Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review

Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. Among CKD patients, adynamic bone disease or low bone turnover is the most common type of renal osteodystrophy. The consequences of CKD-MBD include increased fracture risk, greater morbidity, and mortality. Thus, the goal is to prevent the occurrences of fractures by means of alleviating CKD-induced MBD and treating subsequent osteoporosis. Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. CKD-MBD includes abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. In patients with CKD-MBD, using either DXA or FRAX to screen fracture risk should be considered. Biomarkers such as bALP and iPTH may assist to assess bone turnover. Before initiating an antiresorptive or anabolic agent to treat osteoporosis in CKD patients, lifestyle modifications, such as exercise, calcium, and vitamin D supplementation, smoking cessation, and avoidance of excessive alcohol intake are important. Managing hyperphosphatemia and SHPT are also crucial. Understanding the complex pathogenesis of CKD-MBD is crucial in improving one’s short- and long-term outcomes. Treatment strategies for CKD-associated osteoporosis should be patient-centered to determine the type of renal osteodystrophy. This review focuses on the mechanism, evaluation and management of patients with CKD-MBD. However, further studies are needed to explore more details regarding the underlying pathophysiology and to assess the safety and efficacy of agents for treating CKD-MBD.


Overview
Chronic kidney disease (CKD) is associated with the development of mineral bone disorder (MBD), osteoporosis, and fragility fractures. The grade or severity of CKD can be classified based on glomerular filtration rate (GFR) category, ranging from stage G1 to G5 [1]. In stage G1 and G2, the GFRs are normal (more than 90 mL/min/1.73 m 2 ) and slightly decreased (60-89 mL/min/1.73 m 2 ), respectively. For patients with CKD stage G3a and G3b, the GFRs decrease from mild to moderate (40-59 mL/min/1.73 m 2 ) and moderate to severe (30-44 mL/min/1.73 m 2 ). The renal function is severely

Characteristics of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)
CKD-MBD describes abnormalities in mineral metabolism, skeletal health, and soft tissue calcifications. Possible factors involved in CKD-associated osteoporosis are summarized in Table 1. Kloth is a membrane protein expressed mainly in proximal and distal renal tubules and could be detected in blood, urine, cerebrospinal fluid and osteocytes. In early stage of CKD, the decline of Kloth expression can increase FGF-23 levels [13]. The effects of increase in FGF-23 levels lead to increased urinary phosphate excretion by reducing renal phosphate reabsorption [14] and decreased calcitriol synthesis by inhibiting the proximal tubular expression of 1-alpha-hydroxylase enzyme [14,15]. Furthermore, sclerostin (28 kD) and dickkopf1 (26 kD) and are small secreted glycoproteins. As CKD progress, the consequences of increased serum sclerostin lead to deceased bone formation by inhibiting Wnt-induced signaling through binding to LRP5/6 [14,16] and increased osteoclastogenesis by inducing RANK-L synthesis [17]. The elevated dickkopf1 level could also inhibit bone formation by inhibiting Wnt-induced signaling through binding to LRP5/6 [16,18]. In early CKD, a tendency to phosphate retention plays a central role in the development of SPTH [19] and inhibits calcitriol synthesis by inhibiting the activity of 1-alpha-hydroxylase enzyme in kidney [20]. Moreover, the accumulation of uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, could reduce the expression of PTH receptor in osteoblasts and is associated with skeletal resistance to PTH [21]. The fall of calcitriol concentrations could cause the increase of PTH secretion [20,22] and the decrease of serum calcium level [23]. Decreased free ionized calcium concentration could also accentuate SPTH [23]. Skeletal resistance to the calcemic effect on PTH may be involved in the development of SPTH in CKD [24]. Finally, SPTH is the major feature of CKD-MBD which causes abnormal bone remodeling and osteoporosis [23]. Table 1. Factors affecting bone strength in chronic kidney disease-mineral and bone disorder (CKD-MBD).
In patients with CKD G5D, both hypocalcemia and hypercalcemia are associated with mortality [28,29].
In patients after KT, hypercalcemia is common due to persistence of preexistent hyperparathyroidism, hypophosphatemia, postintervention immobilization, or progressive normalization of calcitriol level [30].
Calcium balance is whole-body calcium retention or deficit total calcium inputs subtract total body loses [31]. A positive balance may increase vascular calcification and cardiovascular events, while a negative balance may increase the risk of osteoporosis and fracture [31]. Serum calcium alone cannot serve as a proxy measurement of the whole-body calcium balance.

