**4. Pathophysiology of elevated risk for fracture in CKD**

Low BMD is a risk for fracture in the general population, and this is also true for CKD patients [29-32]. Recent longitudinal studies using high resolution peripheral quantitative computed tomography (HR-pQCT) have demonstrated that loss of kidney function is associated with a decrease in BMD, independent of age and body mass [29-32]. HR-pQCT is developed to measure volumetric bone mass, and to discriminate between cortical bone and trabecular bone. Volumetric BMD measured by HR-pQCT is more accurate than areal BMD by DXA, because areal BMD depends on body size and cannot exclude aortic calcification [33]. Cejka et al. reported the characteristics of bone microarchitecture of 74 HD patients, where cortical and trabecular microarchitecture was significantly impaired in patients with fracture [34]. Trabec‐ ular BMD at the tibia was the strongest determinant of fracture in these patients. In 70 patients aged ≥50 with CKD stage 2-4, trabecular BMD at the tibia and radius, trabecular number and cortical thickness were significantly decreased and trabecular separation was increased [35]. Another study by Nickolas demonstrated a significant loss of cortical BMD at the distal radius, and marked increase in cortical porosity without any changes in trabecular indices in CKD patients [36]. There was a significant association between kidney dysfunction and cortical bone loss as well as increased porosity [35]. Although DXA has a lower discriminatory power than HR-pQCT measured volumetric density, a recent report suggests a benefit of BMD measure‐ ment even with DXA to identify HD patients with high risk of fracture [32].

Although bone histological analysis is the most accurate method, a few studies have been reported because of its invasiveness and difficulty. Tomiyama et al. conducted bone biopsy at the iliac crest of 50 CKD patients after tetracycline labelling [37]. Interestingly, histomorph‐ ometry showed low turnover of bone in most patients; 100% in stage 2, 88% in stage 3, and 78% in stage 4. This finding suggests that the bone formation rate is markedly depressed in CKD at early stages.

Bone strength depends not only on BMD but also on the other factors, which have been called as a bone quality. In primary osteoporosis, bone strength is explained about 70% by BMD and the rest by bone quality. Since the risk for fracture is dissociated with BMD especially in patients with DM and with glucocorticoid-induced osteoporosis, areal BMD cannot effectively predict fracture [5-8]. This might be the case in CKD, and the factors other than BMD, such as bone quality would play a part in bone fragility, especially in later stages of CKD. Especially in patients with type 2 DM, bone strength is significantly decreased, while BMD tends to be increased due to obesity. Because DM is a leading cause of ESKD, at least to some extent DM affects risk for fracture in CKD population. Actually, previous reports demonstrated the significant elevation of risk for fracture in ESKD patients with DM, compared to those without DM [38]. Pathogenesis of elevated risk for fracture in DM is explained by deteriorated bone quality as well as increased incidence of falls. DM patients treated by insulin have 2.78 times higher risk for falls than non-DM subjects [39]. In addition, DM is an independent risk for falls in HD patients with OR of 2.75 [40]. Increased risk of falls in DM may be caused by impaired neuromuscular function, increased instability, loss of vision, hypoglycemia, arthritis, cardio‐ vascular disorders, depression and medication such as hypnotics or tranquilizers. Thus, these factors including DM should be the risks for falls and fracture in CKD patients.

In this part, terms such as eGFR and CCr were used followed by the original reports. Moreover, CCr was corrected with body surface in some reports and not in others. Kidney function is prone to be underestimated in C-G formula and overestimated in MDRD, which may lead confusion and the discrepancy among study results as described by Ensrud et al. [23].

Low BMD is a risk for fracture in the general population, and this is also true for CKD patients [29-32]. Recent longitudinal studies using high resolution peripheral quantitative computed tomography (HR-pQCT) have demonstrated that loss of kidney function is associated with a decrease in BMD, independent of age and body mass [29-32]. HR-pQCT is developed to measure volumetric bone mass, and to discriminate between cortical bone and trabecular bone. Volumetric BMD measured by HR-pQCT is more accurate than areal BMD by DXA, because areal BMD depends on body size and cannot exclude aortic calcification [33]. Cejka et al. reported the characteristics of bone microarchitecture of 74 HD patients, where cortical and trabecular microarchitecture was significantly impaired in patients with fracture [34]. Trabec‐ ular BMD at the tibia was the strongest determinant of fracture in these patients. In 70 patients aged ≥50 with CKD stage 2-4, trabecular BMD at the tibia and radius, trabecular number and cortical thickness were significantly decreased and trabecular separation was increased [35]. Another study by Nickolas demonstrated a significant loss of cortical BMD at the distal radius, and marked increase in cortical porosity without any changes in trabecular indices in CKD patients [36]. There was a significant association between kidney dysfunction and cortical bone loss as well as increased porosity [35]. Although DXA has a lower discriminatory power than HR-pQCT measured volumetric density, a recent report suggests a benefit of BMD measure‐

**4. Pathophysiology of elevated risk for fracture in CKD**

ment even with DXA to identify HD patients with high risk of fracture [32].

CKD at early stages.

