Fragility Fractures and Osteoporosis in CKD: Pathophysiology and Diagnostic Methods

In Practice Fragility Fractures and Osteoporosis in CKD: Pathophysiology and Diagnostic Methods Syazrah N. Salam, MBChB,1 Richard Eastell, MD,2 and Arif Khwaja, PhD1 Both chronic kidney disease (CKD) and osteoporosis are major public health problems associated with an aging population. Osteoporosis is characterized by reduced bone mineral density, while CKD results in qualitative changes in bone structure; both conditions increase the predisposition to fragility fractures. There is a significant coprevalence of osteoporotic fractures and CKD, particularly in the elderly population. Not only is the risk of fracture higher in the CKD population, but clinical outcomes are significantly worse, with substantial health care costs. Management of osteoporosis in the CKD population is particularly complex given the impact of renal osteodystrophy on bone quality and the limited safety and hard outcome data for current therapy in patients with severe CKD or on dialysis therapy. In this review, we discuss the pathophysiology of osteoporosis, the impact of CKD on bone strength, and the role of novel imaging techniques and biomarkers in predicting underlying renal osteodystrophy on bone histomorphometry in the context of CKD. Am J Kidney Dis. -(-):---. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic kidney disease; dialysis; osteoporosis; renal osteodystrophy; fractures; bone mineral density; imaging; biomarkers; histomorphometry.

CASE PRESENTATION A 58-year-old white woman with recurrent pyelonephritis has been on hemodialysis (HD) therapy for 20 years. She sustained a low-impact fracture of the neck of the femur, but dual-energy x-ray absorptiometry (DEXA) revealed normal bone mineral density (BMD). Intact parathyroid hormone (PTH) levels ranged from 20-40 pg/mL since a parathyroidectomy 8 years ago for secondary hyperparathyroidism. Other laboratory results were as follows: serum calcium, 9.9 mg/dL (2.47 mmol/L); phosphate, 5.6 mg/dL (1.80 mmol/L); total alkaline phosphatase (ALP), 105 U/L; and 25-hydroxyvitamin D, 10.3 ng/mL (25.7 nmol/L). We use this case to discuss the pathophysiology of bone disease and osteoporosis in chronic kidney disease (CKD).

INTRODUCTION CKD and osteoporosis are major public health problems associated with an aging population. Osteoporosis is characterized by reduced bone strength resulting in increased predisposition to fragility fracture. Osteoporosis is extremely common in the elderly, affecting up to 12 million people in the United States alone.1 Similarly, CKD is most common in the elderly, with data from the Third National Health and Nutrition Examination Study (NHANES III) indicating that 73% of those older than 70 years had evidence of CKD,2 whereas more recent data from a large health care population indicated that 55% of patients with CKD stages 3-5 were older than 70 years.3 Hence, there is a significant coprevalence of osteoporotic fractures and CKD in the elderly population.4 Health care costs associated with osteoporotic fractures are substantial. In 2000, an estimated 9 million osteoporotic fractures occurred worldwide.5 The estimated annual cost of osteoporotic fractures is £1.8 billion in the United Kingdom,6 whereas this figure is closer to $19 billion in the United States.7 Management Am J Kidney Dis. 2014;-(-):---

of osteoporosis in the CKD population is complex given the additional impact of renal osteodystrophy on bone turnover, quality, and strength, as well the recognized difficulties using bisphosphonates.8 In this review, we discuss the pathophysiology of osteoporosis, impact of CKD on bone strength, and role of noninvasive tools in predicting fracture risk.

PATHOPHYSIOLOGY OF OSTEOPOROSIS In osteoporosis, which is a systemic skeletal disorder, bone strength is compromised, resulting in increased risk of fracture. Bone strength is reflected by BMD, which is determined by peak bone mass and amount of bone loss, and by bone quality, which refers to architecture, turnover, and mineralization.9 Maturation and activation of osteoclast precursors is critically dependent on the activity of the receptoractivator of nuclear factor-kB (RANK) ligand (RANKL) and macrophage colony-stimulating factor.10 RANKL activates its RANK, which is expressed on preosteoclasts, leading to osteoclast proliferation, activation, and survival. The mature osteoclast attaches itself to the bone surface by ab integrin, which From the 1Sheffield Kidney Institute and 2Academic Unit of Bone Metabolism, Metabolic Bone Centre, Northern General Hospital, Sheffield, United Kingdom. Received August 27, 2013. Accepted in revised form December 19, 2013. Address correspondence to Syazrah N. Salam, MBChB, Sheffield Kidney Institute, Northern General Hospital, Herries Road, Sheffield S5 7AU, United Kingdom. E-mail: syazrah.salam@sth. nhs.uk  2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.12.016 1

Salam, Eastell, and Khwaja Figure 1. Osteoclastic antiresorptive targets. avb3 integrins facilitate binding of the osteoclast to bone surface to create a sealed unit. The release of hydrogen and chloride ions creates a highly acidic microenvironment that enables proteolytic enzymes such as cathepsin K and matrix metalloproteinases to digest bone matrix. The proteolytic activity of cathepsin K is directly inhibited by odanacatib. Src tyrosine kinase has a key role in osteoclast activation by interaction with PI3kinase and focal adhesion kinase (FAK) signaling. The maturation of preosteoclasts to osteoclasts is critically dependent on the presence of receptor-activator of nuclear factor-kB (NF-kB; RANK) ligand (RANKL) and macrophage colonystimulating factor, which are produced by osteoblasts and stromal cells. Osteoclast differentiation is regulated negatively by osteoprotegrin, which also is produced by osteoblasts and binds to RANKL. Denosumab is a monoclonal antibody targeting RANKL, thereby preventing osteoclast activation.