Disorder of Phosphorus Metabolism
Phosphate retention begins early in CKD and plays a central role in the development of secondary hyperparathyroidism (SPTH) by inducing hypocalcemia, decreasing calcitriol synthesis, and increasing PTH gene expression [32,33]. However, serum phosphate levels are not usually elevated in the early stages of CKD because of a reduction in renal proximal tubular phosphate resorption owing to increased levels of PTH and fibroblast-growth-factor (FGF)-23 [15]. The effects of FGF-23 on increasing phosphate secretion may be blunted by decreased Kloth in early CKD. Serum phosphate typically remain normal until eGFR decreased to 20 mL/min/1.73 m 2 [15,25]. In advanced CKD, the consequences of hyperphosphatemia included the stimulating effects on PTH synthesis and secretion [19], FGF-23 secretion [34], and osteoblastic transformation of the vascular smooth muscle cell which directly contributes to cardiovascular calcification [35]. In patients with CKD G5D, both low and high serum phosphate are associated with mortality [29].

Disorder of Parathyroid Hormone Metabolism
Serum intact PTH (iPTH) typically remains normal until the eGFR decreases to approximately 45 mL/min/1.73 m 2 [25,36]. The prevalence of SPTH increases as CKD progress [36]. The causes of increase in initiating and maintaining PTH included phosphate retention, decreased free ionized calcium level, decreased calcitriol level, increased FGF-23 level, and reduced expression of vitamin D receptors (VDRs), calcium-sensing receptors (CaSRs), FGF receptors and kloth in the parathyroid glands. Furthermore, uremic toxins such as indoxyl sulfate and p-presyl sulfate would reduce the expression of PTH receptor and production of PTH-induced cyclic adenosine 3 ,5 monophosphate in osteoblast, which lead to skeletal resistance to PTH and bone fragility [21]. In patients with CKD G5D, both low and high iPTH [28] are associated with mortality [29].

Disorder of Vitamin D Metabolism
A serum 25(OH)D (calcidiol) level < 30 nmol/L indicates vitamin D deficiency [37,38], which is common among patients with CKD. Vitamin D deficiency is associated with cardiovascular events in CKD. One cross-sectional study reported that a high prevalence of calcidiol deficiency and insufficiency in patients with CKD G3-4 not on dialysis therapy [39]. Calcitriol level started to fall until eGFR was <40 mL/min/1.73 m 2 [25]. In the course of eGFR decline, reductions in calcitriol levels occurred earlier than elevations in iPTH levels [25]. The primary cause why calcitriol level declines is the increase in FGF-23 concentration, rather than the loss of functioning renal tissue [15]. In patients with CKD-MBD undergoing HD, low serum calcidiol level was associated with bone-biopsy-proven increase of bone turnover [40].

4.2.
Abnormalities in Bone Turnover, Mineralization, Volume, Volume Linear Growth, or Strength

TMV Characteristics of Renal Osteodystrophy
Bone biopsy is the gold standard for the diagnosis and classification of bone diseases in CKD, or renal osteodystrophy. By definition, renal osteodystrophy is a noticeable transformation of bone morphology in patients with CKD; it is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantified by histomorphometry of bone biopsy [2]. Kidney Disease: Improving Global Outcomes (KDIGO) group recommends three parameters (bone turnover, mineralization, and volume; TMV system) to be used to assess bone pathology [1]. Bone turnover refers to the rate of skeletal remodeling, or the ratio between bone formation, and bone resorption [2]. Mineralization reflects how well bone collagen becomes calcified during the formation phase of skeletal remodeling [2]. Bone resorption is the main function of osteoclasts, which colonized fetal ossification centers coming from embryonic erythron-myeloid progenitors [41]. Volume indicates the amount of bone per unit volume of tissue [2]. Bone strengths is determined by bone quantity, and bone quality. Bone quality refers to the structure and material parameters that enables bone to bear load and resist fracture [42].
In TMV system used for evaluation of CKD-MBD, the bone turnover rates are high in patients with osteitis fibrosa cystica and mixed uremic osteodystrophy but low in patients with adynamic bone disease and osteomalacia [2]. The mineralization of bone is normal in patients with osteitis fibrosa cystica and adynamic bone disease but abnormal in patients with osteomalacia and mixed uremic osteodystrophy [2].

