABD. Serum

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sclerostin levels increase as CKD progresses [195]; by inhibiting osteoblast activity, this increase in serum sclerostin levels induces idiopathic renal ABD in CKD patients.

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Using monoclonal antibodies against sclerostin might be a promising therapy for renal

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ABD in future.

6.1. High-Turnover Bone Disease

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In general, the principal treatment of hyperparathyroidism-related bone and mineral disorders in CKD patients is to lower PTH and normalize calcium, phosphorus, and vitamin D [196]. Calcium- and noncalcium-containing phosphate binders are used clinically; however, only noncalcium-containing phosphate binders may mitigate the risk of vascular calcification. Recently, a study [118] revealed a 23% reduction in all-cause mortality and significant regression of calcification among those treated with noncalcium-containing phosphate binders compared with those treated with calcium-containing phosphate binders. Both 25 (OH) D and active vitamin D analogs are appropriate for treating uncontrolled hyperparathyroidism. Additional basic and clinical studies are required to determine the optimal doses and type of active D analog to avoid inappropriate hyperphosphatemia and hypercalcemia in these patients. Recent studies have suggested that adding a calcimimetic agent, namely 28

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? cinacalcet, can reduce the risk of fractures in secondary hyperparathyroidism patients [197, 198]. A pooled analysis of four randomized trials also revealed a 54% fracture

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risk reduction after the use of cinacalcet therapy in secondary hyperparathyroidism patients (relative risk 0.46, 95% confidence interval 0.22–0.95) [198]. In a large

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placebo-controlled randomized trial (EVOLE), treatment with cinacalcet was

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determined to reduce clinical fracture incidence rates [197].

Many studies have demonstrated the relationship between low bone mass and

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fracture risk among dialysis patients [109, 117], and it is theoretically accepted that

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CKD patients require some kind of antiosteoporotic agents for preventing fracture risk. However, the safety of antiosteoporotic agents has not been confirmed for patients

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with progressive CKD. Bisphosphonate is eliminated mainly through urinary

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excretion, and no clinical trials have been conducted to determine the clinical efficacy and safety of using bisphosphonates in CKD–MBD patients [199–201]. However,

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post hoc analyses of bisphosphonate registration trials have revealed that bisphosphonate use prevented hip and spine fractures in patients with moderate-to-severe CKD [192–194]. The decision to use bisphosphonates should be individualized for CKD patients. In stage 1–3 CKD patients, proper treatment with bisphosphonates can prevent pathological fractures [202]. A meta-analysis of postmenopausal women with stage 1–3 CKD in nine clinical trials concluded that it is safe to provide bisphosphonates to low-BMD patients without secondary causes or deranged blood levels of calcium, phosphate, PTH, or alkaline phosphatase and vitamin D abnormalities (laboratory features of CKD–MBD) to reduce fractures [193]. However, in stage 3b–5 CKD patients, prior vitamin D deficiency, osteomalacia, and hyperparathyroidism must be excluded and corrected before treatment, and bone biopsy might be required to exclude ABD. The value of bisphosphonate treatment in patients with advanced CKD is unclear because suitable data are lacking for stage 29

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? 4–5D CKD patients (eGFR less than 30 mL/min). Among patients with advanced CKD, only those who have low BMD and high bone resorption (e.g., secondary

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hyperparathyroidism) should receive bisphosphonates because these drugs have not been used to prevent fractures in people with normal BMD or with low bone

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formation (e.g., those with ABD) [203]. Some case studies have indicated that

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bisphosphonates such as etidronate and pamidronate are useful in treating a characteristic life-threatening complication of CKD, calciphylaxis (uremic

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arteriolopathy), in patients with high bone turnover status [204]. For management of

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dialysis in patients with osteoporosis, Miller [199] suggested reducing the bisphosphonate dose to half of the FDA-registered dose for postmenopausal

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osteoporosis according to limited pharmacokinetic and dialysis data. In addition,

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Miller [199] advised limiting the treatment to 2–3 years because the reuptake of bisphosphonates might cause accumulation and unknown bone retention of