82 Updates in Hemodialysis

Although bone histological analysis is the most accurate method, a few studies have been reported because of its invasiveness and difficulty. Tomiyama et al. conducted bone biopsy at the iliac crest of 50 CKD patients after tetracycline labelling [37]. Interestingly, histomorph‐ ometry showed low turnover of bone in most patients; 100% in stage 2, 88% in stage 3, and 78% in stage 4. This finding suggests that the bone formation rate is markedly depressed in

Bone strength depends not only on BMD but also on the other factors, which have been called as a bone quality. In primary osteoporosis, bone strength is explained about 70% by BMD and the rest by bone quality. Since the risk for fracture is dissociated with BMD especially in patients with DM and with glucocorticoid-induced osteoporosis, areal BMD cannot effectively predict fracture [5-8]. This might be the case in CKD, and the factors other than BMD, such as bone quality would play a part in bone fragility, especially in later stages of CKD. Especially in patients with type 2 DM, bone strength is significantly decreased, while BMD tends to be increased due to obesity. Because DM is a leading cause of ESKD, at least to some extent DM affects risk for fracture in CKD population. Actually, previous reports demonstrated the significant elevation of risk for fracture in ESKD patients with DM, compared to those without

Many factors are known as a risk for fracture including low BMD, factors independent of BMD such as older age, female sex, prevalent fracture, smoking, drinking, steroid use, family history for fracture, excise, and factors dependent of BMD such as low body weight [3, 4]. On the other hand, in CKD patients, there may be additional factors including history of kidney transplant, decreased 1,25(OH)2D, increased parathyroid hormone (PTH), other hormonal changes, metabolic acidosis, uremic toxins, inflammatory cytokines, and homocysteine play a role [41-48]. Although each occurs at different stages of CKD, all can affect the bone at the endstage. Bone changes can be associated with PTH and bone metabolic markers. However, increase in serum PTH level generally starts at GFR <45mL/min. Actually, recent studies using cystatin C demonstrated that PTH, inflammation, and bone turnover did not affect the risk for fracture at least in early CKD [49, 50]. On the contrary, increasing evidences suggest that fibroblast growth factor 23 (FGF23) level is elevated to suppress bone formation at CKD stage 2, which occurs at an earlier time than the increase in PTH or decrease in 1,25(OH)2D [51-53]. In addition, FGF23 may be an independent risk of vertebral fracture [54].

Bone quality is classified by material and structural properties, both of which are considered to be altered in CKD. As for structural properties, cortical thinning, porosity, and irregular thickness and loss of connectivity in trabecular bone have been reported [36]. On the other hand, material properties are not well understood. Animal study shows the changes in chemical composition of cortical bone and the deterioration in the quality of bone matrix proteins, such as type I collagen and collagen crosslinking [55], although there is a controversy [56]. These changes are thought to be resulted from an increase in advanced glycation end products (AGEs) including pentosidine that causes loss of normal crosslinking; which are mediated by high glucose, homocysteine, reactive oxygen species and low vitamin B6 [57, 58]. Therefore, both loss of bone volume and deterioration of bone quality (altered material and structural properties at micro and macro levels) may be involved in the progression of bone fragility in CKD. Future study is needed to elucidate the deteriorated bone quality in CKD including functional changes in osteocytes and involvement of sclerostin, which regulates osteoblastic activity.

At present, however, most conceivable reason for increased risk for fracture in CKD patients is that CKD and osteoporosis have a lot of common risk factors for the pathogenesis and disease progression (Figure 2). This fact is supported by clinical findings [20, 46]. The factors including aging, inflammation, renin-angiotensin axis, oxidative stress, insulin resistance, hyperglyce‐ mia, AGEs, smoking, menopause, lack of exercise, homocysteine, uremic toxins, ADMA, and FGF23 are possible common candidates. At the same time, these factors are thought to be involved in the development of vascular calcification [46, 59-63]. In addition to the relationship between vascular calcification/ atherosclerosis and osteoporosis, so called bone-vascular relationship, hypertension and chronic obstructive pulmonary disease (COPD) also become aware of fracture risks. On the other hand, cortical bone thickness measured by HR-pQCT was reported to be the best predictor for hip fracture in CKD patients [64]. Since bone turnover markers such as P1NP and TRACP5b are risk factors for fracture independent of BMD in CKD patients, combination of BMD and bone turnover markers makes it possible to discriminate subjects with bone fragility [64]. Further studies are necessary to identify noninvasive assess‐ ment tools for fracture risk.

**Figure 2.** Mechanisms of elevated risk for fracture in CKD patients. Although precise mechanisms remain uncertain, CKD and osteoporosis have many common risk factors, and in addition, CKD progression is associated with increased risk for fracture probably due to bone loss as well as deterioration of bone quality. Aging, inflammation, renin-angio‐ tensin axis, oxidative stress, insulin resistance, hyperglycemia, AGEs, smoking, menopause, lack of exercise, homocys‐ teine, uremic toxins, ADMA, and FGF23 are possible candidates for the common factors, and at the same time, these are thought to be involved in the development of vascular calcification.