Bone Turnover in CKD
Prevalence of Low-Turnover Bone Disease in CKD The majority of renal osteodystrophy among CKD G5 and CKD G5D patients is a low-turnover bone disease (adynamic bone disease), particularly in diabetic patients [43][44][45]. Two large bone biopsy studies showed a high prevalence (58% and 59%) of adynamic bone disease in HD patients [46,47]. Prevalence of high-turnover bone disease (osteitis fibrosa cystica) among dialysis patients has markedly decreased. The incidence of osteomalacia has also been decreased with abandonment of aluminum-based phosphate binders and induction of efficient water treatment for preparing the dialysate [48]. Increased prevalence of low-turnover bone disease may be due to older age, increased number of diabetes patients, early use of vitamin D analogs and calcium-containing phosphate binders, and differences in dialysis techniques [48].
Evaluation of Bone Turnover PTH levels are used as a surrogate to evaluate the status of bone turnover. Very high PTH levels (≥585 pg/mL) are usually associated with osteitis fibrosa [49], while very low PTH levels (<100 pg/mL) are associated with adynamic bone disease. A cross-sectional histomorphometric study of bone turnover showed that a PTH of >323 pg/mL had the best discriminatory ability of high from non-high bone turnover; a PTH < 103.8 pg/mL best discriminated low from non-low turnover [46]. However, PTH levels are not predictive of underlying bone disease when they are modestly elevated [50]. KDIGO suggests using PTH trends instead of absolute targets to guide treatment decision [1].

Evaluation of Bone Strength
Dual-energy X-ray absorptiometry (DXA) evaluates the bone quantity and not the bone quality. Peripheral quantitative computed tomography (pQCT), high resolution pQCT (HRpQCT), and micromagnetic resonance imaging (microMRI) are non-invasive 3D imaging techniques that can detect microarchitecture and mineral density of both trabecular and cortical bones [51]. However, there are few data in evaluating these techniques in patients with CKD.

Vascular or Other Soft Tissue Calcification
Vascular calcification, which significantly increases cardiovascular and all-causes of mortality, is highly prevalent in hemodialysis patients. Extraskeletal calcification is common in patients with CKD G5D [52]. All arteries and arterioles can calcify, whereas veins hardly calcify unless injured or arterialized [53]. Among CKD patients, there are two types of vascular calcification: medial calcification and intimal calcification. Medial calcification is the result of both a phenotype switch of vascular smooth cells to osteoblast-like cells and local inflammation [54]. Intimal calcification is secondary to establish atherosclerosis. There are limited clinical data concerning the results of intimal versus medial lesions among CKD patients. One study of HD patients showed that patients with arterial media calcification had a longer survival than those with arterial intima calcification [55].

Evaluating Fracture Risk in CKD
Several longitudinal studies confirmed that low BMD could predict fractures in patients with CKD [67][68][69][70]. In patients with CKD G3a-G5D with evidence of CKD-MBD and/or risk factors for osteoporosis, KDIGO in 2017 suggest BMD testing to assess fracture risk if results will impact treatment decisions [1]. Although DXA is commonly used technique for quantifying BMD in CKD patients, it has some limitations. First, DXA measures areal BMD, not volumetric BMD. Second, it cannot discriminate between cortical and cancellous bone. Third, it cannot assess bone microarchitecture or bone turnover.
Fracture Risk Assessment Tool (FRAX) developed by WHO can also be helpful for predicting fracture risk in patients with non-dialysis CKD [71] and KT recipients [72]. However, the limitation of FRAX is that it does not include any adjustment of risk according to GFR.
A summary of the mechanism underlying the effects of chronic kidney disease (CKD) on osteoporosis and subsequent decrease in bone strength is displayed in Figure 2. The reduction of GFR in patients with CKD initiates a cascade of metabolic disorder, abnormal bone remodeling and turnover, resulting in osteoporosis and subsequent decrease in bone strength.  [63], calcimimetic agent [64], kloth [13], pyrophosphate [65], osteoprotegerin [66], and RANK-L [66].

Evaluating Fracture Risk in CKD
Several longitudinal studies confirmed that low BMD could predict fractures in patients with CKD [67][68][69][70]. In patients with CKD G3a-G5D with evidence of CKD-MBD and/or risk factors for osteoporosis, KDIGO in 2017 suggest BMD testing to assess fracture risk if results will impact treatment decisions [1]. Although DXA is commonly used technique for quantifying BMD in CKD patients, it has some limitations. First, DXA measures areal BMD, not volumetric BMD. Second, it cannot discriminate between cortical and cancellous bone. Third, it cannot assess bone microarchitecture or bone turnover.
Fracture Risk Assessment Tool (FRAX) developed by WHO can also be helpful for predicting fracture risk in patients with non-dialysis CKD [71] and KT recipients [72]. However, the limitation of FRAX is that it does not include any adjustment of risk according to GFR.