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bisphosphonates in these patients [199]. The use of teriparatide, a recombinant form of PTH, is problematic because most CKD patients are undergoing treatment to lower their serum PTH. Teriparatide is an effective bone formation agent and is used to treat patients with osteoporosis in an intermittent daily administration style. Because PTH can regulate calcium and phosphate levels, it may prevent vascular calcification. In addition, teriparatide may increase serum osteopontin levels. In animal studies, teriparatide appeared to reduce aortic and cardiac valve calcification [205, 206]. Thus, it seemed to benefit bone and blood vessels in the absence of hyperparathyroidism [207]. Denosumab is a monoclonal antibody against the RANKL and inhibits osteoclast-mediated bone resorption. There are no clinical data on the efficacy of denosumab in CKD populations, but the FREEDOM trial demonstrated a lower incidence of vertebral fractures in CKD patients who were treated with denosumab 30

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? [194]. Severe and life-threatening hypocalcemia is a dangerous side effect of denosumab treatment; thus, frequent monitoring of serum calcium is required [208].

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Odanacatib and romosozumab [209, 210] are potential antiosteoporotic agents for treating CKD patients. Similar to bisphosphonate use, ABD, osteomalacia, and severe

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vitamin D deficiency should be excluded before denosumab use in these patients.

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The use of selective estrogen-receptor modulators in treating CKD patients is not fully understood [194]. VDR activator use is generally acceptable for treating these

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patients, even though its use is sometimes associated with acute exacerbation of

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kidney injury. A recent prospective, observational study revealed that the use of renin angiotensin system inhibitors is associated with lower risk of fracture-related

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hospitalization in HD patients [211]. In short, additional prospective clinical trials on

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the efficacy and safety of using these antiresorption agents in treating CKD–MBD patients are urgently required.

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6.2. Low-Turnover Bone Disease One crucial feature of ABD is the coexistance of low-turnover ROD and vascular calcification [205, 212]. Nutritional vitamin D supplementation, osteoanabolic agents (rPTH 1–34), and calcilytic agents might play a role in fracture management. Administration of anabolic agents such as BMP-7 [212] or synthetic PTH (1–34) [205] improve bone turnover and skeletal mineralization as well as reduce aortic calcification. The rationale for using synthetic PTH (1–34) in patients with idiopathic renal ABD is that it can increase bone turnover and improve bone microarchitecture; a strong correlation exists between teriparatide-induced increases in BMD and fracture risk reduction [213]. Since excessive calcium loads might exaggerate vascular calcification, these patients should restrict their dialysate calcium concentration (≤2.5mEq/L), limit their total calcium intake (1.0–1.4 g/day), and avoid calcium that contains P binders [214]. 31

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Achieving optimal phosphate control by using non-calcium-based phosphate binders, optimizing dialysis treatment [215], and improving bone formation through VDRA

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therapy might improve bone mass in these patients. The use of potentially osteoanabolic agents such as testosterone and estrogen or estrogen analogs in

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low-turnover CKD patients is still controversial. In a recent animal study,

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antisclerostin antibody treatment improved the bone properties of low-PTH CKD animals.

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7. Conclusions

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In conclusion, the underlying mechanisms of bone loss and fractures in CKD patients are complex and remain unresolved. In contrast to bone biopsy, recently

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available noninvasive investigative measures for detecting both bone quantity and

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quality loss are still clinically unavailable as screening or diagnosing techniques. Bone-targeted pharmacotherapy was revealed to minimally affect the incidence of

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fractures and is associated with adverse effects in this specific population. Individualized therapy, including vitamin D supplementation, phosphate control, antiresorptive agent use, dialysis, and medical and surgical PTX, might benefit these patients. Researchers should investigate the mechanisms of and targeted therapy for both quality- and quantity-related bone loss in CKD patients.

32

ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? 8.

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality?

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Figure 1. Development of Bone Loss in CKD

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In patients with early CKD (stage 1-2), Wnt signaling inhibitors such as DKK1, SOST & sFRP were secreted from kidney or osteocyte in bone/calcified soft tissue, which could act on the osteoblast resulting decrease OB viability. In addition, retention of protein bound uremic toxins such as IS/PCS further attenuated the OB & OC viability and function. Uremic osteoporosis were used to describe the effects of PBUT on bone quality loss with normal bone mass. When the renal function deteriorated progressively, metabolic acidosis and hyponatremia also contribute to the bone quantity loss. When the renal patients progress (>stage 3) to calcium, phosphate, vit-D and PTH dysregulation, patients may present with high or low PTH levels. High PTH levels drive the indolent OB into high viability and function, but poor quality in behavior, resulting both bone quality and quantity loss. However, medical or surgical treatment of SHPT which removal of the stimulator of PTH, the bone cells may return back to the innate low bone cell viability status, the low bone turnover disorders. We are naming renal osteodystrophy for CKD patients’ bone diseases.