is mediated by Src kinase, to create a seal between itself and the bone surface.11 This microenvironment enables the collagenolytic enzyme cathepsin K to promote bone resorption. Osteoprotegerin is an endogenous inhibitor of RANKL and thereby attenuates osteoclast activation and bone resorption.12 Inhibiting osteoclast activity by targeting RANKL, Src kinase, or cathepsin K13 has led to the development of a number of novel therapies for the treatment of osteoporosis (Fig 1). The reduction in osteoblast activity also will reduce bone matrix formation and mineralization. Vitamin D, calcium, and phosphorus all promote matrix mineralization. In addition, intermittent pulses of PTH enhance osteoblast proliferation and activation, which results in a net anabolic effect on bone formation. Thus, calcilytic drugs that activate calcium-sensing receptor (CaSR) on the parathyroid gland may promote bone formation,14,15 whereas CaSR inhibitors such as cinacalcet theoretically could reduce bone formation. At the molecular level, the Wnt/b-catenin signaling pathway promotes osteoblast proliferation and activation.16 Sclerostin and dickkopf-1 (Dkk-1) are endogenous inhibitors of the Wnt receptor and thereby negatively regulate osteoblast activity.17 A number of therapeutic targets are emerging aiming to promote bone formation,18 and these are highlighted in Fig 2. The traditional risk factors for osteoporosis are well known to predict low bone mass, and chronic mild hyponatremia recently has been reported to be another possible risk factor for osteoporosis. An analysis of data from NHANES III by Verbalis et al19 showed that mild hyponatremia is associated with increased likelihood of osteoporosis as assessed by DEXA. A 2

study in animals by the same authors indicated that hyponatremia increases bone resorption and decreases bone formation. Kinsella et al20 reported that hyponatremia in CKD is associated with a 2-fold increased risk of fracture. This is relevant because a study by Nigwekar et al21 showed that 13% of incident HD patients have hyponatremia.

IMPACT OF CKD ON BONE QUALITY CKD–mineral bone disorder (CKD-MBD) refers to a constellation of mineral, bone, and vascular disorders in CKD, which has been reviewed extensively elsewhere and is beyond the scope of this review.22 Renal osteodystrophy, which is the skeletal component of CKD-MBD, is characterized by a spectrum of bone disease (adynamic bone disease, osteitis fibrosa, osteomalacia, and mixed bone disease; Box 1; Table 1). The prevalence of renal osteodystrophy subtypes differs between CKD, HD, and peritoneal dialysis (PD) populations. An extensive literature review by KDIGO (Kidney Disease: Improving Global Outcomes) found a higher prevalence of osteitis fibrosa in patients with CKD stages 3-5 and HD patients, whereas adynamic bone disease is more prevalent in PD patients.22 The higher prevalence of adynamic bone disease in PD patients could be related to reduced PTH synthesis as a consequence of prolonged glucose exposure from the dialysate, impaired glucose tolerance,23 reduced calcium efflux,24 and hypoalbuminemia.25 However, a recent study by Malluche et al,26 which examined bone biopsies from predominantly HD patients (600 HD vs 30 PD patients) demonstrated that 58% had adynamic bone disease. This changing pattern may have been driven by therapies that focused on PTH suppression. Am J Kidney Dis. 2014;-(-):---

Fragility Fractures in CKD Figure 2. Anabolic targets in osteoporosis: the osteoblast. Inhibition of the calcium-sensing receptor (CaSR) by MK-5442 leads to intermittent parathyroid hormone (PTH) secretion, which activates the PTH receptor on the osteoblast, in turn activating a variety of cyclic adenosine monophosphate (cAMP)dependent protein kinases (eg, protein kinase A [PKA]), leading to upregulation of osteogenesis-promoting genes. Teriparatide and possibly strontium also promote bone formation by acting directly on the PTH receptor. Activation of the canonical Wnt signaling pathway leads to translocation of b-catenin to the cell nucleus, where it acts on a variety of target genes to promote bone formation. Sclerostin and dickkopf-1 (both produced by osteocytes) are natural inhibitors of Wnt signaling and therefore monoclonal antibodies such as AMG-785 and BHQ-880 that target these proteins will enhance bone formation. Abbreviation: LRP5/6, low-density lipoprotein receptor–related proteins 5 and 6.

A study comparing bone parameters in different dialysis modalities found that all dialysis patients have significantly lower hip BMD compared with healthy controls, although bone microarchitecture is more affected in HD compared with PD patients.27 Renal osteodystrophy persists post–kidney transplantation because PTH and fibroblast growth factor 23 (FGF-23) levels remain elevated, though at lower levels compared to pretransplantation, despite normal kidney transplant function.28 Furthermore, there is significant BMD loss in the first 6 months post–kidney transplantation that is mediated primarily by glucocorticoid use,29 although this may change with early steroid withdrawal or steroid-free immunosuppression. A longitudinal study by Perrin et al30 showed that persistently high PTH levels (.130 ng/L) at 3 months posttransplantation are associated with increased risk of Box 1. Definition of Key Terms Osteoporosis40: BMD $ 2.5 standard deviations below the average value of young healthy women (T score # 22.5) CKD-MBD22: A systemic disorder of mineral and bone metabolism due to CKD manifested by one or a combination of the following:  Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism  Abnormalities in bone turnover, mineralization, volume, linear growth, or strength  Vascular or other soft-tissue calcification

fracture, and the risk continues to exceed that of dialysis patients for 1-3 years posttransplantation.31 Renal osteodystrophy significantly impacts on bone quality, as highlighted by a recent study of microstructural and nanomechanical properties of bone in patients with low- and high-turnover bone disease.32 There is a reduction in trabecular bone volume in low bone turnover disease, whereas high-turnover bone have reduced mineralization and stiffness. Although BMD is an important determinant of bone strength, marked changes in bone quality occur in CKD that affect the mechanical competence of bone. These qualitative abnormalities are reflected by the higher fracture risk in the CKD population. For example, analysis of the US Renal Database System indicated a 4-fold increase in risk of hip fracture in the HD population compared to the general population,33 whereas data from a number of studies analyzing the nondialysis CKD population suggest that decreased kidney function is associated with increased risk of hip fracture.34,35 Analysis of NHANES III data by Nickolas et al36 suggested that this association was stronger than many conventional risk factors for fracture, including BMD, sex, race, and age. Furthermore, outcomes of fractures are significantly worse, with a 2- to 3-fold Table 1. Subtypes of Renal Osteodystrophy Renal Osteodystrophy Subtypes

Turnover

Mineralization

Osteitis fibrosa

[

Normal

Osteomalacia

Normal

Y

Adynamic bone disease

Y

Normal

Mixed bone disease

[

Y

22

Renal osteodystrophy : An alteration in bone morphology in patients with CKD that is quantifiable by histomorphometry of bone biopsy. Abbreviations: BMD, bone mineral density; CKD-MBD, chronic kidney disease–mineral bone disease; PTH, parathyroid hormone. Am J Kidney Dis. 2014;-(-):---

Note: Volume for each subtype can be low, normal, or high. 3

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increase in mortality after hip fracture in the CKD population compared to the general population. Therefore, a key challenge in managing fragility fractures in patients with CKD is determining whether fractures have occurred as a result of reduced BMD, impaired bone quality as a result of renal osteodystrophy, or a combination of both. Delineating the precise cause of fracture is essential to determine the most appropriate management strategy.