Lifestyle Modification
Non-pharmacologic interventions include modifying dietary calcium and nutritional vitamin D, increased physical activity, smoking cessation, weight bearing exercise, fall prevention [88], and avoidance of excessive alcohol intake [89,90].

Exercise and Physical Therapy
Exercise improves muscle impairment, physical function, and physical performance across the spectrum of CKD [91]. In a study of partial nephrectomy induced CKD rat model, exercise improved BMD and microstructure by inhibiting serum sclerostin level, therefore mitigating its effect of inhibiting Wnt/ß-catenin signaling pathway [92]. Exercise training prescriptions should be individualized to one's physical function. According to FITT (frequency, intensity, time, and type) principle for exercise prescription, patients should exercise 2 to 3 times per week at the beginning of the training, and then increase frequency to 3 to 5 times per week. Intensity should be tailored based on patient tolerance to exercise. The duration of exercise relies on the health and physical condition of the patient. Type of exercise includes aerobic, resistance, and flexibility exercise [93].

Phosphate
In patients with CKD G3a-G5D, the KDIGO group suggests lowering of hyperphosphatemia levels towards normal range [1]. Phosphate load from phosphate-rich sources should be avoided. Non-calcium-based phosphate binders, such as sevelamer, have advantages over calcium-based binder in increasing the bone formation rate and improving trabecular architecture [43].

Calcium or Cinacalcet
Excessive exogenous calcium in adults may be harmful at all stages of CKD [31,94]. Updated 2017 KDIGO guidelines for CKD-MBD suggest limiting calcium-based phosphate binders for all patients with CKD G3a-5D [1]. Daily dietary calcium intake with 1000 mg/day is recommended for achieving neutral calcium balance [31]. Additional calcium supplements or calcium-containing medications should be avoided for patients with adequate daily calcium intakes of 800-1000 mg per day [31].
Administration of a calcimimetic agent increases the sensitivity of CaSR and vitamin D receptor (VDR) expression [95], decreases PTH gene expression [96] and PTH secretion of the parathyroid gland [97]. In patients with CKD G5D, calcimimetics, such as cinacalcet, is suggested to increase BMD, normalize bone histology and reduce risk of fractures when serum PTH remain elevated despite sufficient calcidiol levels [89]. The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial demonstrated that using cinacalcet for ≤64 months reduces the rate of clinical fracture by 16-29% [98], decreases serum FGF-23 and its-associated cardiovascular death and major cardiovascular events [99] in HD patients with SHPT. Treatment with cinacalcet for 1 year increases the BMD of the femoral neck in patients with iPTH level >300 pg/mL and undergoing HD, especially in those who had higher baseline serum bone-specific alkaline phosphatase (bALP) [100]. In the multicenter Bone Biopsy Study for Dialysis Patients with the Secondary Hyperparathyroidism of End Stage Renal Disease (BONAFIDE) study, long-term treatment with cinacalcet substantially reduced PTH, diminished the elevated bone formation rate, lowered several biochemical markers of high-turnover bone disease toward normal, and generally improved bone histology [101].
In a prospective trial of 41 patients with PD dialysis and biopsy-proven adynamic bone disease, low-calcium dialysate reduced serum calcium levels and hypercalcemic episodes, resulting in increased PTH levels and normalization of bone turnover [102]. Repeated bone biopsy after 16 months found that low-calcium dialysate led to normalization of bone formation rates and a 300% increase in PTH levels.
In patients after KT, calcium levels usually decrease early and elevate at three to six months post-transplantation [103]. Cinacalcet reduced hypercalcemia due to hyperparathyroidism [104]. However, a recent randomized study showed that subtotal parathyroidectomy was superior to cinacalcet in controlling hypercalcemia in patients with KT and tertiary hyperparathyroidism [105]. Cinacalcet is currently not approved for use in KT recipients [103]. Calcium supplementation alone is seldom required post-transplantation [103]. [17]. Nevertheless, the optimal circulating calcidiol and calcitriol levels to be considered remain unknown and controversial [106]. For CKD patients not on dialysis, the 2017 KDIGO guidelines recommend using 30 ng/mL cutoff value [40], which is the same as that used for the general population. For patients at CKD G5D, applying the threshold resulted in an estimated prevalence of vitamin D insufficiency (15-30 ng/mL) and/or deficiency (<15 ng/mL) ranging from 50% to 98% in a total sample size of 3722 HD patients [107]. Vitamin D supplementation is suggested to prescribe early in the process of CKD, but how to appropriately use it is still under debate [90,108]. Experts from Kidney Disease Outcomes Quality Initiative (KDOQI) and KDIGO have recognized that vitamin D insufficiency and deficiency should be avoided in CKD and dialysis patients by using supplementation to prevent SHPT [108]. Cholecalciferol (Vitamin D3) 800 IU/day is recommended for the treatment and prevention of vitamin D deficiency in CKD and dialysis patients [109]. Vitamin D provided during dialysis is more effective than home prescriptions [110]. The effects of vitamin D supplementation on CKD and dialysis patients include decreased serum PTH level, increased serum calcitriol level, reduced proteinuria, endothelial cardiovascular markers improvement and decreased inflammation markers [108].