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality?

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Figure 2. Potential Therapeutic Considerations of Bone Loss in CKD

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Table 1. Common causes of bone loss in CKD/ESKD patients 1. Renal osteodystrophy – High turnover/Low turnover bone disorders

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– Quantity and quality loss

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2. Uremic osteoporosis – PBUT- IS/PCS 3. Vit-D deficiency

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– Quantity and quality loss – Chronic fatigue and myopathies

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– Quality loss

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– Falls/ Fractures – Insulin Resistance and Overweight 4. Electrolyte and acid-base disorders – Chronic metabolic acidosis – Hyponatremia – Hyperphosphatemia and/or hypocalcemia 5. Medications – Prolonged aluminum exposure – Glucocorticoid therapy in glomerular diseases and renal transplant recipients – Hypoparathyroidism related to excessive use of phosphate binders – Iatrogenic hypoparathyroidism due to parathyroidectomy 6. Dialysis Related Bone Loss – Unfractionated heparin use during dialysis sessions – β2-microglobulinemia amyloidosis 7. Miscellaneous

– Anemia, inflammation, hypogonadism

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Table 2. Characteristics of bone quantity loss in CKD (
BMD) 1. Bone changes in early CKD (Osteocyte/Kidney/Calcified soft tissue) – DKK1, SOST & IS/PCS

Low PTH, BAP: NVD/teriparatide (PTH 1-34)

4. Acceptable (normal) bone turnover

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–

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– High PTH, BAP: NVD + AVD/Cinacalcet 3. Low turnover bone loss (BF ≤ BR)

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2. High turnover bone loss (BR >> BF)

Osteomalacia/Resorption /Mineralization


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–

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– Treat as common osteoporosis (avoid over suppress OC) 5. Vitamin-D deficiency

Table 3. Characteristics of bone quality loss in CKD

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1. Uremic osteoporosis? (IS/PCS) 2. Vit-D deficiency –
Crack-growth resistance,  Collagen crosslink ratio,
Bone Age –  Carbonate-phosphate ratio,
Toughness 3. Altered bone turnover, mineralization and microarchitecture – High turnover bone disorders: material and nanomechanical abnormalities •
mineral to matrix ratio •
stiffness • Woven bone in SHPT  Keep resorption capability of OC (Removal of WB) – Low turnover bone disorders: microstructural abnormalities •
cancellous bone volume •
trabecular thickness • Adynamic bone disorder in low PTH level  Rescue OB viability with vit-D/teriparatide (PTH 1-34) Removal of metal intoxication (Aluminum, Pb)

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ACCEPTED MANUSCRIPT Bone loss in CKD: Quantity or quality? Table 4. Effects of Vitamin-D Deficiency on Bone Loss 1. Quantity loss • Higher amount of unmineralized bone matrix

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– Osteoid

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• In the mineralized bone – Higher degree of • Mineralization

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• Cross-link ratio (mature to immature enzymatic cross-links)

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• Carbonate-to-phosphate ratio •  the age of the mineralized bone tissue

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– Osteoid-covered bone surfaces prevent tissue resorption 2. Quality loss •  calcium distribution,  collagen crosslink ratio & calcium phosphate ratio •
crack-initiation toughness – Increase in tissue age of the bone matrix •
crack-growth toughness •
extrinsic toughness – Straighter crack path – Fewer crack bridges

Table 5. Bone quality loss in uremic osteoporosis (No
BMD) 1.
Bone formation and resorption (?) • • 2. • 3.

Abnormal mineral and protein phase of the bone material Abnormal biological apatite (BAp) orientation
Storage modulus by dynamic mechanical analysis Increased pathological collagen crosslinks Exacerbates low bone turnover disease

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