TOOLS TO PREDICT BONE HISTOMORPHOMETRY AND FRACTURE RISK IN CKD Bone Biopsy A transiliac bone biopsy after tetracycline labeling is the gold-standard technique for characterizing the subtype of renal osteodystrophy, with a number of studies highlighting the poor performance of biomarkers such as PTH in predicting underlying bone histology in both the dialysis37 and nondialysis populations.38 Although there have been few studies examining the link between bone histology and fractures, it is clear that abnormalities in bone histomorphometry are associated with microstructural and mechanical abnormalities.32 The KDIGO CKD-MBD guideline recommends performing a bone biopsy in the context of investigating bone pain or unexplained fractures or prior to using antiresorptive agents in patients with low BMD.22 Bone biopsy provides the dynamic feature of bone turnover through double labeling with tetracycline or demeclocycline. Various bone labeling regimens can be used as long as there is a reasonable interval between antibiotic courses. We use 4 days of tetracycline (250 mg, 4 times a day) and, after a 10-day interval, a further 2 days of demeclocycline (300 mg, twice a day). Bone biopsy is performed 2-4 days later. Tetracycline and demeclocycline are deposited within the bone at the sites of active mineralization and thus double fluorescent bands are observed on histomorphometry. A good-quality bone specimen is essential for histomorphometry, and the technique is described in detail elsewhere.39 The incidence of complications is low,39 but bone biopsy is unacceptable to many patients and few centers have access to the expert histomorphometry required to analyze biopsy specimens. As a result, there is increasing interest in noninvasive measures of bone quality, such as imaging and biomarkers. Dual-Energy X-Ray Absorptiometry The clinical utility of DEXA in evaluating those at increased risk of fracture is well established in the general population and forms a key component of the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX).40 The WHO diagnostic 4

criterion for osteoporosis is BMD 2.5 standard deviations below the mean value for a 30-year-old adult (T score # 22.5). Although half of all fractures in postmenopausal women occur in those who fail to meet this diagnostic criterion,41 increases in BMD with treatment can account for up to 80% of the fracture risk reduction,42,43 confirming the critical role of reduced BMD as a risk factor for fractures in the non-CKD population. However, the ability of BMD, as measured by DEXA, in a CKD population to predict fracture risk is weak. A meta-analysis of 683 dialysis patients from 6 observational studies by Jamal et al44 found that low BMD at the lumbar spine and radius was associated with fracture status. However, factors that can significantly affect BMD, such as corticosteroid therapy, body weight, physical activity, and dialysis duration, were not evaluated in most of these studies. Since this meta-analysis, several crosssectional studies also showed that BMD can discriminate fracture status in dialysis patients with abnormal levels of markers of bone metabolism.45-47 In the nondialysis CKD population, a number of cross-sectional48,49 and longitudinal studies50,51 have reported an association between BMD measured by DEXA and kidney function, though none reported on the association between BMD and fracture. Data from the Canadian Multicentre Osteoporosis Study (CaMos) of 635 patients demonstrated that BMD loss was greater in those with CKD, but bone loss did not increase with worsening kidney function.51 A number of randomized controlled trials (RCTs) of antiresorptive therapy52-55 (Table 2) have shown that BMD predicted fracture risk in the subset of patients with CKD stages 3-4. Several cross-sectional studies also have shown that BMD on DEXA predicted fracture status in patients with CKD.56-59 However, it is important to note that only one of these studies56 included patients with abnormal levels of markers of mineral metabolism, implying that BMD may be more predictive of fracture in patients with CKD who do not have coexistent metabolic bone disease. The limited utility of DEXA in CKD may be because it provides a 2-dimensional assessment of a 3-dimensional structure and therefore no effective discrimination between cortical and trabecular bone. CKD mineral abnormalities such as elevation in PTH level also are likely to have different effects on bone compartments. Typically, PTH exerts catabolic effects on cortical bone with increased cortical porosity, whereas there may be an anabolic effect on trabecular bone, with increased turnover resulting in thickened irregular bone.60-62 Peripheral Quantitative Computed Tomography Peripheral quantitative computed tomography (pQCT) provides cross-sectional imaging of bone that Am J Kidney Dis. 2014;-(-):---

Fragility Fractures in CKD Table 2. Post Hoc Analyses of Studies of Antiresorptive Agents in Patients With Osteoporosis and CKD Agent

Source of Data

Clcra

N

Follow-up (y)

Results

Risedronate55

9 pooled randomized controlled trials

.13 mL/min

9,996

2

Risedronate increased BMD at spine and hip with reduced fracture rate irrespective of kidney function

Alendronate53

Fracture Intervention Trial

.20 mL/min

6,458

3

Alendronate improved femoral and spinal BMD and reduced spinal and nonspinal fractures irrespective of kidney function

Denosumab54

FREEDOM Study

.15 mL/min

7,808b

3

Reduction in fracture risk and increase in BMD not affected by kidney function

Raloxifene52

Multiple Outcomes of Raloxifene Evaluation study

.20 mL/min

7,705c

3

Increase in spinal BMD and reduction in vertebral fractures irrespective of kidney function; no impact on nonvertebral fractures; small study in HD cohort indicates increase in vertebral BMD

Note: There was no coexistent CKD-MBD in any study population. Denosumab is not excreted by the kidney, and raloxifene is partially excreted by the kidney. Abbreviations: BMD, bone mineral density; CKD, chronic kidney disease; CKD-MBD, chronic kidney disease–mineral bone disease; Clcr, creatinine clearance; FREEDOM study, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months; HD, hemodialysis. a Clcr calculated using the Cockroft-Gault equation. b Only 73 patients in analysis had CKD stage 4. c Only 55 patients had CKD stage 4.