Synthesis of vitamin D is mainly reduced in CKD-MBD. Both 25(OH)D (calcidiol) and 1,25(OH) 2 D (calcitriol) play a crucial role on bone metabolism. Through vitamin D receptor (VDR) on bone cells, vitamin D stimulates calcium resorption and osteoclast differentiation via induction of Receptor activator of nuclear factor kappa B ligand (RANK-L) synthesis
In patients with CKD G3-4, both calcitriol and paricalcitol effectively decrease PTH and alkaline phosphatase levels with minimal effect on calcium levels and phosphorus balance [111]. Another small randomized trial of bone biopsy-proved adynamic bone disease showed that calcitriol decreased bone turnover [112], leading to the notion about decreasing active vitamin D therapy in these patients. Studies for non-dialysis CKD had shown that cholecalciferol (vitamin D3) may be superior to ergocalciferol (vitamin D2) in raising serum calcidiol for treating nutritional vitamin D deficiency [113,114]. In addition, a meta-analysis of three randomized control studies in patients with CKD G3-4 and hypovitaminosis D showed that supplementation of active/native vitamin D (cholecalciferol) did not show improvement in cardiac function and structure as calcitriol [115].
In CKD G5D, supplementation of calcidiol improves bone mineralization but has limited effect on reducing serum PTH level, while administration of calcitriol efficiently reduces serum PTH level but has little effect on bone mineralization [70]. Currently, there is strong evidence supporting calcidiol supplementation, aiming to control SHPT in CKD patients [116]. Despite the emerging observational data showing the association between lower levels of calcidiol and several deleterious outcomes (such as low bone turnover, risk of falls and fractures, progression of CKD and mortality) [70], there is still a lack of randomized control trials to support the potential beneficial effects of vitamin D supplementation.
In KT recipients with CKD-MBD, low serum calcidiol levels are common. Administration of calcitriol could decrease PTH after transplantation and increase femoral neck and lumbar spine BMD. However, there is no clear evidence in reducing fracture risk [117].

Parathyroidectomy
In a national cohort of long-term CKD G5D patients, parathyroidectomy reduced bone turnover and improved BMD and risk of fractures [118].

Choices of Pharmacologic Treatment
There are a variety of anti-osteoporotic drugs which can be considered as pharmacologic treatment for osteoporosis. The actions and mechanisms of current anti-osteoporotic agents in CKD patients are showed in Figure 3.
calcidiol supplementation, aiming to control SHPT in CKD patients [116]. Despite the emerging observational data showing the association between lower levels of calcidiol and several deleterious outcomes (such as low bone turnover, risk of falls and fractures, progression of CKD and mortality) [70], there is still a lack of randomized control trials to support the potential beneficial effects of vitamin D supplementation.
In KT recipients with CKD-MBD, low serum calcidiol levels are common. Administration of calcitriol could decrease PTH after transplantation and increase femoral neck and lumbar spine BMD. However, there is no clear evidence in reducing fracture risk [117].

Parathyroidectomy
In a national cohort of long-term CKD G5D patients, parathyroidectomy reduced bone turnover and improved BMD and risk of fractures [118].

Choices of Pharmacologic Treatment
There are a variety of anti-osteoporotic drugs which can be considered as pharmacologic treatment for osteoporosis. The actions and mechanisms of current anti-osteoporotic agents in CKD patients are showed in Figure 3.  Osteoprotegerin is a soluble combining inhibitor of RANK-L, which could reduce osteoclasts differentiation. Osteocytes secret sclerostin, which could reduce osteoblastogenesis and stimulate osteoclastogenesis by inducing RANK-L synthesis.
Bisphosphonates have high affinity to hydroxyapatite and selectively inhibit farnesyl pyrophosphate synthase within osteoclasts and induce osteoclast apoptosis. Raloxifene is a selective estrogen receptor modulator and could enhance osteoclast apoptosis [119]. Intermittent administration of teriparatide could stimulate bone formation through the PTH-1 receptor expressed only in osteoblasts. Denosumab targets RANK-L, leading to suppression of osteoclasts differentiation. Romosozumab binds sclerostin, leading to both osteoblast activation and reduced osteoclastogenesis.

Bisphosphonates
Bisphosphonates are chemically stable derivatives of inorganic pyrophosphate that have a high affinity to hydroxyapatite crystals [120]. Nitrogen-containing bisphosphonates, such as zoledronic acid, risedronate, ibandronate and alendronate, selectively inhibit farnesyl pyrophosphate synthase within osteoclasts and induce osteoclast apoptosis [120,121], causing an overall reduction on bone absorption by decreasing osteoclast activity. The bisphosphonates are cleared by the kidney and retained in bone. Because of the unknown implications of greater bone retention of patients with CKD, the US FDA contradicted bisphosphonates exposure in those who have a creatinine clearance <35 mL/min.
In patients with CKD G1-4, a retrospective analysis that pooled nine clinical trials showed that risedronate increased BMD and prevented vertebral fractures regardless of degree of renal impairment [122]. In patients with CKD G1-3, a post hoc analysis of three Japanese trials concluded that risedronate could increase lumbar spine BMD without differences in CKD stage 1-3 [123]. In a secondary analysis of the Fracture Intervention Trial (FIT), administration of alendronate was safe and effective in increasing total hip and BMD and reducing spinal fractures in women with eGFR <45 mL/min [124]. Although there was a small increase in creatinine during the three-year study, the increase was similar to those without renal function impairment. In FIT trial, women with serum creatinine >1.27 mg/dL, serum PTH >85 pg/mL in isolation, or serum PTH >65 pg/mL in combination with abnormal serum calcium, alkaline phosphatase, or phosphate were excluded. In CKD G3-4, administration of weekly alendronate did not decrease the progression of vascular calcification compared with placebo, which was different from previous studies of HD patients [125]. There are insufficient data concerning efficacy of oral bisphosphonates in fracture prevention of patients with CKD-MBD and end-stage renal failure.
The zoledronic acid (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly, HORIZON) trials excluded subjects with CKD G4-5 [126]. Thus, there are too few patients in the zoledronic acid postmenopausal trials to generate data in CKD G4-5. In patients with CKD-MBD undergoing HD, ibandronate significantly increased BMD and decreased bone turnover [127]. In KT recipients, meta-analyses confirmed that bisphosphonates improved the femoral neck and lumbar spine BMD [128][129][130], but their effects on fracture risk and safety among KT recipients are not established [128].

Denosumab
Denosumab is a fully human monoclonal immunoglobulin (Ig)G2 antibody which targets and binds to the DE loop region of RANK-L with high affinity and specificity [131]. RANK-L signaling via RANK is the main factor for osteoclastogenesis and osteoclast activation [132]. RANK-L is also expressed by T-helper cells and involved in dentritic cell maturation [17]. RANK-L knockout mice had been demonstrated to develop severe osteoporosis as well as defective T and B lymphocytes differentiation [133]. Denosumab inhibits osteoclast proliferation and development, making it a potent anti-resorptive agent [8]. Evidence of safety and efficacy of using denosumab in preventing osteoporotic vertebral, non-vertebral, and hip fractures is sufficient in general population [134][135][136][137]. It does not increase the risk of aortic calcification progression or cardiovascular events in post-menopausal women [138]. A pharmacokinetic and pharmacodynamic study of single dose denosumab in patients with CKD or dialysis showed that serum concentration of denosumab did not differ in different degrees of renal insufficiency [139]. Furthermore, the effect of denosumab on increasing BMD and reducing fracture did not differ depending on renal function [140]. Because it is cleared by the reticuloendothelial system and not by the kidney, there is no restriction of its use in patients with eGFR <35 mL/min [89].
In a post hoc analysis of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial, denosumab for 36 months effectively reduced vertebral, hip, and nonvertebral fracture risks without an increase in adverse events among postmenopausal women with CKD G1-4 [140]. However, there are insufficient data about fracture prevention in advance CKD because there were only 73 women with CKD G4 and no women with CKD G5. After previous bisphosphonate therapy, denosumab could increase BMD and is comparable to zoledronate in CKD patients [141]. In a small study in CKD G5D patients with SHPT and high-turnover bone disease, administration of denosumab resulted in an increase in femoral neck and lumbar spine BMD at 6 months [142]. Another small retrospective study also demonstrated the safety and efficacy of denosumab in the treatment of osteoporosis in CKD G5D patients [143]. Administration of denosumab is associated with a significant risk of hypocalcemia in patients with CKD [139,144,145] and KT [146]. In kidney transplant recipients, denosumab could improve hypercalcemia and BMD loss [147]. A recent systemic review and meta-analysis study showed that denosumab could effectively increase BMD and T scores in the lumbar spine and femur neck among KT recipients with good allograft function [148]. Moreover, a retrospective head-to-head study showed that the effect of denosumab in improving lumbar spine and femoral neck BMD was greater compared with that of bisphosphonate treatment [149]. Denosumab treatment should not be discontinued post KT because discontinuation of the treatment would lead to an increased risk of vertebral fractures and rapid loss of BMD [150]. Close monitoring and supplement of calcium and calcitriol preemptively before starting denosumab are needed to avoid the side effect of hypocalcemia [151][152][153]. In addition, CKD G4-5 and male sex were found to be associated with denosumab-induced hypocalcemia [154]. It is not rare that worsening SHPT (intact PTH levels rise greater than 1000 pg/mL) under denosumab treatment, even with concomitant administration of massive active vitamin D [155]. Further studies are needed for its safety in efficacy of fracture prevention in patients with advanced CKD and post kidney transplantation bone loss [103].