enables discrimination of cortical and trabecular bone and allows for accurate calculation of volumetric BMD. A number of cross-sectional studies have evaluated the use of pQCT in the dialysis population,63,64 though only one specifically looked at fracture. In this study of 52 HD patients, a reduction in cortical bone density was associated with fractures, whereas there was no such association with BMD as measured by DEXA.63 Recently, the development of high-resolution pQCT has enabled an even more powerful analysis of bone microarchitecture, allowing more accurate quantification of cortical and trabecular structure. A longitudinal study by Nickolas et al60 with a median follow-up of 1.5 years showed more significant cortical bone loss on high-resolution pQCT compared to the reduction in BMD measured by DEXA in CKD and dialysis patients. In an earlier cross-sectional study by the same author of 32 patients with CKD with fracture and 59 without fracture, DEXA was compared to highresolution pQCT.57 Patients with fracture had a range of abnormal parameters measured on both imaging modalities, but neither tools demonstrated an area under the receiver operating characteristic curve greater than 0.75. Similarly, a recent cross-sectional study of DEXA and high-resolution pQCT in predialysis patients with CKD stages 3-5 demonstrated that although both modalities could discriminate fracture status, use of high-resolution pQCT did not improve discrimination ability.58 In contrast, virtually all parameters of bone microarchitecture on high-resolution pQCT in prevalent dialysis patients are associated significantly with Am J Kidney Dis. 2014;-(-):---

fracture, whereas there was no significant association between fracture and BMD.47 Other studies observed similar reductions in bone microarchitecture in the dialysis population using high-resolution pQCT,65,66 but fracture status was not investigated. However, one study showed an associated reduction in bone strength and stiffness as assessed by finite element analysis of high-resolution pQCT scans.66 Finite element analysis is a mathematical model in a virtual environment to test the mechanical competence of bone. Trabecular Bone Score Specialist software to quantify trabecular bone score may offer a more accessible approach to quantifying fracture risk. Trabecular bone score can be derived from DEXA lumbar spine scans and provides an index of microarchitecture that correlates with trabecular number and separation.67 Emerging evidence indicates that trabecular bone score may increase the sensitivity and specificity of DEXA to predict fracture68,69 and has been demonstrated to predict osteoporotic fractures independent of BMD in the non-CKD population.69 No studies have evaluated trabecular bone score in the CKD population. Magnetic Resonance Imaging Micro–magnetic resonance imaging (micro-MRI) also can provide high-resolution data to evaluate bone microarchitecture. In a study of 17 HD patients, micro-MRI identified marked cortical thinning and a reduction in trabecular number with increased trabecular disruption.70 In a comparative study of 5

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DEXA and micro-MRI before and after kidney transplantation, Link et al71 found that combining the 2 imaging modalities provided the strongest discrimination between those with and without fractures. A recent study by Rajapakse et al72 examined bone changes at 6 months post–kidney transplantation using micro-MRI and micro-finite element analysis, highresolution pQCT, and DEXA. Structural parameters on high-resolution pQCT and BMD on DEXA did not change significantly, but bone stiffness and strength on micro-finite element analysis were significantly reduced. Although high-resolution pQCT, micro-MRI, and trabecular bone score may offer a more qualitative assessment of bone structure and fracture risk in the CKD population, there have been no prospective studies to evaluate their clinical utility in predicting fracture risk or to correlate imaging abnormalities with underlying bone histomorphometry. Quantitative Ultrasound The correlation of quantitative ultrasound of calcaneus and phalanges with DEXA in CKD and dialysis patients has been conflicting.73-78 Dialysis patients have been found to have reduced quantitative ultrasound parameters compared with healthy controls,79-84 although only one study confirmed the association with renal osteodystrophy on bone biopsy.80 However, cross-sectional studies showed that quantitative ultrasound does not predict fracture status in dialysis patients.46,85 Nuclear Bone Scans The number of studies using nuclear imaging in CKD is limited. The radiation dose is substantially higher than that used in the other types of imaging discussed. Using bone scintigraphy, technetium 99m uptake in predominantly cortical bone has been shown to have a linear relationship with PTH levels in dialysis patients,86,87 although findings in trabecular bone have been conflicting.86-88 Uptake also has a negative correlation with BMD in patients with CKD.89 Positron emission tomography has been investigated in only 2 small studies involving dialysis patients. A study by Messa et al90 showed that [18F] fluoride ion uptake correlated with bone turnover on histomorphometry and thus can differentiate between high and low bone turnover. A more recent study by Frost et al91 involving patients with suspected adynamic bone disease based on PTH level , 150 pg/mL, [18F] fluoride ion uptake was not correlated with bone formation on histomorphometry. Role of Biomarkers in Identifying Fracture Risk The value of bone biomarkers in predicting bone histomorphometry and identifying fracture risk is 6

Box 2. Currently Available Biomarkers of Bone Resorption and Formation Bone Resorption  Parathyroid hormone (PTH)  Collagen type 1 cross-linked C-telopeptide (CTX)  Collagen type 1 cross-linked N-telopeptide (NTX)  Tartrate-resistant acid phosphatase 5b (TRAP 5b)a  Osteoprotegerin Bone Formation  Bone alkaline phosphatase (bone ALP)a  Procollagen type 1 N-terminal propeptide (PINP)a  Procollagen type 1 C-terminal propeptide (PICP)  Osteocalcin (OC)  Sclerostin a Indicates biomarkers not affected by decreased kidney function.

limited in the CKD population. Although many have elevated levels in early CKD, this may reflect decreased renal clearance because most are cleared by the kidney, with the exception of bone ALP, procollagen type 1 N-terminal propeptide, and tartrateresistant acid phosphatase 5b. Box 2 highlights the currently available biomarkers of bone formation and resorption. The biomarkers of mineral metabolism that commonly are used clinically, such as calcium, phosphate, PTH, and total ALP, are used widely as surrogate markers of high- or low-turnover bone disease. Although there are powerful observational data to show that tight mineral metabolism control is associated with improved survival in the dialysis population,92 the relationship between mineral metabolism, for example, PTH level and fractures, is conflicting. Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) with 12,782 dialysis patients showed that PTH level . 900 pg/mL was associated with increased risk of fracture.93 In contrast, the Dialysis Morbidity and Mortality Study (DMMS) Wave 1 showed that PTH level had no significant influence on hip fracture risk.94 The subsequent DMMS Waves 1-4 showed a weak U-shaped association between PTH level and hip/vertebral fracture.95 In an extensive review of the published literature, the KDIGO guideline highlighted the variable correlation between PTH levels and bone formation rates on bone biopsy.22 It is not yet clear whether the whole-molecule PTH assay will increase the sensitivity and specificity of predicting bone histomorphometry compared to intact PTH. Similarly, bone ALP, osteocalcin, and collagen crosslink molecules also performed poorly in predicting underlying fracture risk, though combining biomarkers with imaging may be promising. A single-center cohort study of 485 HD patients from Japan suggested that bone ALP level may be useful in predicting incident hip fracture.45 In another small cross-sectional study of Am J Kidney Dis. 2014;-(-):---

Fragility Fractures in CKD

Figure 3. Suggested algorithm for investigation and management of fragility fractures in chronic kidney disease (CKD). Abbreviations: BMD, bone mineral density; CKD-MBD, CKD–mineral bone disorder; DEXA, dual-energy x-ray absorptiometry; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; PTH, parathyroid hormone.