Raloxifene
Raloxifene is a selective estrogen receptor modulator (SERM) approved by FDA for prevention and treatment of osteoporosis in postmenopausal women [156]. It manifests estrogenic activity in bone, and in cardiovascular systems while opposing estrogen action in the uterus and breast [157], thus displaying less risk of invasive breast cancers compared with estrogens.
In a post hoc analysis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene improved BMD and reduced vertebral fractures in patients with postmenopausal osteoporosis and CKD G1-4, irrespective of kidney function [158]. In CKD G5, raloxifene has efficacy of improving BMD without adverse effects and significant effect on controlling hyperparathyroidism [159]. In CKD G5D postmenopausal women on HD, raloxifene significantly increases trabecular BMD, decreases bone resorption markers and LDL-cholesterol values after 1-year of treatment [160]. Larger clinical trials are needed to determine its efficacy and safety on bone in patients with CKD-MBD after KT.

Teriparatide
Teriparatide is a recombinant peptide of the first 34 amino-N-terminal residues of PTH. It is an effective FDA-approved osteoanabolic drug that increases BMD and reduces fracture risk in both age-related and glucocorticoid-induced osteoporosis. Trabecular bone increases more than cortical bone [161]. The anabolic effect of intermittent PTH on bone is likely to be mediated through the PTH-1 receptor [162], which is selective for the N-terminal region of the molecule [163]. PTH-1 receptor is expressed in osteoblast but not in osteoclast [17]. PTH1-receptor activation increases osteoblasts' number and activity initially and leads to new osteoclasts recruitment later via increasing RANK-L synthesis and decreasing osteoprotegerin (OPG) synthesis. Furthermore, PTH inhibits sclerostin binding to osteoblasts, which results in promoting bone formation [164,165]. Its stimulation of bone formation occurs earlier than bone resorption [17]. PTH effects are not persistent after discontinuation of therapy, unless anti-resorptive agents are given [166].
There are no sufficient clinical data examining the efficacy of teriparatide in patients with CKD-MBD because most clinical trials excluded patients with elevated baseline serum levels of PTH. In a post hoc analysis of the Fracture Prevention Trial, teriparatide increases lumbar and femoral neck BMD in female patients with post-menopausal osteoporosis and eGFR as low as 30 mL/min [167]. Another post hoc analysis of a post marketing surveillance study, including thirty patients with CKD G4 and three patients with CKD G5, showed that daily teriparatide improved BMD and incidences of new vertebral and nonvertebral fractures in patients with osteoporosis with high risk of fracture [168]. Some data of using teriparatide on patients with CKD-MBD is available from small observational studies. In patients with CKD G5D and biopsy proven adynamic bone disease, daily administration of teriparatide for 6 months resulted in lumbar spine and femoral neck BMD [169]. Increased bone turnover after using teriparatide has also been found in some CKD G5D cases [170,171]. In patients with CKD G5D with hypothyroidism and osteoporosis, administration of teriparatide once a week increased lumbar spine BMD, bone formation, and resorption markers [172]. Conversely, 6-month daily subcutaneous injections of 20 µg teriparatide did not improve BMD early after KT in a case series [173]. Larger clinical trials are needed to determine the efficacy and safety of teriparatide in the patients with CKD-MBD, undergoing dialysis and post KT.