predialysis patients with CKD, combining biomarkers such as tartrate-resistant acid phosphatase 5b, osteocalcin, or procollagen type 1 N-terminal propeptide with BMD improved the discriminatory power of DEXA to identify those at increased risk of fracture.56 In a non-CKD population, higher collagen type 1 cross-linked C-telopeptide levels are seen in patients with lower BMD and are associated with fracture risk.96 However, cross-linked C-telopeptide levels are elevated in CKD and its use in CKD-MBD is unknown. Collagen type 1 cross-linked N-telopeptide level has shown a strong positive correlation with PTH level in patients with CKD97 and dialysis patients,98 but interpreting cross-linked N-telopeptide levels in the context of advanced CKD has limited clinical utility. Histomorphometric analysis of bone biopsies and bone turnover markers in 60 dialysis patients showed that sclerostin may improve the positive predictive value of PTH level in identifying high-turnover bone disease.99 Larger studies are required to evaluate its utility in predicting fracture risk in a CKD population. Although there is an enormous amount of literature on the role of FGF-23 in regulating mineral metabolism Am J Kidney Dis. 2014;-(-):---

and association with adverse outcomes in CKD,100 there are conflicting data from small studies for whether FGF-23 level associates with BMD, and there are no published data on the relationship between FGF-23 level and fracture risk. In summary, there is limited evidence to suggest that currently available biomarkers are of significant predictive value in correctly identifying the underlying bone histomorphometry in CKD or highlighting those at increased fracture risk. Neuromuscular Function and Fracture Risk Poor performance on tests of neuromuscular function may identify those at higher risk of fracture in CKD. This is likely to reflect, in part, their higher risk of falls due to impaired muscle strength. The mechanism underlying this association is not clear, but a reduction in 1,25-dihydroxyvitamin D level may be important.101,102 A cross-sectional study of 52 HD patients found that neuromuscular function (as measured by the 6-minute walk test and timed upand-go test) was associated with fracture risk, unlike hip or spinal BMD.103 These inexpensive, easily used 7

Salam, Eastell, and Khwaja

tests have the potential to be practical clinical tools in discriminating fracture risk in the CKD population.104

MANAGEMENT OF FRAGILITY FRACTURES IN CKD Nonpharmacologic interventions should be considered for all patients with low-trauma fractures (Fig 3). Correction of metabolic acidosis is important because it reduces urinary calcium loss, reduces bone resorption, increases BMD, and may prevent muscle wasting. Other interventions will be based on identifying the underlying bone disease and determining whether an individual has osteoporosis with or without coexistent renal osteodystrophy. The management of renal osteodystrophy has been reviewed exhaustively elsewhere, but in general focuses on optimizing vitamin D status and correcting underlying abnormalities of mineral metabolism using dietary intervention, phosphate binders, activated vitamin D, and calcimimetics.22 It is worth noting that although activated vitamin D has been shown to reduce PTH levels and increase BMD, there have been no RCTs on its effect on fracture risk. In one study of 172 HD patients with vitamin D insufficiency or deficiency, daily 25-hydroxyvitamin D supplementation was shown to reduce PTH and bone ALP levels, although fracture risk was not assessed.105 There also is some evidence to support the use of cinacalcet with severe hyperparathyroidism, with a pooled analysis of 1,184 patients from 4 RCTs demonstrating a 54% reduction in fracture risk.106 However, the more recent EVOLVE (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events) trial, which was an RCT of HD patients, showed no reduction in fracture risk using cinacalcet compared to placebo.107 For those with osteoporosis, that is, BMD T score # 22.5 with absence of abnormal levels of markers of bone metabolism, therapy will consist of either antiresorptive agents such as bisphosphonate and denosumab or anabolic agents such as teriparatide. However, applicability of the published data to the CKD population is limited because patients with advanced CKD or those with abnormalities in mineral metabolism were largely excluded from the major studies. A pragmatic approach to managing fragility fractures in CKD is summarized in Fig 3. CONCLUSION The investigation and management of low-impact fractures in CKD remains difficult. Although some patients with CKD can be considered to have pure osteoporosis, many will have coexistent renal osteodystrophy. Because such patients were excluded from the large bisphosphonate studies, there is no substantive evidence base to support optimal management. The pharmacokinetics of denosumab and 8

teriparatide make them attractive drugs to use in CKD, but they may exacerbate the underlying renal osteodystrophy. Future research needs to focus on developing validated surrogate markers of bone histology and fracture risk and testing interventions specifically in the CKD population with coexistent abnormalities of mineral metabolism.

CASE REVIEW Our patient sustained a fragility fracture despite normal BMD as measured by DEXA. This highlights that BMD measured by DEXA does not predict fracture in dialysis patients. We treated her with a phosphate binder (sevelamer) and calciferol, but there is a strong suspicion that she has adynamic bone disease due to the relatively low PTH level since parathyroidectomy. Bone biopsy would confirm the diagnosis, but the patient was unwilling to undergo the procedure. Bone turnover markers were not measured because most that are used currently in osteoporosis accumulate in dialysis patients and correlation with bone histomorphometry is yet to be fully evaluated. Teriparatide would be a potential treatment option for this patient if adynamic bone disease was confirmed on histomorphometry.

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Salam has received financial support from Baxter to attend a conference. Dr Eastell has received consulting fees from ONO Pharma, Fonterra, Alere, Janssen, Johnson & Johnson, Immuno Diagnostic Systems, and Merck; research grants from Amgen, Warner Chilcott, AstraZeneca, and Immuno Diagnostic Systems; and honoraria (last 2 years) from Immuno Diagnostic Systems, Novartis, Alexion, Lilly, Amgen, and Shire. Dr Arif Khwaja has received travel grants from Sanofi and Shire to attend conferences.

REFERENCES 1. Looker AC, Orwoll ES, Johnston CC Jr, et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res. 1997;12(11):1761-1768. 2. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41(1):1-12. 3. Schold JD, Navaneethan SD, Jolly SE, et al. Implications of the CKD-EPI GFR estimation equation in clinical practice. Clin J Am Soc Nephrol. 2011;6(3):497-504. 4. Klawansky S, Komaroff E, Cavanaugh PF Jr, et al. Relationship between age, renal function and bone mineral density in the US population. Osteoporos Int. 2003;14(7):570-576. 5. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006;17(12):1726-1733. 6. Burge RT, Worley D, Johansen A, Bhattacharyya S, Bose U. The cost of osteoporotic fractures in the UK: projections for 2000-2020. J Med Econ. 2001;4(1-4):51-62. 7. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of Am J Kidney Dis. 2014;-(-):---

Fragility Fractures in CKD osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22(3):465-475. 8. Nickolas TL, Leonard MB, Shane E. Chronic kidney disease and bone fracture: a growing concern. Kidney Int. 2008;74(6): 721-731. 9. Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement. 2000;17(1):1-45. 10. Lewiecki EM. New targets for intervention in the treatment of postmenopausal osteoporosis. Nat Rev Rheumatol. 2011;7(11): 631-638. 11. Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3(suppl 3):S131-S139. 12. D’Amelio P, Isaia G, Isaia GC. The osteoprotegerin/RANK/ RANKL system: a bone key to vascular disease. J Endocrinol Invest. 2009;32(4)(suppl 1):6-9. 13. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276-1287. 14. Brown EM. The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics. Subcell Biochem. 2007;45:139-167. 15. Steddon SJ, Cunningham J. Calcimimetics and calcilytics— fooling the calcium receptor. Lancet. 2005;365(9478):22372239. 16. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9-26. 17. Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med. 2007;357(9):905-916. 18. Marie PJ, Kassem M. Osteoblasts in osteoporosis: past, emerging, and future anabolic targets. Eur J Endocrinol. 2011;165(1):1-10. 19. Verbalis JG, Barsony J, Sugimura Y, et al. Hyponatremiainduced osteoporosis. J Bone Miner Res. 2010;25(3):554-563. 20. Kinsella S, Chavrimootoo S, Molloy MG, Eustace JA. Moderate chronic kidney disease in women is associated with fracture occurrence independently of osteoporosis. Nephron Clin Pract. 2010;116(3):c256-c262. 21. Nigwekar SU, Wenger J, Thadhani R, Bhan I. Hyponatremia, mineral metabolism, and mortality in incident maintenance hemodialysis patients: a cohort study. Am J Kidney Dis. 2013;62(4):755-762. 22. Kidney Disease: Improving Global Outcomes CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130. 23. Sugimoto T, Ritter C, Morrissey J, Hayes C, Slatopolsky E. Effects of high concentrations of glucose on PTH secretion in parathyroid cells. Kidney Int. 1990;37(6):1522-1527. 24. Kurz P, Tsobanelis T, Roth P, et al. Differences in calcium kinetic pattern between CAPD and HD patients. Clin Nephrol. 1995;44(4):255-261. 25. Fukagawa M, Akizawa T, Kurokawa K. Is aplastic osteodystrophy a disease of malnutrition? Curr Opin Nephrol Hypertens. 2000;9(4):363-367. 26. Malluche HH, Mawad HW, Monier-Faugere MC. Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J Bone Miner Res. 2011;26(6):1368-1376. 27. Pelletier S, Vilayphiou N, Boutroy S, et al. Bone microarchitecture is more severely affected in patients on hemodialysis than in those receiving peritoneal dialysis. Kidney Int. 2012;82(5): 581-588.

Am J Kidney Dis. 2014;-(-):---

28. Evenepoel P, Meijers BK, de Jonge H, et al. Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation. Clin J Am Soc Nephrol. 2008;3(6):1829-1836. 29. Mikuls TR, Julian BA, Bartolucci A, Saag KG. Bone mineral density changes within six months of renal transplantation. Transplantation. 2003;75(1):49-54. 30. Perrin P, Caillard S, Javier RM, et al. Persistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation. Am J Transplant. 2013;13(10): 2653-2663. 31. Ball AM, Gillen DL, Sherrard D, et al. Risk of hip fracture among dialysis and renal transplant recipients. JAMA. 2002;288(23):3014-3018. 32. Malluche HH, Porter DS, Monier-Faugere MC, Mawad H, Pienkowski D. Differences in bone quality in low- and highturnover renal osteodystrophy. J Am Soc Nephrol. 2012;23(3): 525-532. 33. Alem AM, Sherrard DJ, Gillen DL, et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 2000;58(1):396-399. 34. Ensrud KE, Ewing SK, Taylor BC, et al. Frailty and risk of falls, fracture, and mortality in older women: the study of osteoporotic fractures. J Gerontol A Biol Sci Med Sci. 2007;62(7): 744-751. 35. Fried LF, Biggs ML, Shlipak MG, et al. Association of kidney function with incident hip fracture in older adults. J Am Soc Nephrol. 2007;18(1):282-286. 36. Nickolas TL, McMahon DJ, Shane E. Relationship between moderate to severe kidney disease and hip fracture in the United States. J Am Soc Nephrol. 2006;17(11):3223-3232. 37. Barreto FC, Barreto DV, Moyses RM, et al. K/DOQI-recommended intact PTH levels do not prevent low-turnover bone disease in hemodialysis patients. Kidney Int. 2008;73(6): 771-777. 38. Gal-Moscovici A, Sprague SM. Role of bone biopsy in stages 3 to 4 chronic kidney disease. Clin J Am Soc Nephrol. 2008;3(suppl 3):S170-S174. 39. Hernandez JD, Wesseling K, Pereira R, Gales B, Harrison R, Salusky IB. Technical approach to iliac crest biopsy. Clin J Am Soc Nephrol. 2008;3(suppl 3):S164-S169. 40. Kanis JA, McCloskey EV, Johansson H, Oden A, Strom O, Borgstrom F. Development and use of FRAX in osteoporosis. Osteoporos Int. 2010;21(suppl 2):S407-S413. 41. Schuit SC, van der Klift M, Weel AE, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone. 2004;34(1): 195-202. 42. Austin M, Yang YC, Vittinghoff E, et al. Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res. 2012;27(3):687-693. 43. Jacques RM, Boonen S, Cosman F, et al. Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZONPivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27(8): 1627-1634. 44. Jamal SA, Hayden JA, Beyene J. Low bone mineral density and fractures in long-term hemodialysis patients: a meta-analysis. Am J Kidney Dis. 2007;49(5):674-681. 45. Iimori S, Mori Y, Akita W, et al. Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in