Abaloparatide
Abaloparatide is a recombinant peptide of the first 20 amino-N-terminal residues of PTH. It was designed to have relatively greater transient affinity of PTH/PTH1 receptor [174] and be more purely anabolic. Although it has been proven for its efficacy in improving lumbar spine and total hip BMD in postmenopausal women with osteoporosis [175,176], there are no available data concerning abaloparatide in patients with CKD-MBD. The ability of abaloparatide to increase bone mass and formation with less risk of hypercalcemia than teriparatide makes it become an ideal drug to treat patients with CKD-MBD and low-to-normal bone turnover with high fracture risk [175].

Romosozumab
Romosozumab is a humanized monoclonal IgG2 anti-sclerostin antibody [17]. It targets and binds sclerostin, a Wnt antagonist produced by osteocytes that reduces osteoblastogenesis and promotes osteoclastogenesis [177]. This monoclonal antibody against sclerostin increases bone formation and decreases bone resorption [17,178]. Although clinical studies with romosozumab have shown to increase bone density and reduce vertebral and nonvertebral fractures in postmenopausal women [178][179][180], the precise role and its action in CKD patients remain unknown [90].
Sclerostin may promote vascular calcification [177]. Extra-skeletal effects, such as vascular calcification should be cautious when dealing with romosozumab. Because of the activity of Wnt signaling influencing the integrity of the arterial wall [181], blocking sclerostin will impact the vascular calcification processes. It has not been elucidated how anti-sclerostin antibody affect vascular calcifications [8,17] and cardiovascular mortality in CKD patients [23].

Discussion
Changes in mineral and humoral metabolism as well as bone structure develop early in the course of CKD. CKD-MBD included abnormalities of calcium, phosphorus, PTH, and/or vitamin D; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification [2]. In patients with CKD-MBD, using DXA or FRAX to screen fracture risk should be considered. Biomarkers such as bALP and iPTH may assist to assess bone turnover, except for bone biopsy [8]. Among CKD patients, adynamic bone disease or low bone turnover is the most common type of renal osteodystrophy. Before initiating an antiresorptive or anabolic agent to treat osteoporosis in CKD patients, lifestyle modifications, such as exercise, calcium, vitamin D supplementation, smoking cessation, and avoidance of excessive alcohol intake are important. Managing hyperphosphatemia and SHPT are also crucial. Non-calcium-based phosphate binders, such as sevelamer, are superior to calcium-based binder in increasing the bone formation rate and improving trabecular architecture [43]. In patients with CKD G1-3, physicians should use bisphosphonates and other osteoporosis treatments the same as for patients without CKD. Bisphosphonates are generally not recommended in patients with eGFR <35 mL/min or evidence of adynamic bone disease due to avoiding over-suppression of bone remodeling. In KT recipients, bisphosphonates have efficacy in improving femoral neck and lumbar spine BMD [128][129][130]. Denosumab can be safely administered to CKD-associated osteoporosis, but its side effect of hypocalcemia should be cautious. Data concerning using anabolic agents in patients with CKD-MBD are limited. Larger studies are needed to assess the role of teriparatide or abaloparatide in adynamic bone disease. Since mounting evidence points to a central role of a disturbed Wnt-β-catenin signaling in the pathogenesis of CKD-MBD and its cross-talk between the kidneys, the vasculature, and the bone [16], targeting Wnt inhibitors, such as sclerostin or dickkopf1, by monoclonal antibodies would be a potential choice to treat osteoporosis in CKD-MBD. Studies evaluating the optimal diagnostic and management strategy in patients with CKD G4-5D are needed.

Conclusions
Understanding the complex pathogenesis of CKD-MBD is crucial in helping us to improve one's short-and long-term outcomes. Treatment strategies for CKD-associated osteoporosis should be patient-centered to determine the type of renal osteodystrophy. This review focuses on the mechanism, evaluation and management of patients with CKD-MBD. However, further studies are needed to explore more details regarding the underlying pathophysiology and to assess the safety and efficacy of agents for treating CKD-MBD. Funding: This work and APC was funded by a grant of Taipei Tzu-Chi Hospital, Taiwan (TCRD-TPE-109-10) for KH Chen. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Conflicts of Interest:
The authors declare no conflict of interest.