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Salam, Eastell, and Khwaja predicting fracture in CKD stage 5D patients—a single-center cohort study. Nephrol Dial Transplant. 2012;27(1):345-351. 46. Ambrus C, Almasi C, Berta K, et al. Vitamin D insufficiency and bone fractures in patients on maintenance hemodialysis. Int Urol Nephrol. 2011;43(2):475-482. 47. Cejka D, Patsch JM, Weber M, et al. Bone microarchitecture in hemodialysis patients assessed by HR-pQCT. Clin J Am Soc Nephrol. 2011;6(9):2264-2271. 48. Hsu CY, Cummings SR, McCulloch CE, Chertow GM. Bone mineral density is not diminished by mild to moderate chronic renal insufficiency. Kidney Int. 2002;61(5):1814-1820. 49. Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K. Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int. 1999;56(3):1084-1093. 50. Ishani A, Paudel M, Taylor BC, et al. Renal function and rate of hip bone loss in older men: the Osteoporotic Fractures in Men Study. Osteoporos Int. 2008;19(11):1549-1556. 51. Jamal SA, Swan VJ, Brown JP, et al. Kidney function and rate of bone loss at the hip and spine: the Canadian Multicentre Osteoporosis Study. Am J Kidney Dis. 2010;55(2):291-299. 52. Ishani A, Blackwell T, Jamal SA, Cummings SR, Ensrud KE; MORE Investigators. The effect of raloxifene treatment in postmenopausal women with CKD. J Am Soc Nephrol. 2008;19(7):1430-1438. 53. Jamal SA, Bauer DC, Ensrud KE, et al. Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial. J Bone Miner Res. 2007;22(4):503-508. 54. Jamal SA, Ljunggren O, Stehman-Breen C, et al. Effects of denosumab on fracture and bone mineral density by level of kidney function. J Bone Miner Res. 2011;26(8):1829-1835. 55. Miller PD, Roux C, Boonen S, Barton IP, Dunlap LE, Burgio DE. Safety and efficacy of risedronate in patients with agerelated reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials. J Bone Miner Res. 2005;20(12):2105-2115. 56. Nickolas TL, Cremers S, Zhang A, et al. Discriminants of prevalent fractures in chronic kidney disease. J Am Soc Nephrol. 2011;22(8):1560-1572. 57. Nickolas TL, Stein E, Cohen A, et al. Bone mass and microarchitecture in CKD patients with fracture. J Am Soc Nephrol. 2010;21(8):1371-1380. 58. Jamal S, Cheung AM, West S, Lok C. Bone mineral density by DXA and HR pQCT can discriminate fracture status in men and women with stages 3 to 5 chronic kidney disease. Osteoporos Int. 2012;23(12):2805-2813. 59. Yenchek RH, Ix JH, Shlipak MG, et al. Bone mineral density and fracture risk in older individuals with CKD. Clin J Am Soc Nephrol. 2012;7(7):1130-1136. 60. Nickolas TL, Stein EM, Dworakowski E, et al. Rapid cortical bone loss in patients with chronic kidney disease. J Bone Miner Res. 2013;28(8):1811-1820. 61. Fujimori A, Okada S, Sakai M, Tome K, Fukagawa M. Relationship between biochemical markers and radial cortical bone changes in hemodialysis patients. Nephron Clin Pract. 2011;118(4):c375-c379. 62. Okuno S, Inaba M, Kitatani K, Ishimura E, Yamakawa T, Nishizawa Y. Serum levels of C-terminal telopeptide of type I collagen: a useful new marker of cortical bone loss in hemodialysis patients. Osteoporos Int. 2005;16(5):501-509. 63. Jamal SA, Gilbert J, Gordon C, Bauer DC. Cortical pQCT measures are associated with fractures in dialysis patients. J Bone Miner Res. 2006;21(4):543-548.

10

64. Russo CR. Correlation of radial SPA and pQCT with the femoral DEXA measurement in elderly women. J Intern Med. 1998;244(4):358-359. 65. Negri AL, Del Valle EE, Zanchetta MB, et al. Evaluation of bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hemodialysis patients. Osteoporos Int. 2012;23(10):2543-2550. 66. Trombetti A, Stoermann C, Chevalley T, et al. Alterations of bone microstructure and strength in end-stage renal failure. Osteoporos Int. 2013;24(5):1721-1732. 67. Pothuaud L, Carceller P, Hans D. Correlations between grey-level variations in 2D projection images (TBS) and 3D microarchitecture: applications in the study of human trabecular bone microarchitecture. Bone. 2008;42(4):775-787. 68. Rabier B, Heraud A, Grand-Lenoir C, Winzenrieth R, Hans D. A multicentre, retrospective case-control study assessing the role of trabecular bone score (TBS) in menopausal Caucasian women with low areal bone mineral density (BMDa): analysing the odds of vertebral fracture. Bone. 2010;46(1):176-181. 69. Winzenrieth R, Dufour R, Pothuaud L, Hans D. A retrospective case-control study assessing the role of trabecular bone score in postmenopausal Caucasian women with osteopenia: analyzing the odds of vertebral fracture. Calcif Tissue Int. 2010;86(2):104-109. 70. Wehrli FW, Leonard MB, Saha PK, Gomberg BR. Quantitative high-resolution magnetic resonance imaging reveals structural implications of renal osteodystrophy on trabecular and cortical bone. J Magn Reson Imaging. 2004;20(1):83-89. 71. Link TM, Saborowski, Kisters K, et al. Changes in calcaneal trabecular bone structure assessed with high-resolution MR imaging in patients with kidney transplantation. Osteoporos Int. 2002;13(2):119-129. 72. Rajapakse CS, Leonard MB, Bhagat YA, Sun W, Magland JF, Wehrli FW. Micro-MR imaging-based computational biomechanics demonstrates reduction in cortical and trabecular bone strength after renal transplantation. Radiology. 2012;262(3): 912-920. 73. Tribl B, Vogelsang H, Pohanka E, Grampp S, Gangl A, Horl WH. Broadband ultrasound attenuation of the calcaneus. A tool for assessing bone status in patients with chronic renal failure. Acta Radiol. 1998;39(6):637-641. 74. ter Meulen CG, Hilbrands LB, van den Bergh JP, Hermus AR, Hoitsma AJ. The influence of corticosteroids on quantitative ultrasound parameters of the calcaneus in the 1st year after renal transplantation. Osteoporos Int. 2005;16(3):255-262. 75. Guglielmi G, de Terlizzi F, Aucella F, Scillitani A. Quantitative ultrasound technique at the phalanges in discriminating between uremic and osteoporotic patients. Eur J Radiol. 2006;60(1):108-114. 76. Taal MW, Cassidy MJ, Pearson D, Green D, Masud T. Usefulness of quantitative heel ultrasound compared with dualenergy x-ray absorptiometry in determining bone mineral density in chronic haemodialysis patients. Nephrol Dial Transplant. 1999;14(8):1917-1921. 77. Przedlacki J, Pluskiewicz W, Wieliczko M, et al. Quantitative ultrasound of phalanges and dual-energy x-ray absorptiometry of forearm and hand in patients with end-stage renal failure treated with dialysis. Osteoporos Int. 1999;10(1):1-6. 78. Peretz A, Penaloza A, Mesquita M, et al. Quantitative ultrasound and dual x-ray absorptiometry measurements of the calcaneus in patients on maintenance hemodialysis. Bone. 2000;27(2):287-292. 79. Kuo CW, Ho SY, Chang TH, Chu TC. Quantitative ultrasound of the calcaneus in hemodialysis patients. Ultrasound Med Biol. 2010;36(4):589-594.

Am J Kidney Dis. 2014;-(-):---

Fragility Fractures in CKD 80. da Costa JA, de Castro JA, Foss MC. The evaluation of renal osteodystrophy with cortical quantitative ultrasound at various bone sites. Ren Fail. 2004;26(3):237-241. 81. Pluskiewicz W, Przedlacki J, Drozdzowska B, Wlodarczyk D, Matuszkiewicz-Rowinska J, Adamczyk P. Quantitative ultrasound at hand phalanges in adults with end-stage renal failure. Ultrasound Med Biol. 2004;30(4):455-459. 82. Foldes AJ, Arnon E, Popovtzer MM. Reduced speed of sound in tibial bone of haemodialysed patients: association with serum PTH level. Nephrol Dial Transplant. 1996;11(7): 1318-1321. 83. Zywiec J, Pluskiewicz W, Adamczyk P, Skubala A, Gumprecht J. Phalangeal quantitative ultrasound measurements in chronic hemodialysis patients: a 4-year follow-up. Ultrasound Med Biol. 2012;38(6):962-971. 84. Montagnani A, Gonnelli S, Cepollaro C, et al. Quantitative ultrasound in the assessment of skeletal status in uremic patients. J Clin Densitom. 1999;2(4):389-395. 85. Jamal SA, Chase C, Goh YI, Richardson R, Hawker GA. Bone density and heel ultrasound testing do not identify patients with dialysis-dependent renal failure who have had fractures. Am J Kidney Dis. 2002;39(4):843-849. 86. Nishida H, Kaida H, Ishibashi M, et al. Usefulness of bone uptake ratio of bone scintigraphy in hemodialysis patients. Ann Nucl Med. 2005;19(2):91-94. 87. Kurata S, Ishibashi M, Nishida H, Hiromatsu Y, Hayabuchi N. A clinical assessment of the relationship between bone scintigraphy and serum biochemical markers in hemodialysis patients. Ann Nucl Med. 2004;18(6):513-518. 88. Sarikaya A, Sen S, Hacimahmutoglu S, Pekindil G. 99m Tc(V)-DMSA scintigraphy in monitoring the response of bone disease to vitamin D3 therapy in renal osteodystrophy. Ann Nucl Med. 2002;16(1):19-23. 89. Israel O, Gips S, Hardoff R, et al. Bone loss in patients with chronic renal disease: prediction with quantitative bone scintigraphy with SPECT. Radiology. 1995;196(3):643-646. 90. Messa C, Goodman WG, Hoh CK, et al. Bone metabolic activity measured with positron emission tomography and [18F] fluoride ion in renal osteodystrophy: correlation with bone histomorphometry. J Clin Endocrinol Metab. 1993;77(4):949-955. 91. Frost ML, Compston JE, Goldsmith D, et al. (18)F-Fluoride positron emission tomography measurements of regional bone formation in hemodialysis patients with suspected adynamic bone disease. Calcif Tissue Int. 2013;93(5):436-447. 92. Danese MD, Belozeroff V, Smirnakis K, Rothman KJ. Consistent control of mineral and bone disorder in incident hemodialysis patients. Clin J Am Soc Nephrol. 2008;3(5): 1423-1429. 93. Jadoul M, Albert JM, Akiba T, et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients

Am J Kidney Dis. 2014;-(-):---

in the Dialysis Outcomes and Practice Patterns Study. Kidney Int. 2006;70(7):1358-1366. 94. Stehman-Breen CO, Sherrard DJ, Alem AM, et al. Risk factors for hip fracture among patients with end-stage renal disease. Kidney Int. 2000;58(5):2200-2205. 95. Danese MD, Kim J, Doan QV, Dylan M, Griffiths R, Chertow GM. PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis. Am J Kidney Dis. 2006;47(1): 149-156. 96. Bauer DC, Garnero P, Harrison SL, et al. Biochemical markers of bone turnover, hip bone loss, and fracture in older men: the MrOS study. J Bone Miner Res. 2009;24(12):2032-2038. 97. Tolouian R, Hernandez GT, Chiang WY, Gupta A. A new approach for evaluating bone turnover in chronic kidney disease. Eur J Intern Med. 2010;21(3):230-232. 98. Takano M, Okano K, Tsuruta Y, et al. Correlation of new bone metabolic markers with conventional biomarkers in hemodialysis patients. Clin Invest Med. 2011;34(5):E267. 99. Cejka D, Herberth J, Branscum AJ, et al. Sclerostin and dickkopf-1 in renal osteodystrophy. Clin J Am Soc Nephrol. 2011;6(4):877-882. 100. Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. J Am Soc Nephrol. 2010;21(9):1427-1435. 101. Gallagher JC, Rapuri P, Smith L. Falls are associated with decreased renal function and insufficient calcitriol production by the kidney. J Steroid Biochem Mol Biol. 2007;103(3-5): 610-613. 102. Gallagher JC, Rapuri PB, Smith LM. An age-related decrease in creatinine clearance is associated with an increase in number of falls in untreated women but not in women receiving calcitriol treatment. J Clin Endocrinol Metab. 2007;92(1):51-58. 103. Jamal SA, Leiter RE, Jassal V, Hamilton CJ, Bauer DC. Impaired muscle strength is associated with fractures in hemodialysis patients. Osteoporos Int. 2006;17(9):1390-1397. 104. West SL, Jamal SA, Lok CE. Tests of neuromuscular function are associated with fractures in patients with chronic kidney disease. Nephrol Dial Transplant. 2012;27(6):2384-2388. 105. Jean G, Terrat JC, Vanel T, et al. Daily oral 25hydroxycholecalciferol supplementation for vitamin D deficiency in haemodialysis patients: effects on mineral metabolism and bone markers. Nephrol Dial Transplant. 2008;23(11):3670-3676. 106. Cunningham J, Danese M, Olson K, Klassen P, Chertow GM. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int. 2005;68(4): 1793-1800. 107. EVOLVE Trial Investigators; Chertow GM, Block GA, Correa-Rotter R, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012;367(26): 2482-2494.

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